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Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in W

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Enfermedad por coronavirus (COVID-19) « vitrinas (bvsalud.org)

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Documentos científicas y tecnicos en más de 35 bases de datos

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Affiliation

Kim YR; University of Surrey, School of Hospitality and Tourism Management, Faculty of Arts and Social Sciences, Guildford, Surrey, GU2 7XH, United Kingdom.

Liu A; University of Surrey, School of Hospitality and Tourism Management, Faculty of Arts and Social Sciences, Guildford, Surrey, GU2 7XH, United Kingdom.

Article in English | MEDLINE | ID: mdl-34629610

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Social distancing, trust and post-COVID-19 recovery. | Tour Manag;88: 104416, 2022 Feb. | MEDLINE

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Affiliation Kim YR; University of Surrey, School of Hospitality and Tourism Management, Faculty of Arts and Social Sciences, Guildford, Surrey, GU2 7XH, United Kingdom. Liu A; University of Surrey, School of Hospitality and Tourism Management, Faculty of Arts and Social Sciences, Guildford, Surrey, GU2 7XH, United Kingdom.

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DATA-driven shock impact of COVID-19 on the market financial system. | Inf Process Manag;59(1): 102768, 2022 Jan. | MEDLINE

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Después de la gran acogida del artículo titulado “¿Cuál es el papel del psicólogo ante el nuevo Coronavirus (COVID-19)?” que publiqué en la Cátedra Abierta de Psicología y Neurociencias el pasado 12 de febrero del 2020, y en vistas al interés suscitado entre los compañeros psicólogos y otras persona…

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COVID-19: Epidemiología, virología y prevención

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COVID-19: Epidemiología, virología y prevención

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This topic will discuss the virology, epidemiology, and prevention of COVID-19. The clinical features and diagnosis of COVID-19 are discussed in detail elsewhere. (See "COVID-19: Clinical features".)

The management of COVID-19 is also discussed in detail elsewhere:

●(See "COVID-19: Management in hospitalized adults".)

●(See "COVID-19: Infection control for persons with SARS-CoV-2 infection".)

Issues related to COVID-19 in pregnant women and children are discussed elsewhere:

●(See "COVID-19: Pregnancy issues and antenatal care".)

●(See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

See specific topic reviews for details on complications of COVID-19 and issues related to COVID-19 in other patient populations.

Coronavirus virology - Coronaviruses are enveloped positive-stranded RNA viruses. Full-genome sequencing and phylogenic analysis indicated that the coronavirus that causes COVID-19 is a betacoronavirus in the same subgenus as the severe acute respiratory syndrome (SARS) virus (as well as several bat coronaviruses), but in a different clade. The Coronavirus Study Group of the International Committee on Taxonomy of Viruses has proposed that this virus be designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) [ 4]. The Middle East respiratory syndrome (MERS) virus, another betacoronavirus, appears more distantly related [ 5,6]. The closest RNA sequence similarity is to two bat coronaviruses, and it appears likely that bats are the primary source; whether COVID-19 virus is transmitted directly from bats or through some other mechanism (eg, through an intermediate host) is unknown [ 7]. (See "Coronaviruses", section on 'Virology'.)

Variants of concern - Like other viruses, SARS-CoV-2 evolves over time. Most mutations in the SARS-CoV-2 genome have no impact on viral function. Certain variants have garnered widespread attention because of their rapid emergence within populations and evidence for transmission or clinical implications; these are considered variants of concern ( table 1). Each variant has several designations based on the nomenclature used by distinct phylogenetic classification systems; the World Health Organization (WHO) has also designated labels for notable variants based on the Greek alphabet [ 10].

In the United States, the proportions of circulating viruses that are variants of concern are detailed on the CDC website.

Infection with Delta may be associated with a higher risk of severe disease and hospitalization than with Alpha [ 15,19,20]. As an example, in a cohort study of over 40,000 individuals with SARS-CoV-2 infection, 74 percent of whom were unvaccinated, the risk of hospitalization within 14 days of testing was higher among those with Delta compared with Alpha variant infection, although the absolute risk difference was small (2.3 versus 2.2 percent, adjusted hazard ratio 2.26, 95% CI 1.32-3.89) [ 20].

Several studies suggest that vaccine effectiveness is slightly attenuated against symptomatic infection with Delta but remains high against severe disease and hospitalization. These data are discussed elsewhere. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

Alpha (B.1.1.7 lineage) - This variant, also known as 20I/501Y.V1, was first identified in the United Kingdom in late 2020 and was temporally associated with an increase in regional infections ( table 1) [ 21-23]. This variant contains more than a dozen mutations compared with other circulating strains, with several within the spike protein. It subsequently became the predominant variant in many countries, including the United States, until the emergence of the Delta variant (B.1.617.2), after which it declined in prevalence globally.

Several studies had suggested that Alpha is approximately 50 to 75 percent more transmissible than previously circulating strains and is associated with higher secondary attack rates (eg, 13 versus 10 percent) [ 21,24-27]. Some [ 28,29], but not all, studies [ 30] suggest that the Alpha variant may also be associated with greater disease severity. Thus far, there is no evidence that the Alpha variant is associated with clinically significant immune escape. Several studies indicate that serum from COVID-19 vaccine recipients maintains neutralizing activity against the Alpha variant, and some vaccines maintain efficacy against the variant [ 31-34]. These data are discussed elsewhere. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

A mutation in this variant is a deletion in the spike protein at amino acids 69-70 (del 69-70). Some SARS-CoV-2 molecular tests are unable to detect the S gene (which encodes the spike protein) target when this deletion is present. These tests would still be able to detect viral RNA since they employ more than one gene target and thus would not result in false-negative results. Nevertheless, S gene target failure has been used as a marker to detect the Alpha variant, with the caveat that del 69-70 has also been reported in other variants [ 32].

● Beta (B.1.351 lineage) - This variant, also known as 20H/501Y.V2, was identified in South Africa in late 2020 ( table 1) [ 35]. It is phylogenetically distinct from B.1.1.7 but shares several spike protein mutations. Surveillance data in South Africa indicate that this variant rapidly became the dominant strain there, suggesting that it also has the potential for increased transmissibility. Although it was subsequently identified in other countries, including the United States, it has since declined in prevalence globally, including in South Africa.

● Gamma (P.1 lineage) -This variant, also known as 20J/501Y.V3, was first identified in Japan in four travelers from Brazil and was later reported to account for 42 percent of 31 sequenced specimens in the Amazonas state of Brazil in December 2020 ( table 1) [ 41]. It was subsequently identified in other countries, including the United States, but has since declined in prevalence globally. It has several mutations, including three in the spike protein receptor-binding domain, N501Y, E484K, and K417T, which raise concern about the potential for increased transmissibility and an impact on immunity [ 42].

EPIDEMIOLOGY

The reported case counts underestimate the overall burden of COVID-19, as only a fraction of acute infections are diagnosed and reported. Seroprevalence surveys in the United States and Europe have suggested that after accounting for potential false positives or negatives, the rate of prior exposure to SARS-CoV-2, as reflected by seropositivity, exceeds the incidence of reported cases by approximately 10-fold or more [ 43-45].

Transmission - Person-to-person spread is the main mode of SARS-CoV-2 transmission.

Person-to-person

SARS-CoV-2 can also be transmitted longer distances through the airborne route (through inhalation of particles that remain in the air over time and distance), but the extent to which this mode of transmission has contributed to the pandemic is uncertain [ 47-50]. Scattered reports of SARS-CoV-2 outbreaks (eg, in a restaurant, on a bus) have highlighted the potential for longer distance airborne transmission in enclosed, poorly ventilated spaces [ 51-53]. Experimental studies have also supported the feasibility of airborne transmission. As examples, studies using specialized imaging to visualize respiratory exhalations have suggested that respiratory droplets may get aerosolized or carried in a gas cloud and have horizontal trajectories beyond six feet (two meters) with speaking, coughing, or sneezing [ 54-56]. Other studies have identified viral RNA in ventilation systems and in air samples of hospital rooms of patients with COVID-19, including patients with mild infection [ 57-61]; attempts to find viable virus in air and surface specimens in health care settings have only rarely been successful [ 60-64]. Nevertheless, the overall transmission and secondary attack rates of SARS-CoV-2 suggest that long-range airborne transmission is not a primary mode [ 49,50]. Furthermore, in a few reports of health care workers exposed to patients with undiagnosed infection while using only contact and droplet precautions, no secondary infections were identified despite the absence of airborne precautions [ 65,66]. Reflecting the current uncertainty regarding the relative contribution of different transmission mechanisms, recommendations on airborne precautions in the health care setting vary by location; airborne precautions are universally recommended when aerosol-generating procedures are performed. This is discussed in detail elsewhere. (See "COVID-19: Infection control for persons with SARS-CoV-2 infection", section on 'Aerosol-generating procedures/treatments'.)

SARS-CoV-2 has been detected in non-respiratory specimens, including stool, blood, ocular secretions, and semen, but the role of these sites in transmission is uncertain [ 67-74]. In particular, several reports have described detection of SARS-CoV-2 RNA from stool specimens, even after viral RNA could no longer be detected from upper respiratory specimens [ 70,71], and replicative virus has been cultured from stool in rare cases [ 68,75]. Scattered reports of clusters in a residential building and in a dense urban community with poor sanitation have suggested the possibility of transmission through aerosolization of virus from sewage drainage [ 76,77]. However, according to a joint WHO-China report, transmission through the fecal-oral route did not appear to be a significant factor in the spread of infection [ 78].

There is also no evidence that SARS-CoV-2 can be transmitted through contact with non-mucous membrane sites (eg, abraded skin).

The risk of vertical transmission of SARS-CoV-2 is discussed elsewhere. (See "COVID-19: Pregnancy issues and antenatal care", section on 'Frequency of congenital infection'.)

Viral shedding and period of infectiousness - The precise interval during which an individual with SARS-CoV-2 infection can transmit infection to others is uncertain. The potential to transmit SARS-CoV-2 begins prior to the development of symptoms and is highest early in the course of illness; the risk of transmission decreases thereafter. Transmission after 7 to 10 days of illness is unlikely, particularly for otherwise immunocompetent patients with nonsevere infection.

● Period of greatest infectiousness - Infected individuals are more likely to be contagious in the earlier stages of illness when viral RNA levels from upper respiratory specimens are the highest [ 82-88]. One modeling study, in which the mean serial interval between the onset of symptoms among 77 transmission pairs in China was 5.8 days, estimated that infectiousness peaked between two days before and one day after symptom onset and declined within seven days [ 85]. In another study that evaluated over 2500 close contacts of 100 patients with COVID-19 in Taiwan, all of the 22 secondary cases had their first exposure to the index case within six days of symptom onset; there were no infections documented in the 850 contacts whose exposure was after this interval [ 89].

● Prolonged viral RNA detection does not indicate prolonged infectiousness - The duration of viral RNA shedding is variable and may increase with age and the severity of illness [ 71,84,90-96]. In a review of 28 studies, the pooled median duration of viral RNA detection in respiratory specimens was 18 days following the onset of symptoms; in some individuals, viral RNA was detected from the respiratory tract several months after the initial infection [ 95]. Detectable viral RNA, however, does not necessarily indicate the presence of infectious virus, and there appears to be a threshold of viral RNA level below which infectiousness is unlikely.

As an example, in a study of nine patients with mild COVID-19, infectious virus was not detected from respiratory specimens when the viral RNA level was <10 ⁶ copies/mL [ 84]. In other studies, infectious virus has only been detected in respiratory specimens with high concentrations of viral RNA. Such high viral RNA concentrations are reflected by lower numbers of reverse transcriptase polymerase chain reaction (RT-PCR) amplification cycles necessary for detection. Depending on the study, the cycle threshold (Ct) for specimen culture positivity may vary from <24 to ≤32 [ 97,98]. According to information from the United States Centers for Disease Control and Prevention (CDC), by three days after clinical recovery, if viral RNA is still detectable in upper respiratory specimens, the RNA concentrations are generally at or below the levels at which replication-competent virus can be reliably isolated; additionally, isolation of infectious virus from upper respiratory specimens more than 10 days after illness onset has only rarely been documented in patients who had nonsevere infection and whose symptoms have resolved [ 84,97-102]. Except for sporadic reports of reinfection, infectious virus has not been isolated from respiratory specimens of immunocompetent patients who have a repeat positive RNA test following clinical improvement and initial viral RNA clearance, and in studies evaluating such patients, secondary infections in their close contacts have not been documented despite opportunities for transmission [ 103]. (See 'Risk of reinfection' below.)

Occasional reports have described isolation of infectious virus from respiratory specimens for several months following symptom onset in immunocompromised patients [ 104-108]. Prolonged shedding of virus in fecal specimens has also been described [ 75]. Further data are needed to understand the frequency and clinical significance of these findings.

The relevance of virus and viral RNA detection to duration of infection control precautions is discussed elsewhere. (See "COVID-19: Infection control for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

Risk of transmission depends on exposure type - The risk of transmission from an individual with SARS-CoV-2 infection varies by the type and duration of exposure, use of preventive measures, and likely individual factors (eg, the amount of virus in respiratory secretions) [ 109]. Many individuals do not transmit SARS-CoV-2 to anyone else, and epidemiologic data suggest that the minority of index cases result in the majority of secondary infections [ 110-112].

The risk of transmission after contact with an individual with COVID-19 increases with the closeness and duration of contact and appears highest with prolonged contact in indoor settings. Thus, most secondary infections have been described in the following settings:

●Among household contacts [ 113-116]. In a systematic review of 87 studies published through June 2021 that included over 1.2 million household contacts of individuals with SARS-CoV-2 infection in 30 countries, the overall secondary household attack rate was 18.9 percent (95% CI 16.2-22), although there was substantial heterogeneity across studies [ 116]. There was also a trend toward higher attack rates over time (pooled rate 31 percent from studies from June 2020 to March 2021 compared with 13 percent from studies from January to February 2020). Possible explanations for this difference include changes in behavior or testing patterns, emergence of more transmissible variants, and publication bias. Most studies were performed prior to the current global prevalence of the Delta variant, which has been associated with higher secondary attack rates than previously circulating lineages (see 'Delta (B.1.617.2 lineage)' above). Conversely, the studies did not account for vaccination rates in household contacts, which would also impact attack rates.

●In health care settings when personal protective equipment was not used (including hospitals [ 120] and long-term care facilities [ 121]).

●In other congregate settings where individuals are residing or working in close quarters (eg, cruise ships [ 122], homeless shelters [ 123,124], detention facilities [ 125,126], college dormitories [ 127], and food processing facilities [ 128,129]).

Superspreading events, in which large clusters of infections can been traced back to a single index case, are thought to be major drivers of the pandemic [ 109,110,135]. They have been mainly described following prolonged group exposure in an enclosed, usually crowded, indoor space. As an example, in an outbreak among a choir group, 33 confirmed and 20 probable cases were identified among 61 members who attended a practice session with a symptomatic index case [ 52]. This outbreak also highlighted the possibility of a high transmission risk through singing in close proximity.

Variable amounts of virus in respiratory secretions may contribute to the variable risk of transmission from different individuals. In an observational study that included 282 individuals with COVID-19 who had undergone respiratory tract viral RNA quantification as part of a trial and 753 of their close contacts, transmission was identified from only 32 percent of index patients [ 136]. Higher respiratory tract RNA levels (taken at a median of four days after symptom onset) were independently associated with higher secondary attack rates.

The risk of transmission in outdoor settings appears to be substantially lower than indoors, although data are limited [ 140]. Nevertheless, close contact with an individual with COVID-19 remains a risk outdoors.

The risk of transmission with more indirect contact (eg, passing someone with infection on the street, handling items that were previously handled by someone with infection) is not well established and is likely very low. However, many individuals with COVID-19 do not report having had a specific close contact with COVID-19 in the weeks prior to diagnosis [ 141].

The risk of transmission from children with COVID-19 is discussed in detail elsewhere. (See "COVID-19: Clinical manifestations and diagnosis in children", section on 'Do children transmit SARS-CoV-2 to others?'.)

The biologic basis for this is supported by a study of a SARS-CoV-2 outbreak in a long-term care facility, in which infectious virus was cultured from RT-PCR-positive upper respiratory tract specimens in presymptomatic and asymptomatic patients as early as six days prior to the development of typical symptoms [ 149]. The levels and duration of viral RNA in the upper respiratory tract of asymptomatic patients are also similar to those of symptomatic patients [ 150].

Nevertheless, asymptomatic or presymptomatic individuals are less likely to isolate themselves from other people, and the extent to which transmission from such individuals contributes to the pandemic is uncertain. A CDC modeling study estimated that 59 percent of transmission could be attributed to individuals without symptoms: 35 percent from presymptomatic individuals, and 24 percent from those who remained asymptomatic [ 156]. This estimate was based on several assumptions, including that 30 percent of infected individuals never develop symptoms and are 75 percent as infectious as those who do.

Environmental contamination - Virus present on contaminated surfaces may be another source of infection if susceptible individuals touch these surfaces and then transfer infectious virus to mucous membranes in the mouth, eyes, or nose. The frequency and relative importance of this type of transmission are uncertain, although contaminated surfaces are not thought to be a major source of transmission. It may be more likely a potential source of infection in settings where there is heavy viral contamination (eg, in an infected individual's household or in health care settings).

It is unknown how long SARS-CoV-2 can persist on surfaces [ 159-161]; other coronaviruses have been tested and may survive on inanimate surfaces for up to six to nine days without disinfection. In a study evaluating the survival of viruses dried on a plastic surface at room temperature, a specimen containing SARS-CoV (a virus closely related to SARS-CoV-2) had detectable infectivity at six but not nine days [ 160]. However, in a systematic review of similar studies, various disinfectants (including ethanol at concentrations between 62 and 71%) inactivated a number of coronaviruses related to SARS-CoV-2 within one minute [ 159]. Simulated sunlight has also been shown to inactivate SARS-CoV-2 over the course of 15 to 20 minutes in experimental conditions, with higher levels of ultraviolet-B (UVB) light associated with more rapid inactivation [ 162]. Based on data concerning other coronaviruses, duration of viral persistence on surfaces also likely depends on the ambient temperature, relative humidity, and the size of the initial inoculum [ 163].

These data highlight the importance of environmental disinfection in the home and health care setting. (See "COVID-19: Infection control for persons with SARS-CoV-2 infection", section on 'Environmental disinfection'.)

Risk of animal contact - SARS-CoV-2 infection is thought to have originally been transmitted to humans from an animal host, but the ongoing risk of transmission through animal contact is uncertain. There is no evidence suggesting animals (including domesticated animals) are a major source of infection in humans.

Given the uncertainty regarding the transmission risk and the apparent susceptibility of some animals to SARS-CoV-2 infection, the United States CDC recommends that pets be kept away from other animals or people outside of the household and that people with confirmed or suspected COVID-19 try to avoid close contact with household pets, as they should with human household members, for the duration of their self-isolation period. There have been no reports of domesticated animals (other than mink) transmitting SARS-CoV-2 infection to humans.

Immune responses following infection - Protective SARS-CoV-2-specific antibodies and cell-mediated responses are induced following infection. Evidence suggests that some of these responses can be detected for at least a year following infection.

● Humoral immunity - Following infection with SARS-CoV-2, the majority of patients develop detectable serum antibodies to the receptor-binding domain of the viral spike protein and associated neutralizing activity [ 83,84]. However, the magnitude of antibody response may be associated with severity of disease, and patients with mild infection may not mount detectable neutralizing antibodies [ 173,174]. When neutralizing antibodies are elicited, they generally decline over several months after infection, although studies have reported detectable neutralizing activity up to 12 months [ 175-179]. In one study of 121 convalescent plasma donors with initial spike-binding titers ≥1:80, titers declined slightly over five months but remained ≥1:80 in the vast majority, and neutralizing titers correlated with the binding titers [ 180]. Other studies have also identified spike- and receptor-binding domain memory B cells that increased over the few months after infection as well as spike protein-specific plasma cells, and these findings suggest the potential for a long-term memory humoral response [ 175,177,178,181].

● Cell-mediated immunity - Studies have also identified SARS-CoV-2-specific CD4 and CD8 T cell responses in patients who had recovered from COVID-19 and in individuals who had received COVID-19 vaccination, which suggest the potential for a durable T cell immune response [ 175,181,187,188].

Antibodies that neutralize SARS-CoV-2 and SARS-CoV-2-reactive CD4 T cells have been identified in some individuals without known exposure to SARS-CoV-2, and some of these appear to be cross-reactive with antigens from common cold coronaviruses [ 188-191]. Whether these pre-existing immune responses impact the risk or the severity of COVID-19 and whether they will influence COVID-19 vaccine responses remain unknown.

Immune responses following vaccination are discussed in detail elsewhere. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection", section on 'Immunogenicity, efficacy, and safety of select vaccines'.)

An observational study from Denmark attempted to evaluate the risk of reinfection by analyzing the risk of a positive PCR test during the second COVID-19 surge (September to December 2020) among individuals who had undergone PCR testing during the first COVID-19 surge (February to June 2020) [ 192]. Of 11,068 individuals with a positive PCR test during the first surge, 72 tested positive during the second surge (0.65 percent), compared with 16,819 of 514,271 individuals (3.27 percent) who had tested negative during the first surge; the estimated "protective effect" of previous infection was approximately 80 percent. Age greater than 65 years was associated with a higher rate of testing positive in both surges.

Reinfection with variants of concern (such as B.1.351, which is less susceptible to neutralizing antibodies generated against wild-type virus) has been documented following infection with wild-type virus, but the overall risk of reinfection with such variants is uncertain [ 193,194]. (See 'Variants of concern' above.)

Simply having a positive SARS-CoV-2 viral test after recovery does not necessarily indicate reinfection; sequencing that demonstrates a different strain at the time of presumptive reinfection is necessary to make the distinction between reinfection and prolonged or intermittent viral RNA shedding following an initial infection. (See "COVID-19: Diagnosis", section on 'Diagnosis of reinfection'.)

Sporadic cases of confirmed reinfection using sequencing data have been described throughout the world [ 195-203]. In some of these cases, the second infection was asymptomatic or milder than the first, raising the possibility that immunity from an initial infection might attenuate the severity of a reinfection even if it does not prevent it. However, not all cases of purported reinfection have been less severe than the initial infection, and at least one fatal reinfection has been reported in a patient undergoing B cell-depleting therapy and chemotherapy [ 199].

PREVENTION

Personal preventive measures - If community transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is present, residents are generally encouraged to practice social distancing by avoiding crowds and maintaining a distance of six feet (two meters) from others when in public [ 209]. In particular, individuals should avoid close contact with ill individuals. Individuals are also encouraged to wear masks when out in public. These and other general public health measures are discussed elsewhere. (See 'Wearing masks in the community' below and 'Social/physical distancing' below and 'Other public health measures' below.)

The following general measures are additionally recommended to reduce transmission of infection:

●Diligent hand washing, particularly after touching surfaces in public. Use of hand sanitizer that contains at least 60% alcohol is a reasonable alternative if the hands are not visibly dirty. The importance of hand hygiene was illustrated by a study in which mucus specimens inoculated with cultured SARS-CoV-2 virus were applied to human skin collected from autopsy [ 210]. SARS-CoV-2 remained viable on the skin for about nine hours but was completely inactivated within 15 seconds of exposure to 80% alcohol.

●Respiratory hygiene (eg, covering the cough or sneeze).

●Avoiding touching the face (in particular eyes, nose, and mouth). The American Academy of Ophthalmology suggests that people not wear contact lenses, because they make people touch their eyes more frequently [ 211].

●Ensure adequate ventilation of indoor spaces. This includes opening windows and doors, placing fans in front of windows to exhaust air to the outside, running heating/air conditioning fans continuously, and using portable high-efficiency particulate air (HEPA) filtration systems [ 212,213].

●Cleaning and disinfecting objects and surfaces that are frequently touched. The United States Centers for Disease Control and Prevention (CDC) has issued guidance on disinfection in the home setting; a list of Environmental Protection Agency-registered products can be found here.

These measures should be followed by all individuals when there is community transmission of SARS-CoV-2 but should be emphasized for older adults and individuals with chronic medical conditions, in particular.

The CDC has included recommended measures to prevent spread in the community on its website [ 209].

Wearing masks in the community

Individuals who are caring for individuals with suspected or documented COVID-19 at home should also wear a mask when in the same room as that person. Precautions for individuals with suspected or documented COVID-19 and their caretakers are discussed in detail elsewhere. (See "COVID-19: Infection control for persons with SARS-CoV-2 infection", section on 'Isolation at home'.)

Type of masks - In the United States, cloth masks and disposable masks (eg, commercially available surgical masks) are recommended for community use [ 216]. Cloth masks should be made with several layers of tightly woven fabric [ 217,218]. All masks should fit snugly over the face without gaps. Strategies to improve mask fit include using a mask with an adjustable nose bridge, wearing a cloth mask over a disposable mask, knotting the ear loops of a disposable mask to cinch the sides of the mask and secure it against the face, using masks with ties rather than ear loops, and using a mask brace [ 219]. Masks should not have exhalation valves. The CDC notes that the importance of fit and filtration likely increases in situations where the risk of exposure is high (eg, prolonged close contact indoors with people outside the household). Some individuals may opt to wear respirators (eg, N95 or KN95 respirators), which are intended to have a very high filtration efficacy when fit tightly against the face and are available commercially. People should be aware, however, that many marketed KN95 respirators do not meet the advertised filtration standards; if used, KN95 respirators that have been granted emergency use authorization by the US Food and Drug Administration (FDA) should be chosen [ 220]. Detailed information on the types of recommended masks can be found on the CDC website.

When advising patients on the use of masks, clinicians should counsel them to avoid touching the eyes, nose, and mouth when putting on or removing the mask, to practice hand hygiene before and after handling the mask, and to launder cloth masks routinely. Clinicians should also emphasize that the mask does not diminish the importance of other preventive measures, such as social distancing and hand hygiene. Patients can also be counseled that masks have not been associated with impairment in gas exchange, including among patients with underlying lung disease [ 223,224].

Rationale - The rationale for wearing masks in the community is primarily to contain secretions of and prevent transmission from individuals with infection, including those who have asymptomatic or presymptomatic infection. Masks can also reduce exposure to SARS-CoV-2 for the wearer.

● Source control - Several studies support the use of masks to provide source control and reduce transmission in the community [ 217,225-232]. In a retrospective study of 124 patients with confirmed COVID-19 and their families in Beijing, China, secondary transmission occurred in 41 families; use of masks by family members (including the index patient) prior to illness onset in the index patient was independently associated with a reduced risk of infection [ 225]. The type of mask used (medical or cloth) was not specified. In a case report of two hair stylists with COVID-19 who worked while symptomatic prior to the diagnosis but wore face coverings, there were no subsequent COVID-19 diagnoses among 139 clients with close contact, all of whom were also wearing face coverings; both medical masks and cloth face coverings were used [ 233]. In epidemiologic studies, government-issued mask mandates and high rates of self-reported mask wearing have each been associated with decreased community incidence rates and, in some cases, decreased COVID-19 hospitalization rates [ 232,234-236]. Although limited by assumptions and estimates, modeling studies have also suggested that high adoption of mask-wearing by the general public can reduce transmission, even if masks are only moderately effective in containing infectious respiratory secretions [ 237,238].

● Prevent exposure - Mask-wearing in the community may also be associated with protection for the wearer [ 239-241]. In a report of 382 service members who were surveyed about personal preventive strategies in the setting of a SARS-CoV-2 outbreak on a United States Navy aircraft carrier, self-report of wearing a face cover was independently associated with a lower likelihood of infection (odds ratio [OR] 0.3), as were avoiding common areas (OR 0.6) and observing social distancing (OR 0.5) [ 239]. In a retrospective analysis of 1060 individuals identified by contact tracing following clusters of infections in Thailand, wearing a mask all the time was associated with a lower odds of infection compared with not wearing a mask; there was no significant association between wearing a mask some of the time and infection rate [ 240]. A randomized trial from Denmark did not identify a decreased rate of infection among individuals who were provided with surgical masks and advised to wear them when outside of the house for a month (1.8 versus 2.1 percent among individuals who were not given masks or the recommendation) [ 242]; however, clear conclusions about mask efficacy cannot be made from this study because of a low rate of community transmission during the time of the study and other limitations.

Mask-wearing has also been hypothesized to reduce the viral inoculum, even if it doesn't eliminate exposure, and thereby reduce the risk of severe illness [ 243,244].

● Filtration efficacy - Filtering facepiece respirators (FFR) have the highest filtration efficacy. In the United States, the prototypical FFR is the N95 respirator, which filters at least 95 percent of 0.3 micrometer particles. Medical masks have lower filtration efficacy, which depends on how closely the mask lies against the face. In one study, medical masks with ties versus ear loops filtered 72 and 38 percent of particles, respectively (approximately 0.02 to 3.00 micrometers) [ 245]. Other strategies to improve the fit of a medical mask, such as using a cloth mask over it or knotting the ear loops to eliminate gaps, also appear to increase filtration efficacy [ 246]. Studies on the filtration efficacy of fabrics suggest that certain fabrics (eg, tea towel fabric [termed dish towel fabric in the United States], cotton-polypropylene blends), particularly when double-layered, can approach the filtration efficacy of medical masks [ 217,247-249]. In an experimental model, universal masking with a three-ply cotton mask was shown to substantially reduce aerosol exposure [ 213]. Tight-weave fabric, two or more layers, and a tight fit are essential for adequate filtration.

Despite the variability in filtration efficacy of different masks (respirators, medical masks, cloth masks) in experimental settings, data on clinical efficacy differences in preventing transmission of SARS-CoV-2 are lacking.

Physical distancing is likely independently associated with a reduced risk of SARS-CoV-2 transmission [ 229,253-255]. In a meta-analysis of observational studies evaluating the relationship between physical distance and transmission of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome coronavirus (MERS-CoV), proximity and risk of infection were closely associated, and the infection rate was higher with contact within three feet (one meter) compared with contact beyond that distance (12.8 versus 2.6 percent) [ 229]. A distance more than six feet (two meters) was associated with further reduction in transmission.

Screening in high-risk settings - Screening for SARS-CoV-2 infection with serial viral testing is recommended in long-term care facilities to quickly identify cases so that infected individuals can be isolated, contacts can be quarantined, and outbreaks can be prevented [ 256,257] (see "COVID-19: Management in nursing homes", section on 'Screening and testing'). Similar strategies have been employed in other congregate environments, such as college campuses [ 258]. Some have proposed more widespread use of serial testing as a measure to slow community transmission [ 259,260].

Both nucleic acid amplification tests (NAATs) and antigen tests have been used for serial screening. Although antigen tests are generally less sensitive than NAAT, modelling studies have suggested that if the frequency of testing is high enough, tests with lower sensitivity can be successfully used to reduce cumulative infection rates [ 261,262]. Accessibility and fast turnaround time are also important features of a useful screening test. (See "COVID-19: Diagnosis", section on 'Specific diagnostic techniques'.)

Testing-based screening strategies have the advantage of identifying asymptomatic or presymptomatic infections. Several studies have highlighted the limitations of symptom-based screening methods because of the high proportion of asymptomatic cases [ 263,264]. (See "COVID-19: Clinical features", section on 'Asymptomatic infections'.)

Other public health measures - On January 30, 2020, the WHO declared the COVID-19 outbreak a public health emergency of international concern and, in March 2020, began to characterize it as a pandemic in order to emphasize the gravity of the situation and urge all countries to take action in detecting infection and preventing spread. Throughout the world, countries have employed various nonpharmaceutical interventions to reduce transmission. In addition to personal preventive measures (eg, masks, hand hygiene, respiratory etiquette, and environmental disinfection), transmission reduction strategies include:

●Social/physical distancing orders

●Stay-at-home orders

●School, venue, and nonessential business closure

●Bans on public gatherings

●Travel restriction with exit and/or entry screening

●Aggressive case identification and isolation (separating individuals with infection from others)

●Contact tracing and quarantine (separating individuals who have been exposed from others)

These measures have been associated with reductions in the incidence of SARS-CoV-2 infection over time, with epidemiologic studies showing reductions in cases, and in some situations, COVID-19-related deaths following implementation of these mitigation measures [ 265-273].

For countries where incidence has declined and relaxation of transmission reduction measures is being considered, the WHO has issued interim guidance on implementation, which includes a step-wise approach that is adjusted according to local circumstances and prioritizes protecting vulnerable populations; it recommends that personal preventive measures be maintained and that public health efforts to detect cases for isolation and to identify contacts for quarantine be strengthened [ 274,275].

Specific recommendations on global travel are available on the WHO website.

Testing and quarantine - Testing and quarantine are strategies to quickly identify secondary infections in an exposed individual and reduce the risk of that individual exposing others before an infection is recognized. In the United States, CDC suggestions on testing and quarantine following an exposure in the community depend on the vaccination status and history of infection. The following measures are recommended for those who have had close contact with a person with suspected or confirmed SARS-CoV-2 infection in the community (including during the 48 hours prior to that patient developing symptoms and regardless of whether the individuals involved were wearing masks) [ 278]:

● For unvaccinated individuals:

*Daily monitoring for fever, cough, or dyspnea for 14 days. Individuals who develop such signs or symptoms should stay home and maintain distance from other individuals, including those in their household, if they are not doing so already (as below), and contact their medical providers. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Management and counseling for all outpatients'.)

*Self-quarantine at home, with maintenance of at least six feet (two meters) from others at all times. In particular, they should avoid contact with individuals at high risk for severe illness. (See "COVID-19: Clinical features", section on 'Risk factors for severe illness'.)

The preferred quarantine period is 14 days following the date of the last exposure (so long as the individual remains asymptomatic) and is based on the incubation period for SARS-CoV-2 infection. (See "COVID-19: Clinical features", section on 'Incubation period'.)

However, the CDC acknowledges that shorter durations of quarantine may ameliorate the associated community burdens and adherence challenges in exchange for a slightly increased risk of post-quarantine transmission [ 279]. Thus, it notes that acceptable alternatives are:

-A seven-day quarantine period, provided that the individual remained asymptomatic throughout and has a negative NAAT or antigen SARS-CoV-2 test within 48 hours of the planned end of quarantine

-A 10-day quarantine period, provided that the individual remained asymptomatic throughout

These intervals were based on modeling performed by the CDC that suggested median post-quarantine transmission rates of 4 percent (range 2.3 to 8.6) for the 7-day quarantine with negative NAAT and 1.4 percent (range 0.1 to 10.6) for the 10-day quarantine, compared with 0.1 percent (range 0 to 3.0) for the 14-day quarantine. In another study of individuals who had household exposure to SARS-CoV-2 and underwent daily symptom monitoring and polymerase chain reaction (PCR) testing, there was an 81 percent probability that those who were asymptomatic with negative testing through day 7 would remain so through day 14 [ 280].

If quarantine periods shorter than 14 days are used, individuals should be counseled to continue symptom monitoring and maintain strict adherence to other prevention efforts within and outside of the household (eg, mask wearing, physical distancing) for a full 14 days.

For household members of an individual with COVID-19 who cannot physically separate themselves (eg, maintain physical distance, sleep in a separate room, use a separate bathroom) from that person, the quarantine period begins once the isolation period of the individual with COVID-19 is complete.

*Testing (ideally five to seven days following exposure) is also recommended following close contact to promptly identify new infections [ 281]. However, a negative test performed earlier after exposure should not be used to reduce the quarantine period to shorter than seven days. (See "COVID-19: Diagnosis", section on 'Select asymptomatic individuals'.)

● For vaccinated individuals: Fully vaccinated individuals are exempted from the self-quarantine suggestions above but should get tested 3 to 5 days following exposure and wear a mask in public for 14 days or until the test is negative [ 282]. They should also continue to self-monitor for fever and symptoms for 14 days following exposure and undergo evaluation if features of COVID-19 develop.

● For individuals with a recent history of infection: Individuals who had documented SARS-CoV-2 infection within the three months prior to the exposure are exempted from these self-quarantine and testing recommendations [ 283]. (See "COVID-19: Diagnosis", section on 'Symptomatic patients'.)

Management of health care workers with a documented exposure is discussed in detail elsewhere. (See "COVID-19: Infection control for persons with SARS-CoV-2 infection".)

●They have had close contact with an individual with SARS-CoV-2 infection or are at high risk of exposure to individuals with infection in an institutional setting
and
●They are at high risk for progression to severe COVID-19 based on age or underlying conditions, as outlined in the table ( table 2)
and
●They are expected to have an inadequate immune response to COVID-19 vaccination (eg, patients who have immunocompromising conditions or are taking immunosuppressive agents), or they have not been fully vaccinated (ie, have not received a complete primary vaccine series at least two weeks before exposure)

The doses for post-exposure prophylaxis are:

● Casirivimab-imdevimab 600 mg-600 mg as a single subcutaneous injection or intravenous infusion

●Bamlanivimab 700 mg plus etesevimab 1400 mg administered together as a single intravenous infusion

The monoclonal antibody dose should be given as soon as possible following exposure. The National Institutes of Health COVID-19 treatment guidelines suggest administration within seven days [ 286]; we prefer a 96-hour window for administration following exposure, which was the interval used in the supporting trial for casirivimab-imdevimab. For those who are expected to have an inadequate immune response to vaccination and have ongoing exposure to SARS-CoV-2, subsequent doses of casirivimab-imdevimab 300 mg-300 mg can be given every four weeks for the duration of the exposure.

Individuals in the community should continue to follow post-exposure quarantine and testing suggestions, as discussed above, regardless of monoclonal antibody receipt (see 'Testing and quarantine' above). We recommend future COVID-19 vaccination for those who have not yet received it; the CDC has suggested that individuals wait 90 days after receiving a monoclonal antibody before vaccination to avoid potential interference with the vaccine response [ 287].

●Among 1505 participants who had no evidence of prior or baseline SARS-CoV-2 infection and who had a household contact with SARS-CoV-2, receipt of casirivimab-imdevimab within 96 hours of the index case's positive test reduced the risk of symptomatic COVID-19 (1.5 versus 7.8 percent with placebo, adjusted OR 0.17, 95% CI 0.09-0.33) and the risk of any SARS-CoV-2 infection (4.8 versus 14.2 percent with placebo, adjusted OR 0.31, 95% CI 0.21-0.46) [ 288]. Among those who were infected, receipt of casirivimab-imdevimab was associated with a shorter duration of symptoms and lower upper respiratory tract viral RNA levels. Mutations in the Delta variant are not expected to impact the antiviral activity of casirivimab-imdevimab.

In this trial and others assessing casirivimab-imdevimab for treatment of COVID-19, injection site reactions occurred in approximately 4 to 12 percent and were nonsevere. Infusion-related reactions (eg, flushing, pyrexia, shortness of breath) occurred very rarely and at doses higher than authorized doses.

●The use of bamlanivimab-etesevimab is supported by a randomized trial including 300 nursing home residents and 666 staff members at facilities where there was at least one index case of SARS-CoV-2 infection [ 289]. A single infusion of 4200 mg of bamlanivimab reduced the risk of COVID-19 over the subsequent eight weeks (8.5 versus 15.2 percent with placebo, OR 0.4, 95% CI 0.28-0.68); all four COVID-19-associated deaths occurred in the placebo group. However, this trial was performed when circulating SARS-CoV-2 strains were susceptible to bamlanivimab, and subsequent emergence of resistant viral variants has diminished its utility so that bamlanivimab monotherapy is no longer recommended. Bamlanivimab-etesevimab retains activity against such variants (including the Delta variant) and thus is presumed to be as effective in preventing infection as bamlanivimab alone was in the trial.

We recommend against using other agents for prophylaxis outside a clinical trial.

Data from placebo-controlled randomized trials indicate that hydroxychloroquine is not effective in preventing infection [ 290-295]; the World Health Organization specifically recommends against using hydroxychloroquine to prevent COVID-19 [ 296]. Ivermectin has also been proposed as a potential prophylactic agent, but it has only been evaluated in low-quality unpublished studies [ 297], and clinical evidence supporting its use is lacking. Furthermore, although ivermectin has demonstrated activity against SARS-CoV-2 in vitro, plasma levels high enough for antiviral activity cannot be achieved with safe drug doses [ 298].

Vaccines - Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the pandemic [ 299]. COVID-19 vaccines are discussed in detail elsewhere. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection".)

INFORMATION FOR PATIENTS - UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)" and "Patient education: Recovery after COVID-19 (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Burden of disease -Since the first reports of coronavirus disease 2019 (COVID-19) and identification of the novel coronavirus that causes it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), infection has spread to include more than 250 million confirmed cases worldwide. An interactive map highlighting confirmed cases throughout the world can be found here. (See 'Epidemiology' above.)

● Variants of concern -Several variants of SARS-CoV-2 have emerged that are notable because of the potential for increased transmissibility ( table 1). Possible immune escape is another concern for some recently isolated variants. (See 'Variants of concern' above.)

● Modes of transmission -Direct person-to-person transmission is the primary means of SARS-CoV-2 transmission. It is thought to occur mainly through close-range contact via respiratory particles; virus released in respiratory secretions when a person with infection coughs, sneezes, or talks can infect another person if it is inhaled or makes direct contact with the mucous membranes. SARS-CoV-2 can also be transmitted longer distances, particularly in enclosed, poorly ventilated spaces. (See 'Route of person-to-person transmission' above and 'Environmental contamination' above.)

SARS-CoV-2 has been detected in non-respiratory specimens, including stool, but the role of these sites in transmission is uncertain. (See 'Route of person-to-person transmission' above.)

● Period of infectiousness -Individuals with SARS-CoV-2 infection are most infectious in the earlier stages of infection (starting a few days prior to the development of symptoms). Transmission after 7 to 10 days of illness is unlikely, particularly for otherwise immunocompetent patients with nonsevere infection. Prolonged viral RNA shedding after symptom resolution is not clearly associated with prolonged infectiousness. (See 'Viral shedding and period of infectiousness' above.)

● Immune response and risk of reinfection -Infection induces a protective immune response for at least six to eight months. However, it is unclear how long the protective effect lasts beyond that period. The risk of reinfection within the first several months after initial infection is low. (See 'Immune responses following infection' above and 'Risk of reinfection' above.)

● Personal preventive measures -In settings where there is community transmission of SARS-CoV-2, personal measures to reduce the risk of transmission include mask-wearing in public, diligent hand washing, respiratory hygiene, physical distancing, and avoiding crowds and close contact with ill individuals. Masks should have multiple layers, cover the nose and mouth, and fit snugly against the face. (See 'Personal preventive measures' above and 'Wearing masks in the community' above and 'Social/physical distancing' above and 'Other public health measures' above.)

● Quarantine -Unvaccinated individuals who have close contact with someone with known or suspected COVID-19 should monitor for symptoms and self-quarantine (ie, stay at home, physically distanced from others). The preferred quarantine period is 14 days; shorter quarantine periods of 7 days (following a negative viral test within 48 hours) or 10 days are acceptable alternatives, although they are associated with a higher risk of post-quarantine transmission. (See 'Post-exposure management' above.)

● Post-exposure prophylaxis -Administration of the monoclonal antibody casirivimab-imdevimab within 96 hours of exposure to SARS-CoV-2 can reduce the risk of infection. We suggest post-exposure prophylaxis with casirivimab-imdevimab in individuals who meet all of the following criteria ( Grade 2B) (see 'Post-exposure prophylaxis for select individuals' above):

*They had close contact with an individual with infection or have a high risk of exposure to individuals with infection in an institutional setting.

*They are at high risk for progression to severe COVID-19 based on age or underlying conditions ( table 2).

*They are expected to have an inadequate immune response to COVID-19 vaccination or they are not fully vaccinated.

Bamlanivimab-etesevimab is an alternative monoclonal antibody combination that can be used for post-exposure prophylaxis, but it has not been directly studied in a trial; data supporting its use are with bamlanivimab alone.

● Vaccines -Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the pandemic. COVID-19 vaccines are discussed in detail elsewhere. (See "COVID-19: Vaccines to prevent SARS-CoV-2 infection".)

● Public health guidance - Guidance has been issued by the WHO and the United States Centers for Disease Control and Prevention (CDC), as well as other expert organizations. These are updated on an ongoing basis. Links to these guidelines can be found elsewhere. (See 'Society guideline links' above.)

REFERENCES

1. World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. http://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 (Accessed on February 12, 2020).

2. Centers for Disease Control and Prevention. 2019 Novel coronavirus, Wuhan, China. Information for Healthcare Professionals. https://www.cdc.gov/coronavirus/2019-nCoV/hcp/index.html (Accessed on February 14, 2020).

3. World Health Organization. Novel Coronavirus (2019-nCoV) technical guidance. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance (Accessed on February 14, 2020).

4. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol 2020; 5:536.

5. Zhu N, Zhang D, Wang W, et al. A Novel Coronavirus from Patients with Pneumonia in China, 2019. N Engl J Med 2020; 382:727.

6. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet 2020; 395:565.

7. Perlman S. Another Decade, Another Coronavirus. N Engl J Med 2020; 382:760.

8. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270.

9. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020; 181:271.

10. https://www.who.int/en/activities/tracking-SARS-CoV-2-variants/ (Accessed on June 07, 2021).

11. Korber B, Fischer WM, Gnanakaran S, et al. Tracking Changes in SARS-CoV-2 Spike: Evidence that D614G Increases Infectivity of the COVID-19 Virus. Cell 2020; 182:812.

12. Plante JA, Liu Y, Liu J, et al. Spike mutation D614G alters SARS-CoV-2 fitness. Nature 2021; 592:116.

13. Zhou B, Thao TTN, Hoffmann D, et al. SARS-CoV-2 spike D614G change enhances replication and transmission. Nature 2021; 592:122.

14. Klumpp-Thomas C, Kalish H, Hicks J, et al. Effect of D614G Spike Variant on Immunoglobulin G, M, or A Spike Seroassay Performance. J Infect Dis 2021; 223:802.

15. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/991343/Variants_of_Concern_VOC_Technical_Briefing_14.pdf (Accessed on June 07, 2021).

16. Dougherty K, Mannell M, Naqvi O, et al. SARS-CoV-2 B.1.617.2 (Delta) Variant COVID-19 Outbreak Associated with a Gymnastics Facility - Oklahoma, April-May 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1004.

17. Li B, Deng A, Li K, et al. Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant. UNPUBLISHED. https://www.medrxiv.org/content/10.1101/2021.07.07.21260122v2 (Accessed on September 16, 2021).

18. Ong SWX, Chiew CJ, Ang LW, et al. Clinical and virological features of SARS-CoV-2 variants of concern: a retrospective cohort study comparing B.1.1.7 (Alpha), B.1.315 (Beta), and B.1.617.2 (Delta). Clin Infect Dis 2021.

19. Sheikh A, McMenamin J, Taylor B, et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet 2021; 397:2461.

20. Twohig KA, Nyberg T, Zaidi A, et al. Hospital admission and emergency care attendance risk for SARS-CoV-2 delta (B.1.617.2) compared with alpha (B.1.1.7) variants of concern: a cohort study. Lancet Infect Dis 2021.

21. European Centre for Disease Prevention and Control. Rapid increase of a SARS-CoV-2 variant with multiple spike protein mutations observed in the United Kingdom, December 2020. https://www.ecdc.europa.eu/sites/default/files/documents/SARS-CoV-2-variant-multiple-spike-protein-mutations-United-Kingdom.pdf (Accessed on December 21, 2020).

22. NERVTAG meetingon SARS-CoV-2 variant under investigation VUI-202012/01 https://app.box.com/s/3lkcbxepqixkg4mv640dpvvg978ixjtf/file/756963730457 (Accessed on January 08, 2021).

23. NERVTAG/SPI-M Extraordinary meetingon SARS-CoV-2 variant of concern 202012/01 (variant B.1.1.7) https://app.box.com/s/3lkcbxepqixkg4mv640dpvvg978ixjtf/file/756964987830 (Accessed on January 08, 2021).

24. New and Emerging Respiratory Virus Threats Advisory Group. NERVTAG meeting on SARS-CoV-2 variant under investigation VUI-202012/01. https://www.gov.uk/government/groups/new-and-emerging-respiratory-virus-threats-advisory-group#meetings (Accessed on December 21, 2020).

25. Davies NG, Abbott S, Barnard RC, et al. Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England. Science 2021; 372.

26. Volz E, Mishra S, Chand M, et al. Assessing transmissibility of SARS-CoV-2 lineage B.1.1.7 in England. Nature 2021; 593:266.

27. Public Health England. Investigation of novel SARS-CoV-2 variant: Variant of Concern 202012/01. Technical briefing 5. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/957504/Variant_of_Concern_VOC_202012_01_Technical_Briefing_5_England.pdf (Accessed on February 05, 2021).

28. Challen R, Brooks-Pollock E, Read JM, et al. Risk of mortality in patients infected with SARS-CoV-2 variant of concern 202012/1: matched cohort study. BMJ 2021; 372:n579.

29. Davies NG, Jarvis CI, CMMID COVID-19 Working Group, et al. Increased mortality in community-tested cases of SARS-CoV-2 lineage B.1.1.7. Nature 2021; 593:270.

30. Frampton D, Rampling T, Cross A, et al. Genomic characteristics and clinical effect of the emergent SARS-CoV-2 B.1.1.7 lineage in London, UK: a whole-genome sequencing and hospital-based cohort study. Lancet Infect Dis 2021; 21:1246.

31. Muik A, Wallisch AK, Sänger B, et al. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine-elicited human sera. Science 2021; 371:1152.

32. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/949639/Technical_Briefing_VOC202012-2_Briefing_2_FINAL.pdf (Accessed on January 06, 2021).

33. Wu K, Werner AP, Moliva JI, et al. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv 2021.

34. Emary KRW, Golubchik T, Aley PK, et al. Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial. Lancet 2021; 397:1351.

35. Tegally H, Wilkinson E, Giovanetti M, et al. Detection of a SARS-CoV-2 variant of concern in South Africa. Nature 2021; 592:438.

36. Greaney AJ, Loes AN, Crawford KHD, et al. Comprehensive mapping of mutations in the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human plasma antibodies. Cell Host Microbe 2021; 29:463.

37. Wibmer CK, Ayres F, Hermanus T, et al. SARS-CoV-2 501Y.V2 escapes neutralization by South African COVID-19 donor plasma. Nat Med 2021; 27:622.

38. Xie X, Liu Y, Liu J, et al. Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and N501Y variants by BNT162b2 vaccine-elicited sera. Nat Med 2021; 27:620.

39. Johnson and Johnson. Johnson & Johnson Announces Single-Shot Janssen COVID-19 Vaccine Candidate Met Primary Endpoints in Interim Analysis of its Phase 3 ENSEMBLE Trial. https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial (Accessed on January 29, 2021).

40. Novavax. Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial. https://ir.novavax.com/news-releases/news-release-details/novavax-covid-19-vaccine-demonstrates-893-efficacy-uk-phase-3 (Accessed on January 28, 2021).

41. Virological. Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings. https://virological.org/t/genomic-characterisation-of-an-emergent-sars-cov-2-lineage-in-manaus-preliminary-findings/586 (Accessed on January 19, 2021).

42. Faria NR, Mellan TA, Whittaker C, et al. Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil. Science 2021; 372:815.

43. Stringhini S, Wisniak A, Piumatti G, et al. Seroprevalence of anti-SARS-CoV-2 IgG antibodies in Geneva, Switzerland (SEROCoV-POP): a population-based study. Lancet 2020; 396:313.

44. Centers for Disease Control and Prevention. Commercial Laboratory Seroprevalence Survey Data. https://www.cdc.gov/coronavirus/2019-ncov/cases-updates/commercial-lab-surveys.html (Accessed on July 06, 2020).

45. Havers FP, Reed C, Lim T, et al. Seroprevalence of Antibodies to SARS-CoV-2 in 10 Sites in the United States, March 23-May 12, 2020. JAMA Intern Med 2020.

46. Meyerowitz EA, Richterman A, Gandhi RT, Sax PE. Transmission of SARS-CoV-2: A Review of Viral, Host, and Environmental Factors. Ann Intern Med 2021; 174:69.

47. Morawska L, Milton DK. It Is Time to Address Airborne Transmission of Coronavirus Disease 2019 (COVID-19). Clin Infect Dis 2020; 71:2311.

48. World Health Organization. Transmission of SARS-CoV-2: Implications for infection prevention precautions. https://www.who.int/publications/i/item/modes-of-transmission-of-virus-causing-covid-19-implications-for-ipc-precaution-recommendations (Accessed on July 10, 2020).

49. Klompas M, Baker MA, Rhee C. Airborne Transmission of SARS-CoV-2: Theoretical Considerations and Available Evidence. JAMA 2020.

50. Chagla Z, Hota S, Khan S, et al. Airborne Transmission of COVID-19. Clin Infect Dis 2020.

51. Lu J, Gu J, Li K, et al. COVID-19 Outbreak Associated with Air Conditioning in Restaurant, Guangzhou, China, 2020. Emerg Infect Dis 2020; 26:1628.

52. Hamner L, Dubbel P, Capron I, et al. High SARS-CoV-2 Attack Rate Following Exposure at a Choir Practice - Skagit County, Washington, March 2020. MMWR Morb Mortal Wkly Rep 2020; 69:606.

53. Shen Y, Li C, Dong H, et al. Community Outbreak Investigation of SARS-CoV-2 Transmission Among Bus Riders in Eastern China. JAMA Intern Med 2020; 180:1665.

54. Bahl P, Doolan C, de Silva C, et al. Airborne or droplet precautions for health workers treating COVID-19? J Infect Dis 2020.

55. Bourouiba L. Turbulent Gas Clouds and Respiratory Pathogen Emissions: Potential Implications for Reducing Transmission of COVID-19. JAMA 2020; 323:1837.

56. Stadnytskyi V, Bax CE, Bax A, Anfinrud P. The airborne lifetime of small speech droplets and their potential importance in SARS-CoV-2 transmission. Proc Natl Acad Sci U S A 2020; 117:11875.

57. Ong SWX, Tan YK, Chia PY, et al. Air, Surface Environmental, and Personal Protective Equipment Contamination by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) From a Symptomatic Patient. JAMA 2020; 323:1610.

58. Guo ZD, Wang ZY, Zhang SF, et al. Aerosol and Surface Distribution of Severe Acute Respiratory Syndrome Coronavirus 2 in Hospital Wards, Wuhan, China, 2020. Emerg Infect Dis 2020; 26:1583.

59. Liu Y, Ning Z, Chen Y, et al. Aerodynamic analysis of SARS-CoV-2 in two Wuhan hospitals. Nature 2020; 582:557.

60. Zhou J, Otter JA, Price JR, et al. Investigating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Surface and Air Contamination in an Acute Healthcare Setting During the Peak of the Coronavirus Disease 2019 (COVID-19) Pandemic in London. Clin Infect Dis 2021; 73:e1870.

61. Santarpia JL, Rivera DN, Herrera VL, et al. Aerosol and surface contamination of SARS-CoV-2 observed in quarantine and isolation care. Sci Rep 2020; 10:12732.

62. Lednicky JA, Lauzardo M, Fan ZH, et al. Viable SARS-CoV-2 in the air of a hospital room with COVID-19 patients. Int J Infect Dis 2020; 100:476.

63. Ben-Shmuel A, Brosh-Nissimov T, Glinert I, et al. Detection and infectivity potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) environmental contamination in isolation units and quarantine facilities. Clin Microbiol Infect 2020; 26:1658.

64. Birgand G, Peiffer-Smadja N, Fournier S, et al. Assessment of Air Contamination by SARS-CoV-2 in Hospital Settings. JAMA Netw Open 2020; 3:e2033232.

65. Ng K, Poon BH, Kiat Puar TH, et al. COVID-19 and the Risk to Health Care Workers: A Case Report. Ann Intern Med 2020; 172:766.

66. Wong SCY, Kwong RT, Wu TC, et al. Risk of nosocomial transmission of coronavirus disease 2019: an experience in a general ward setting in Hong Kong. J Hosp Infect 2020; 105:119.

67. Chen W, Lan Y, Yuan X, et al. Detectable 2019-nCoV viral RNA in blood is a strong indicator for the further clinical severity. Emerg Microbes Infect 2020; 9:469.

68. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA 2020; 323:1843.

69. Colavita F, Lapa D, Carletti F, et al. SARS-CoV-2 Isolation From Ocular Secretions of a Patient With COVID-19 in Italy With Prolonged Viral RNA Detection. Ann Intern Med 2020; 173:242.

70. Cheung KS, Hung IFN, Chan PPY, et al. Gastrointestinal Manifestations of SARS-CoV-2 Infection and Virus Load in Fecal Samples From a Hong Kong Cohort: Systematic Review and Meta-analysis. Gastroenterology 2020; 159:81.

71. Zheng S, Fan J, Yu F, et al. Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study. BMJ 2020; 369:m1443.

72. Li D, Jin M, Bao P, et al. Clinical Characteristics and Results of Semen Tests Among Men With Coronavirus Disease 2019. JAMA Netw Open 2020; 3:e208292.

73. Pham TD, Huang C, Wirz OF, et al. SARS-CoV-2 RNAemia in a Healthy Blood Donor 40 Days After Respiratory Illness Resolution. Ann Intern Med 2020; 173:853.

74. Azzolini C, Donati S, Premi E, et al. SARS-CoV-2 on Ocular Surfaces in a Cohort of Patients With COVID-19 From the Lombardy Region, Italy. JAMA Ophthalmol 2021; 139:956.

75. Xiao F, Sun J, Xu Y, et al. Infectious SARS-CoV-2 in Feces of Patient with Severe COVID-19. Emerg Infect Dis 2020; 26:1920.

76. Kang M, Wei J, Yuan J, et al. Probable Evidence of Fecal Aerosol Transmission of SARS-CoV-2 in a High-Rise Building. Ann Intern Med 2020; 173:974.

77. Yuan J, Chen Z, Gong C, et al. Sewage as a Possible Transmission Vehicle During a Coronavirus Disease 2019 Outbreak in a Densely Populated Community: Guangzhou, China, April 2020. Clin Infect Dis 2021; 73:e1487.

78. Report of the WHO-China Joint Mission on Coronavirus DIsease 2019 (COVID-2019). February 16-24, 2020. http://www.who.int/docs/default-source/coronaviruse/who-china-joint-mission-on-covid-19-final-report.pdf (Accessed on March 04, 2020).

79. Yu F, Yan L, Wang N, et al. Quantitative Detection and Viral Load Analysis of SARS-CoV-2 in Infected Patients. Clin Infect Dis 2020; 71:793.

80. Xu D, Zhou F, Sun W, et al. Relationship Between Serum Severe Acute Respiratory Syndrome Coronavirus 2 Nucleic Acid and Organ Damage in Coronavirus 2019 Patients: A Cohort Study. Clin Infect Dis 2021; 73:68.

81. AABB. AABB's Coronavirus Resources. http://www.aabb.org/advocacy/regulatorygovernment/Pages/AABB-Coronavirus-Resources.aspx (Accessed on April 21, 2020).

82. Zou L, Ruan F, Huang M, et al. SARS-CoV-2 Viral Load in Upper Respiratory Specimens of Infected Patients. N Engl J Med 2020; 382:1177.

83. To KK, Tsang OT, Leung WS, et al. Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study. Lancet Infect Dis 2020; 20:565.

84. Wölfel R, Corman VM, Guggemos W, et al. Virological assessment of hospitalized patients with COVID-2019. Nature 2020; 581:465.

85. He X, Lau EHY, Wu P, et al. Temporal dynamics in viral shedding and transmissibility of COVID-19. Nat Med 2020; 26:672.

86. COVID-19 Investigation Team. Clinical and virologic characteristics of the first 12 patients with coronavirus disease 2019 (COVID-19) in the United States. Nat Med 2020; 26:861.

87. Jones TC, Biele G, Mühlemann B, et al. Estimating infectiousness throughout SARS-CoV-2 infection course. Science 2021; 373.

88. Ge Y, Martinez L, Sun S, et al. COVID-19 Transmission Dynamics Among Close Contacts of Index Patients With COVID-19: A Population-Based Cohort Study in Zhejiang Province, China. JAMA Intern Med 2021; 181:1343.

89. Cheng HY, Jian SW, Liu DP, et al. Contact Tracing Assessment of COVID-19 Transmission Dynamics in Taiwan and Risk at Different Exposure Periods Before and After Symptom Onset. JAMA Intern Med 2020; 180:1156.

90. Liu Y, Yan LM, Wan L, et al. Viral dynamics in mild and severe cases of COVID-19. Lancet Infect Dis 2020; 20:656.

91. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395:1054.

92. Xu K, Chen Y, Yuan J, et al. Factors Associated With Prolonged Viral RNA Shedding in Patients with Coronavirus Disease 2019 (COVID-19). Clin Infect Dis 2020; 71:799.

93. Van Vinh Chau N, Lam VT, Dung NT, et al. The Natural History and Transmission Potential of Asymptomatic Severe Acute Respiratory Syndrome Coronavirus 2 Infection. Clin Infect Dis 2020; 71:2679.

94. Xiao AT, Tong YX, Zhang S. Profile of RT-PCR for SARS-CoV-2: A Preliminary Study From 56 COVID-19 Patients. Clin Infect Dis 2020; 71:2249.

95. Fontana LM, Villamagna AH, Sikka MK, McGregor JC. Understanding viral shedding of severe acute respiratory coronavirus virus 2 (SARS-CoV-2): Review of current literature. Infect Control Hosp Epidemiol 2021; 42:659.

96. Cevik M, Tate M, Lloyd O, et al. SARS-CoV-2, SARS-CoV, and MERS-CoV viral load dynamics, duration of viral shedding, and infectiousness: a systematic review and meta-analysis. Lancet Microbe 2021; 2:e13.

97. Bullard J, Dust K, Funk D, et al. Predicting Infectious Severe Acute Respiratory Syndrome Coronavirus 2 From Diagnostic Samples. Clin Infect Dis 2020; 71:2663.

98. Basile K, McPhie K, Carter I, et al. Cell-based culture of SARS-CoV-2 informs infectivity and safe de-isolation assessments during COVID-19. Clin Infect Dis 2020.

99. Centers for Disease Control and Prevention. Symptom-Based Strategy to Discontinue Isolation for Persons with COVID-19: Decision Memo. https://www.cdc.gov/coronavirus/2019-ncov/community/strategy-discontinue-isolation.html (Accessed on May 04, 2020).

100. Liu WD, Chang SY, Wang JT, et al. Prolonged virus shedding even after seroconversion in a patient with COVID-19. J Infect 2020; 81:318.

101. Perera RAPM, Tso E, Tsang OTY, et al. SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease. Emerg Infect Dis 2020; 26:2701.

102. Kim MC, Cui C, Shin KR, et al. Duration of Culturable SARS-CoV-2 in Hospitalized Patients with Covid-19. N Engl J Med 2021; 384:671.

103. Mack CD, DiFiori J, Tai CG, et al. SARS-CoV-2 Transmission Risk Among National Basketball Association Players, Staff, and Vendors Exposed to Individuals With Positive Test Results After COVID-19 Recovery During the 2020 Regular and Postseason. JAMA Intern Med 2021; 181:960.

104. Avanzato VA, Matson MJ, Seifert SN, et al. Case Study: Prolonged Infectious SARS-CoV-2 Shedding from an Asymptomatic Immunocompromised Individual with Cancer. Cell 2020; 183:1901.

105. Choi B, Choudhary MC, Regan J, et al. Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host. N Engl J Med 2020; 383:2291.

106. Aydillo T, Gonzalez-Reiche AS, Aslam S, et al. Shedding of Viable SARS-CoV-2 after Immunosuppressive Therapy for Cancer. N Engl J Med 2020; 383:2586.

107. Tarhini H, Recoing A, Bridier-Nahmias A, et al. Long-Term Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infectiousness Among Three Immunocompromised Patients: From Prolonged Viral Shedding to SARS-CoV-2 Superinfection. J Infect Dis 2021; 223:1522.

108. Baang JH, Smith C, Mirabelli C, et al. Prolonged Severe Acute Respiratory Syndrome Coronavirus 2 Replication in an Immunocompromised Patient. J Infect Dis 2021; 223:23.

109. Cevik M, Marcus JL, Buckee C, Smith TC. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Transmission Dynamics Should Inform Policy. Clin Infect Dis 2021; 73:S170.

110. Adam DC, Wu P, Wong JY, et al. Clustering and superspreading potential of SARS-CoV-2 infections in Hong Kong. Nat Med 2020; 26:1714.

111. Laxminarayan R, Wahl B, Dudala S, et al. Epidemiology and transmission dynamics of COVID-19 in two Indian states. Science 2020; :eabd7672.

112. Sun K, Wang W, Gao L, et al. Transmission heterogeneities, kinetics, and controllability of SARS-CoV-2. Science 2021; 371.

113. Fung HF, Martinez L, Alarid-Escudero F, et al. The Household Secondary Attack Rate of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): A Rapid Review. Clin Infect Dis 2021; 73:S138.

114. Madewell ZJ, Yang Y, Longini IM Jr, et al. Household Transmission of SARS-CoV-2: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e2031756.

115. Pollán M, Pérez-Gómez B, Pastor-Barriuso R, et al. Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. Lancet 2020; 396:535.

116. Madewell ZJ, Yang Y, Longini IM Jr, et al. Factors Associated With Household Transmission of SARS-CoV-2: An Updated Systematic Review and Meta-analysis. JAMA Netw Open 2021; 4:e2122240.

117. Grijalva CG, Rolfes MA, Zhu Y, et al. Transmission of SARS-COV-2 Infections in Households - Tennessee and Wisconsin, April-September 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1631.

118. Li F, Li YY, Liu MJ, et al. Household transmission of SARS-CoV-2 and risk factors for susceptibility and infectivity in Wuhan: a retrospective observational study. Lancet Infect Dis 2021; 21:617.

119. Chu VT, Yousaf AR, Chang K, et al. Household Transmission of SARS-CoV-2 from Children and Adolescents. N Engl J Med 2021; 385:954.

120. Wang D, Hu B, Hu C, et al. Clinical Characteristics of 138 Hospitalized Patients With 2019 Novel Coronavirus-Infected Pneumonia in Wuhan, China. JAMA 2020; 323:1061.

121. McMichael TM, Clark S, Pogosjans S, et al. COVID-19 in a Long-Term Care Facility - King County, Washington, February 27-March 9, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:339.

122. Kakimoto K, Kamiya H, Yamagishi T, et al. Initial Investigation of Transmission of COVID-19 Among Crew Members During Quarantine of a Cruise Ship - Yokohama, Japan, February 2020. MMWR Morb Mortal Wkly Rep 2020; 69:312.

123. Mosites E, Parker EM, Clarke KEN, et al. Assessment of SARS-CoV-2 Infection Prevalence in Homeless Shelters - Four U.S. Cities, March 27-April 15, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:521.

124. Baggett TP, Keyes H, Sporn N, Gaeta JM. Prevalence of SARS-CoV-2 Infection in Residents of a Large Homeless Shelter in Boston. JAMA 2020; 323:2191.

125. Wallace M, Hagan L, Curran KG, et al. COVID-19 in Correctional and Detention Facilities - United States, February-April 2020. MMWR Morb Mortal Wkly Rep 2020; 69:587.

126. Saloner B, Parish K, Ward JA, et al. COVID-19 Cases and Deaths in Federal and State Prisons. JAMA 2020; 324:602.

127. Wilson E, Donovan CV, Campbell M, et al. Multiple COVID-19 Clusters on a University Campus - North Carolina, August 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1416.

128. Steinberg J, Kennedy ED, Basler C, et al. COVID-19 Outbreak Among Employees at a Meat Processing Facility - South Dakota, March-April 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1015.

129. Dyal JW, Grant MP, Broadwater K, et al. COVID-19 Among Workers in Meat and Poultry Processing Facilities - 19 States, April 2020. MMWR Morb Mortal Wkly Rep 2020; 69.

130. Ghinai I, Woods S, Ritger KA, et al. Community Transmission of SARS-CoV-2 at Two Family Gatherings - Chicago, Illinois, February-March 2020. MMWR Morb Mortal Wkly Rep 2020; 69:446.

131. Pung R, Chiew CJ, Young BE, et al. Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures. Lancet 2020; 395:1039.

132. Mahale P, Rothfuss C, Bly S, et al. Multiple COVID-19 Outbreaks Linked to a Wedding Reception in Rural Maine - August 7-September 14, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1686.

133. Fisher KA, Tenforde MW, Feldstein LR, et al. Community and Close Contact Exposures Associated with COVID-19 Among Symptomatic Adults ≥18 Years in 11 Outpatient Health Care Facilities - United States, July 2020. MMWR Morb Mortal Wkly Rep 2020.

134. Tenforde MW, Fisher KA, Patel MM. Identifying COVID-19 Risk Through Observational Studies to Inform Control Measures. JAMA 2021; 325:1464.

135. Chang S, Pierson E, Koh PW, et al. Mobility network models of COVID-19 explain inequities and inform reopening. Nature 2021; 589:82.

136. Marks M, Millat-Martinez P, Ouchi D, et al. Transmission of COVID-19 in 282 clusters in Catalonia, Spain: a cohort study. Lancet Infect Dis 2021.

137. Bi Q, Wu Y, Mei S, et al. Epidemiology and transmission of COVID-19 in 391 cases and 1286 of their close contacts in Shenzhen, China: a retrospective cohort study. Lancet Infect Dis 2020; 20:911.

138. Khanh NC, Thai PQ, Quach HL, et al. Transmission of SARS-CoV 2 During Long-Haul Flight. Emerg Infect Dis 2020; 26:2617.

139. Hu M, Lin H, Wang J, et al. Risk of Coronavirus Disease 2019 Transmission in Train Passengers: an Epidemiological and Modeling Study. Clin Infect Dis 2021; 72:604.

140. Bulfone TC, Malekinejad M, Rutherford GW, Razani N. Outdoor Transmission of SARS-CoV-2 and Other Respiratory Viruses: A Systematic Review. J Infect Dis 2021; 223:550.

141. Tenforde MW, Billig Rose E, Lindsell CJ, et al. Characteristics of Adult Outpatients and Inpatients with COVID-19 - 11 Academic Medical Centers, United States, March-May 2020. MMWR Morb Mortal Wkly Rep 2020; 69:841.

142. Rothe C, Schunk M, Sothmann P, et al. Transmission of 2019-nCoV Infection from an Asymptomatic Contact in Germany. N Engl J Med 2020; 382:970.

143. Yu P, Zhu J, Zhang Z, Han Y. A Familial Cluster of Infection Associated With the 2019 Novel Coronavirus Indicating Possible Person-to-Person Transmission During the Incubation Period. J Infect Dis 2020; 221:1757.

144. Bai Y, Yao L, Wei T, et al. Presumed Asymptomatic Carrier Transmission of COVID-19. JAMA 2020; 323:1406.

145. Hu Z, Song C, Xu C, et al. Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing, China. Sci China Life Sci 2020; 63:706.

146. Qian G, Yang N, Ma AHY, et al. COVID-19 Transmission Within a Family Cluster by Presymptomatic Carriers in China. Clin Infect Dis 2020; 71:861.

147. Böhmer MM, Buchholz U, Corman VM, et al. Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series. Lancet Infect Dis 2020; 20:920.

148. Wang Y, He Y, Tong J, et al. Characterization of an Asymptomatic Cohort of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infected Individuals Outside of Wuhan, China. Clin Infect Dis 2020; 71:2132.

149. Arons MM, Hatfield KM, Reddy SC, et al. Presymptomatic SARS-CoV-2 Infections and Transmission in a Skilled Nursing Facility. N Engl J Med 2020; 382:2081.

150. Lee S, Kim T, Lee E, et al. Clinical Course and Molecular Viral Shedding Among Asymptomatic and Symptomatic Patients With SARS-CoV-2 Infection in a Community Treatment Center in the Republic of Korea. JAMA Intern Med 2020; 180:1447.

151. Wei WE, Li Z, Chiew CJ, et al. Presymptomatic Transmission of SARS-CoV-2 - Singapore, January 23-March 16, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:411.

152. Buitrago-Garcia D, Egli-Gany D, Counotte MJ, et al. Occurrence and transmission potential of asymptomatic and presymptomatic SARS-CoV-2 infections: A living systematic review and meta-analysis. PLoS Med 2020; 17:e1003346.

153. Plucinski MM, Wallace M, Uehara A, et al. Coronavirus Disease 2019 (COVID-19) in Americans Aboard the Diamond Princess Cruise Ship. Clin Infect Dis 2021; 72:e448.

154. Luo L, Liu D, Liao X, et al. Contact Settings and Risk for Transmission in 3410 Close Contacts of Patients With COVID-19 in Guangzhou, China : A Prospective Cohort Study. Ann Intern Med 2020; 173:879.

155. Sayampanathan AA, Heng CS, Pin PH, at al. Infectivity of asymptomatic versus symptomatic COVID-19. Lancet 2020.

156. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 Transmission From People Without COVID-19 Symptoms. JAMA Netw Open 2021; 4:e2035057.

157. Yung CF, Kam KQ, Wong MSY, et al. Environment and Personal Protective Equipment Tests for SARS-CoV-2 in the Isolation Room of an Infant With Infection. Ann Intern Med 2020; 173:240.

158. Yamagishi T, Ohnishi M, Matsunaga N, et al. Environmental Sampling for Severe Acute Respiratory Syndrome Coronavirus 2 During a COVID-19 Outbreak on the Diamond Princess Cruise Ship. J Infect Dis 2020; 222:1098.

159. Kampf G, Todt D, Pfaender S, Steinmann E. Persistence of coronaviruses on inanimate surfaces and their inactivation with biocidal agents. J Hosp Infect 2020; 104:246.

160. Rabenau HF, Cinatl J, Morgenstern B, et al. Stability and inactivation of SARS coronavirus. Med Microbiol Immunol 2005; 194:1.

161. van Doremalen N, Bushmaker T, Morris DH, et al. Aerosol and Surface Stability of SARS-CoV-2 as Compared with SARS-CoV-1. N Engl J Med 2020; 382:1564.

162. Ratnesar-Shumate S, Williams G, Green B, et al. Simulated Sunlight Rapidly Inactivates SARS-CoV-2 on Surfaces. J Infect Dis 2020; 222:214.

163. Otter JA, Donskey C, Yezli S, et al. Transmission of SARS and MERS coronaviruses and influenza virus in healthcare settings: the possible role of dry surface contamination. J Hosp Infect 2016; 92:235.

164. World Organization for Animal Health. Questions and Answers on the 2019 Coronavirus Disease (COVID-19), section on Surveillance and events in animals. https://www.oie.int/en/scientific-expertise/specific-information-and-recommendations/questions-and-answers-on-2019novel-coronavirus/ (Accessed on April 13, 2020).

165. Sit THC, Brackman CJ, Ip SM, et al. Infection of dogs with SARS-CoV-2. Nature 2020; 586:776.

166. Newman A, Smith D, Ghai RR, et al. First Reported Cases of SARS-CoV-2 Infection in Companion Animals - New York, March-April 2020. MMWR Morb Mortal Wkly Rep 2020.

167. McAloose D, Laverack M, Wang L, et al. From People to Panthera: Natural SARS-CoV-2 Infection in Tigers and Lions at the Bronx Zoo. mBio 2020; 11.

168. Halfmann PJ, Hatta M, Chiba S, et al. Transmission of SARS-CoV-2 in Domestic Cats. N Engl J Med 2020; 383:592.

169. Shi J, Wen Z, Zhong G, et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS-coronavirus 2. Science 2020; 368:1016.

170. Munnink BBO, Sikkema RS, Nieuwenhuijse DF, et al. Transmission of SARS-CoV-2 on mink farms between humans and mink and back to humans. Science 2020.

171. European Ministry of Africulture, Nature and Food Quality. SARS-CoV-2 infections of mink in the Netherlands. https://ec.europa.eu/food/sites/food/files/animals/docs/reg-com_ahw_20200618_covid_mink_nld.pdf (Accessed on July 24, 2020).

172. SARS-CoV-2 mink-associated variant strain - Denmark. https://www.who.int/csr/don/06-november-2020-mink-associated-sars-cov2-denmark/en/ (Accessed on November 10, 2020).

173. Rijkers G, Murk JL, Wintermans B, et al. Differences in Antibody Kinetics and Functionality Between Severe and Mild Severe Acute Respiratory Syndrome Coronavirus 2 Infections. J Infect Dis 2020; 222:1265.

174. Lynch KL, Whitman JD, Lacanienta NP, et al. Magnitude and kinetics of anti-SARS-CoV-2 antibody responses and their relationship to disease severity. Clin Infect Dis 2020.

175. Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection. Science 2021; 371.

176. Crawford KHD, Dingens AS, Eguia R, et al. Dynamics of Neutralizing Antibody Titers in the Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection. J Infect Dis 2021; 223:197.

177. Wang Z, Muecksch F, Schaefer-Babajew D, et al. Naturally enhanced neutralizing breadth against SARS-CoV-2 one year after infection. Nature 2021; 595:426.

178. Turner JS, Kim W, Kalaidina E, et al. SARS-CoV-2 infection induces long-lived bone marrow plasma cells in humans. Nature 2021; 595:421.

179. Yao L, Wang GL, Shen Y, et al. Persistence of Antibody and Cellular Immune Responses in Coronavirus Disease 2019 Patients Over Nine Months After Infection. J Infect Dis 2021; 224:586.

180. Wajnberg A, Amanat F, Firpo A, et al. Robust neutralizing antibodies to SARS-CoV-2 infection persist for months. Science 2020; 370:1227.

181. Rodda LB, Netland J, Shehata L, et al. Functional SARS-CoV-2-Specific Immune Memory Persists after Mild COVID-19. Cell 2021; 184:169.

182. Khoury DS, Cromer D, Reynaldi A, et al. Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection. Nat Med 2021; 27:1205.

183. Lumley SF, O'Donnell D, Stoesser NE, et al. Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers. N Engl J Med 2021; 384:533.

184. Harvey RA, Rassen JA, Kabelac CA, et al. Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection. JAMA Intern Med 2021; 181:672.

185. Hall VJ, Foulkes S, Charlett A, et al. SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN). Lancet 2021; 397:1459.

186. Letizia AG, Ge Y, Vangeti S, et al. SARS-CoV-2 seropositivity and subsequent infection risk in healthy young adults: a prospective cohort study. Lancet Respir Med 2021; 9:712.

187. Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020; 395:1845.

188. Grifoni A, Weiskopf D, Ramirez SI, et al. Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 2020; 181:1489.

189. Mateus J, Grifoni A, Tarke A, et al. Selective and cross-reactive SARS-CoV-2 T cell epitopes in unexposed humans. Science 2020.

190. Braun J, Loyal L, Frentsch M, et al. SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 2020; 587:270.

191. Ng KW, Faulkner N, Cornish GH, et al. Preexisting and de novo humoral immunity to SARS-CoV-2 in humans. Science 2020; 370:1339.

192. Hansen CH, Michlmayr D, Gubbels SM, et al. Assessment of protection against reinfection with SARS-CoV-2 among 4 million PCR-tested individuals in Denmark in 2020: a population-level observational study. Lancet 2021; 397:1204.

193. Harrington D, Kele B, Pereira S, et al. Confirmed Reinfection with SARS-CoV-2 Variant VOC-202012/01. Clin Infect Dis 2021.

194. Zucman N, Uhel F, Descamps D, et al. Severe reinfection with South African SARS-CoV-2 variant 501Y.V2: A case report. Clin Infect Dis 2021.

195. To KK, Hung IF, Ip JD, et al. COVID-19 re-infection by a phylogenetically distinct SARS-coronavirus-2 strain confirmed by whole genome sequencing. Clin Infect Dis 2020.

196. Van Elslande J, Vermeersch P, Vandervoort K, et al. Symptomatic Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Reinfection by a Phylogenetically Distinct Strain. Clin Infect Dis 2021; 73:354.

197. Gupta V, Bhoyar RC, Jain A, et al. Asymptomatic reinfection in two healthcare workers from India with genetically distinct SARS-CoV-2. Clin Infect Dis 2020.

198. Tillett RL, Sevinsky JR, Hartley PD, et al. Genomic evidence for reinfection with SARS-CoV-2: a case study. Lancet Infect Dis 2021; 21:52.

199. Mulder M, van der Vegt DSJM, Oude Munnink BB, et al. Reinfection of SARS-CoV-2 in an immunocompromised patient: a case report. Clin Infect Dis 2020.

200. Lee JS, Kim SY, Kim TS, et al. Evidence of Severe Acute Respiratory Syndrome Coronavirus 2 Reinfection After Recovery from Mild Coronavirus Disease 2019. Clin Infect Dis 2020.

201. Selhorst P, Van Ierssel S, Michiels J, et al. Symptomatic SARS-CoV-2 reinfection of a health care worker in a Belgian nosocomial outbreak despite primary neutralizing antibody response. Clin Infect Dis 2020.

202. To KK, Hung IF, Chan KH, et al. Serum Antibody Profile of a Patient With Coronavirus Disease 2019 Reinfection. Clin Infect Dis 2021; 72:e659.

203. BNO News. COVID-19 reinfection tracker. https://bnonews.com/index.php/2020/08/covid-19-reinfection-tracker/ (Accessed on March 31, 2021).

204. Lan L, Xu D, Ye G, et al. Positive RT-PCR Test Results in Patients Recovered From COVID-19. JAMA 2020; 323:1502.

205. Yuan J, Kou S, Liang Y, et al. Polymerase Chain Reaction Assays Reverted to Positive in 25 Discharged Patients With COVID-19. Clin Infect Dis 2020; 71:2230.

206. Wu J, Liu X, Liu J, et al. Coronavirus Disease 2019 Test Results After Clinical Recovery and Hospital Discharge Among Patients in China. JAMA Netw Open 2020; 3:e209759.

207. Hu R, Jiang Z, Gao H, et al. Recurrent Positive Reverse Transcriptase-Polymerase Chain Reaction Results for Coronavirus Disease 2019 in Patients Discharged From a Hospital in China. JAMA Netw Open 2020; 3:e2010475.

208. Korean Centers for Disease Control and Prevention. Findings from Investigation and analysis of re-positive cases https://www.cdc.go.kr/board/board.es?mid=a30402000000&bid=0030 (Accessed on May 19, 2020).

209. Honein MA, Christie A, Rose DA, et al. Summary of Guidance for Public Health Strategies to Address High Levels of Community Transmission of SARS-CoV-2 and Related Deaths, December 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1860.

210. Hirose R, Ikegaya H, Naito Y, et al. Survival of SARS-CoV-2 and influenza virus on the human skin: Importance of hand hygiene in COVID-19. Clin Infect Dis 2020.

211. American Academy of Ophthalmology. Coronavirus Eye Safety. https://www.aao.org/eye-health/tips-prevention/coronavirus-covid19-eye-infection-pinkeye (Accessed on April 06, 2020).

212. Centers for Disease Control and Prevention. Ventilation in Buildings. https://www.cdc.gov/coronavirus/2019-ncov/community/ventilation.html (Accessed on December 17, 2020).

213. Lindsley WG, Derk RC, Coyle JP, et al. Efficacy of Portable Air Cleaners and Masking for Reducing Indoor Exposure to Simulated Exhaled SARS-CoV-2 Aerosols - United States, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:972.

214. WHO. Advice on the use of masks in the context of COVID-19. December 1, 2020. https://www.who.int/publications/i/item/advice-on-the-use-of-masks-in-the-community-during-home-care-and-in-healthcare-settings-in-the-context-of-the-novel-coronavirus-(2019-ncov)-outbreak (Accessed on January 18, 2021).

215. Centers for Disease Control and Prevention. Federal Register Notice: Wearing of face masks while on conveyances and at transportation hubs. https://www.cdc.gov/quarantine/masks/mask-travel-guidance.html (Accessed on February 05, 2021).

216. Centers for Disease Control and Prevention. Types of Masks. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/types-of-masks.html (Accessed on February 11, 2021).

217. Clase CM, Fu EL, Joseph M, et al. Cloth Masks May Prevent Transmission of COVID-19: An Evidence-Based, Risk-Based Approach. Ann Intern Med 2020; 173:489.

218. Bahl P, Bhattacharjee S, de Silva C, et al. Face coverings and mask to minimise droplet dispersion and aerosolisation: a video case study. Thorax 2020; 75:1024.

219. Centers for Disease Control and Prevention. Improve the Fit and Filtration of Your Mask to Reduce the Spread of COVID-19. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/mask-fit-and-filtration.html (Accessed on February 11, 2021).

220. US FDA. Personal Protective Equipment EUAs. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/personal-protective-equipment-euas#appendixa (Accessed on February 11, 2021).

221. World Health Organization. Advice on the use of masks in the context of COVID-19. https://www.who.int/publications/i/item/advice-on-the-use-of-masks-in-the-community-during-home-care-and-in-healthcare-settings-in-the-context-of-the-novel-coronavirus-(2019-ncov)-outbreak (Accessed on June 08, 2020).

222. CNN. European countries mandate medical-grade masks over homemade cloth face coverings. https://www.cnn.com/2021/01/22/europe/europe-covid-medical-masks-intl/index.html (Accessed on January 24, 2021).

223. Samannan R, Holt G, Calderon-Candelario R, et al. Effect of Face Masks on Gas Exchange in Healthy Persons and Patients with Chronic Obstructive Pulmonary Disease. Ann Am Thorac Soc 2021; 18:541.

224. Chan NC, Li K, Hirsh J. Peripheral Oxygen Saturation in Older Persons Wearing Nonmedical Face Masks in Community Settings. JAMA 2020; 324:2323.

225. Wang Y, Tian H, Zhang L, et al. Reduction of secondary transmission of SARS-CoV-2 in households by face mask use, disinfection and social distancing: a cohort study in Beijing, China. BMJ Glob Health 2020; 5.

226. Leung NHL, Chu DKW, Shiu EYC, et al. Respiratory virus shedding in exhaled breath and efficacy of face masks. Nat Med 2020; 26:676.

227. Chan JF, Yuan S, Zhang AJ, et al. Surgical Mask Partition Reduces the Risk of Noncontact Transmission in a Golden Syrian Hamster Model for Coronavirus Disease 2019 (COVID-19). Clin Infect Dis 2020; 71:2139.

228. Liang M, Gao L, Cheng C, et al. Efficacy of face mask in preventing respiratory virus transmission: A systematic review and meta-analysis. Travel Med Infect Dis 2020; 36:101751.

229. Chu DK, Akl EA, Duda S, et al. Physical distancing, face masks, and eye protection to prevent person-to-person transmission of SARS-CoV-2 and COVID-19: a systematic review and meta-analysis. Lancet 2020; 395:1973.

230. Wang X, Ferro EG, Zhou G, et al. Association Between Universal Masking in a Health Care System and SARS-CoV-2 Positivity Among Health Care Workers. JAMA 2020; 324:703.

231. Czypionka T, Greenhalgh T, Bassler D, Bryant MB. Masks and Face Coverings for the Lay Public : A Narrative Update. Ann Intern Med 2021; 174:511.

232. Rader B, White LF, Burns MR, et al. Mask-wearing and control of SARS-CoV-2 transmission in the USA: a cross-sectional study. Lancet Digit Health 2021; 3:e148.

233. Hendrix MJ, Walde C, Findley K, and Trotman R. Absence of Apparent Transmission of SARS-CoV-2 from Two Stylists After Exposure at a Hair Salon with a Universal Face Covering Policy - Springfield, Missouri, May 2020. MMWR Morb Mortal Wkly Rep 2020.

234. Van Dyke ME, Rogers TM, Pevzner E, et al. Trends in County-Level COVID-19 Incidence in Counties With and Without a Mask Mandate - Kansas, June 1-August 23, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1777.

235. Joo H, Miller GF, Sunshine G, et al. Decline in COVID-19 Hospitalization Growth Rates Associated with Statewide Mask Mandates - 10 States, March-October 2020. MMWR Morb Mortal Wkly Rep 2021.

236. Guy GP Jr, Lee FC, Sunshine G, et al. Association of State-Issued Mask Mandates and Allowing On-Premises Restaurant Dining with County-Level COVID-19 Case and Death Growth Rates - United States, March 1-December 31, 2020. MMWR Morb Mortal Wkly Rep 2021; 70:350.

237. Stutt ROJH, Retkute R, Bradley M, et al. A modelling framework to assess the likely effectiveness of facemasks in combination with 'lock-down' in managing the COVID-19 pandemic. Proc Math Phys Eng Sci 2020; 476:20200376.

238. Ngonghala CN, Iboi E, Eikenberry S, et al. Mathematical assessment of the impact of non-pharmaceutical interventions on curtailing the 2019 novel Coronavirus. Math Biosci 2020; 325:108364.

239. Payne DC, Smith-Jeffcoat SE, Nowak G, et al. SARS-CoV-2 Infections and Serologic Responses from a Sample of U.S. Navy Service Members - USS Theodore Roosevelt, April 2020. MMWR Morb Mortal Wkly Rep 2020.

240. Doung-Ngern P, Suphanchaimat R, Panjangampatthana A, et al. Case-Control Study of Use of Personal Protective Measures and Risk for SARS-CoV 2 Infection, Thailand. Emerg Infect Dis 2020; 26:2607.

241. Freedman DO, Wilder-Smith A. In-flight transmission of SARS-CoV-2: a review of the attack rates and available data on the efficacy of face masks. J Travel Med 2020; 27.

242. Bundgaard H, Bundgaard JS, Raaschou-Pedersen DET, et al. Effectiveness of Adding a Mask Recommendation to Other Public Health Measures to Prevent SARS-CoV-2 Infection in Danish Mask Wearers : A Randomized Controlled Trial. Ann Intern Med 2021; 174:335.

243. Gandhi M, Beyrer C, Goosby E. Masks Do More Than Protect Others During COVID-19: Reducing the Inoculum of SARS-CoV-2 to Protect the Wearer. J Gen Intern Med 2020; 35:3063.

244. Gandhi M, Rutherford GW. Facial Masking for Covid-19 - Potential for "Variolation" as We Await a Vaccine. N Engl J Med 2020; 383:e101.

245. Sickbert-Bennett EE, Samet JM, Clapp PW, et al. Filtration Efficiency of Hospital Face Mask Alternatives Available for Use During the COVID-19 Pandemic. JAMA Intern Med 2020; 180:1607.

246. Brooks JT, Beezhold DH, Noti JD, et al. Maximizing Fit for Cloth and Medical Procedure Masks to Improve Performance and Reduce SARS-CoV-2 Transmission and Exposure, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:254.

247. Fischer EP, Fischer MC, Grass D, et al. Low-cost measurement of facemask efficacy for filtering expelled droplets during speech. Sci Adv 2020.

248. Clase CM, Fu EL, Ashur A, et al. Forgotten Technology in the COVID-19 Pandemic: Filtration Properties of Cloth and Cloth Masks-A Narrative Review. Mayo Clin Proc 2020; 95:2204.

249. Clapp PW, Sickbert-Bennett EE, Samet JM, et al. Evaluation of Cloth Masks and Modified Procedure Masks as Personal Protective Equipment for the Public During the COVID-19 Pandemic. JAMA Intern Med 2021; 181:463.

250. Marra AR, Edmond MB, Popescu SV, Perencevich EN. Examining the need for eye protection for coronavirus disease 2019 (COVID-19) prevention in the community. Infect Control Hosp Epidemiol 2021; 42:646.

251. Perencevich EN, Diekema DJ, Edmond MB. Moving Personal Protective Equipment Into the Community: Face Shields and Containment of COVID-19. JAMA 2020; 323:2252.

252. Zeng W, Wang X, Li J, et al. Association of Daily Wear of Eyeglasses With Susceptibility to Coronavirus Disease 2019 Infection. JAMA Ophthalmol 2020; 138:1196.

253. Islam N, Sharp SJ, Chowell G, et al. Physical distancing interventions and incidence of coronavirus disease 2019: natural experiment in 149 countries. BMJ 2020; 370:m2743.

254. Rubin D, Huang J, Fisher BT, et al. Association of Social Distancing, Population Density, and Temperature With the Instantaneous Reproduction Number of SARS-CoV-2 in Counties Across the United States. JAMA Netw Open 2020; 3:e2016099.

255. Tsai AC, Harling G, Reynolds Z, et al. Coronavirus Disease 2019 (COVID-19) Transmission in the United States Before Versus After Relaxation of Statewide Social Distancing Measures. Clin Infect Dis 2021; 73:S120.

256. Centers for Disease Control and Prevention. Testing guidance for nursing homes. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/nursing-homes-testing.html (Accessed on July 01, 2020).

257. World Health Organization. Preventing and managing COVID-19 across long-term care services: Web annex. 2020. Available at: https://www.who.int/publications/i/item/WHO-2019-nCoV-Policy_Brief-Long-term_Care-web-annex-2020.1 (Accessed on September 02, 2020).

258. Denny TN, Andrews L, Bonsignori M, et al. Implementation of a Pooled Surveillance Testing Program for Asymptomatic SARS-CoV-2 Infections on a College Campus - Duke University, Durham, North Carolina, August 2-October 11, 2020. MMWR Morb Mortal Wkly Rep 2020.

259. Peto J, Alwan NA, Godfrey KM, et al. Universal weekly testing as the UK COVID-19 lockdown exit strategy. Lancet 2020; 395:1420.

260. Mina MJ, Parker R, Larremore DB. Rethinking Covid-19 Test Sensitivity - A Strategy for Containment. N Engl J Med 2020; 383:e120.

261. Paltiel AD, Zheng A, Walensky RP. Assessment of SARS-CoV-2 Screening Strategies to Permit the Safe Reopening of College Campuses in the United States. JAMA Netw Open 2020; 3:e2016818.

262. Larremore DB, Wilder B, Lester E, et al. Test sensitivity is secondary to frequency and turnaround time for COVID-19 screening. Sci Adv 2021; 7.

263. Dollard P, Griffin I, Berro A, et al. Risk Assessment and Management of COVID-19 Among Travelers Arriving at Designated U.S. Airports, January 17-September 13, 2020. MMWR Morb Mortal Wkly Rep 2020; 69:1681.

264. Ng OT, Marimuthu K, Koh V, et al. SARS-CoV-2 seroprevalence and transmission risk factors among high-risk close contacts: a retrospective cohort study. Lancet Infect Dis 2021; 21:333.

265. Pan A, Liu L, Wang C, et al. Association of Public Health Interventions With the Epidemiology of the COVID-19 Outbreak in Wuhan, China. JAMA 2020; 323:1915.

266. Tian H, Liu Y, Li Y, et al. An investigation of transmission control measures during the first 50 days of the COVID-19 epidemic in China. Science 2020; 368:638.

267. Lyu W, Wehby GL. Comparison of Estimated Rates of Coronavirus Disease 2019 (COVID-19) in Border Counties in Iowa Without a Stay-at-Home Order and Border Counties in Illinois With a Stay-at-Home Order. JAMA Netw Open 2020; 3:e2011102.

268. Jüni P, Rothenbühler M, Bobos P, et al. Impact of climate and public health interventions on the COVID-19 pandemic: a prospective cohort study. CMAJ 2020; 192:E566.

269. Sen S, Karaca-Mandic P, Georgiou A. Association of Stay-at-Home Orders With COVID-19 Hospitalizations in 4 States. JAMA 2020; 323:2522.

270. Flaxman S, Mishra S, Gandy A, et al. Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe. Nature 2020; 584:257.

271. Hsiang S, Allen D, Annan-Phan S, et al. The effect of large-scale anti-contagion policies on the COVID-19 pandemic. Nature 2020; 584:262.

272. Marriott D, Beresford R, Mirdad F, et al. Concomitant Marked Decline in Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Other Respiratory Viruses Among Symptomatic Patients Following Public Health Interventions in Australia: Data from St Vincent's Hospital and Associated Screening Clinics, Sydney, NSW. Clin Infect Dis 2021; 72:e649.

273. Fuller JA, Hakim A, Victory KR, et al. Mitigation Policies and COVID-19-Associated Mortality - 37 European Countries, January 23-June 30, 2020. MMWR Morb Mortal Wkly Rep 2021; 70:58.

274. World Health Organization. Considerations in adjusting public health and social measures in the context of COVID-19. Interim guidance. April 16, 2020. https://www.who.int/publications-detail/considerations-in-adjusting-public-health-and-social-measures-in-the-context-of-covid-19-interim-guidance (Accessed on May 12, 2020).

275. WHO. Overview of public health and social measures in the context of COVID-19. https://www.who.int/publications-detail/overview-of-public-health-and-social-measures-in-the-context-of-covid-19 (Accessed on May 20, 2020).

276. Centers for Disease Control and Prevention. Testing and International Air Travel. https://www.cdc.gov/coronavirus/2019-ncov/travelers/testing-air-travel.html (Accessed on December 02, 2020).

277. Centers for Disease Control and Prevention. Domestic Travel During the COVID-19 Pandemic. https://www.cdc.gov/coronavirus/2019-ncov/travelers/travel-during-covid19.html (Accessed on December 02, 2020).

278. Centers for Disease Control and Prevention. Public Health Recommendations for People in U.S. Communities Exposed to a Person with Known or Suspected COVID-19, other than Health Workers or other Critical Infrastructure Workers. https://www.cdc.gov/coronavirus/2019-ncov/php/public-health-recommendations.html (Accessed on July 31, 2020).

279. Centers for Disease Control and Prevention. Options to reduce quarantine for contacts of persons with SARS-CoV-2 infection using symptom monitoring and diagnostic testing. Available at: https://www.cdc.gov/coronavirus/2019-ncov/more/scientific-brief-options-to-reduce-quarantine.html (Accessed on December 02, 2020).

280. Rolfes MA, Grijalva CG, Zhu Y, et al. Implications of Shortened Quarantine Among Household Contacts of Index Patients with Confirmed SARS-CoV-2 Infection - Tennessee and Wisconsin, April-September 2020. MMWR Morb Mortal Wkly Rep 2021; 69:1633.

281. Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19, updated December 23, 2020. https://www.idsociety.org/practice-guideline/covid-19-guideline-diagnostics/ (Accessed on January 14, 2021).

282. United States Centers for Disease Control and Prevention. Interim public health recommendations for fully vaccinated people. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated-guidance.html (Accessed on November 10, 2021).

283. Centers for Disease Control and Prevention. When to Quarantine. https://www.cdc.gov/coronavirus/2019-ncov/if-you-are-sick/quarantine.html (Accessed on February 11, 2021).

284. FACT SHEET FOR HEALTH CARE PROVIDERS. EMERGENCY USE AUTHORIZATION (EUA) OF REGEN-COVTM (casirivimab and imdevimab) https://www.fda.gov/media/145611/download (Accessed on August 03, 2021).

285. FACT SHEET FOR HEALTH CARE PROVIDERS EMERGENCY USE AUTHORIZATION (EUA) OF BAMLANIVIMAB AND ETESEVIMAB https://www.fda.gov/media/145802/download (Accessed on October 01, 2021).

286. https://www.covid19treatmentguidelines.nih.gov/therapies/statement-on-casirivimab-plus-imdevimab-as-pep/ (Accessed on September 20, 2021).

287. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html (Accessed on August 03, 2021).

288. O'Brien MP, Forleo-Neto E, Musser BJ, et al. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med 2021; 385:1184.

289. Cohen MS, Nirula A, Mulligan M, et al.. Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. JAMA 2021.

290. Boulware DR, Pullen MF, Bangdiwala AS, et al. A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19. N Engl J Med 2020; 383:517.

291. Abella BS, Jolkovsky EL, Biney BT, et al. Efficacy and Safety of Hydroxychloroquine vs Placebo for Pre-exposure SARS-CoV-2 Prophylaxis Among Health Care Workers: A Randomized Clinical Trial. JAMA Intern Med 2021; 181:195.

292. Rajasingham R, Bangdiwala AS, Nicol MR, et al. Hydroxychloroquine as Pre-exposure Prophylaxis for Coronavirus Disease 2019 (COVID-19) in Healthcare Workers: A Randomized Trial. Clin Infect Dis 2021; 72:e835.

293. Mitjà O, Corbacho-Monné M, Ubals M, et al. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of Covid-19. N Engl J Med 2021; 384:417.

294. Barnabas RV, Brown ER, Bershteyn A, et al. Hydroxychloroquine as Postexposure Prophylaxis to Prevent Severe Acute Respiratory Syndrome Coronavirus 2 Infection : A Randomized Trial. Ann Intern Med 2021; 174:344.

295. Bartoszko JJ, Siemieniuk RAC, Kum E, et al. Prophylaxis against covid-19: living systematic review and network meta-analysis. BMJ 2021; 373:n949.

296. Lamontagne F, Agoritsas T, Siemieniuk R, et al. A living WHO guideline on drugs to prevent covid-19. BMJ 2021; 372:n526.

297. Shouman W. Prophylactic Ivermectin in COVID-19 Contacts. Zagazig University. https://clinicaltrials.gov/ct2/show/study/NCT04422561 (Accessed on December 17, 2020).

298. Heidary F, Gharebaghi R. Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen. J Antibiot (Tokyo) 2020; 73:593.

299. World Health Organization. https://www.who.int/publications-detail/an-international-randomised-trial-of-candidate-vaccines-against-covid-19 (Accessed on April 22, 2020).

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COVID-19: Epidemiology, virology, and prevention - UpToDate

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Coronaviruses are important human and animal pathogens. At the end of 2019, a novel coronavirus was identified as the cause of a cluster of pneumonia cases in W

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Opciones para controlar la nueva infección por el virus Corona - 2019-nCoV

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Opciones para controlar la nueva infección por el virus Corona - 2019-nCoV

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[Options for controlling new Corona virus infection - 2019-nCoV]

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El 49% cree que medidas del Gobierno controlarán parcialmente el Covid-19

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Encuesta realizada por Datum, de manera online a 410 personas en distintas regiones del país. Observe a detalle los resultados.

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La inmunización es el proceso por el que una persona se hace resistente a una enfermedad, tanto por el contacto con ciertas enfermedades, o mediante la administración de una vacuna. Las vacunas estimulan el sistema inmunitario del cuerpo para proteger a la persona contra infecciones o enfermedades.

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Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the pandemic and are being vigorously pursued. By the end of 2020, several vaccines had become available for use in different parts of the world, over 40 candidate vaccines were in human trials, and over 150 were in preclinical trials. The World Health Organization maintains an updated list of vaccine candidates under evaluation [ 2].

This topic will cover vaccines for SARS-CoV-2, with a focus on vaccines available in the United States, vaccines in the later stages of development, and anticipated issues related to licensure, allocation, uptake, and post-licensure monitoring. Other aspects related to prevention of COVID-19 are discussed in detail elsewhere. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention'.)

GENERAL PRINCIPLES

● Phase I trials - These are designed to test vaccine safety, although immunogenicity is also measured; dose-ranging studies are also often included.

● Phase II trials - These expand the safety profile and immune response assessment in larger numbers of participants.

Traditionally, these steps occur sequentially, and each usually takes several years for completion. COVID-19 vaccine development has accelerated to an unprecedented pace, with each step occurring over several months. Additionally, in the COVID-19 vaccine initiative, phase I and II and phase II and III studies have frequently been combined with a seamless transition from one phase into the next. Nevertheless, safety criteria remain stringent; data safety and monitoring committees (DSMCs) composed of independent vaccine experts and study sponsors assess adverse events that are reported in each phase of clinical study and approve advancement to the next phase. In the United States, the Food and Drug Administration (FDA) must also approve progression to each next step in human trials, from initiation of phase I trials through progression to phase III trials, based on data generated in the prior step.

Antigenic target - The major antigenic target for both SARS-CoV-1 and MERS vaccines was the large surface spike protein [ 8-10]. An analogous protein is also present in SARS-CoV-2 ( figure 1); it binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells and induces membrane fusion ( figure 2) [ 11]. Based on data from SARS-CoV-1 and MERS-CoV vaccine studies, as well as observations that antibodies binding to the receptor-binding domain of the SARS-CoV-2 spike protein can prevent attachment to the host cell and neutralize the virus, the spike protein became the predominant antigenic target for COVID-19 vaccine development [ 12].

Immunologic basis for SARS-CoV-2 vaccination - Several observations support the concept that vaccination has the potential to prevent SARS-CoV-2 infection. In nonhuman primate studies, experimental infection with wild-type SARS-CoV-2 virus protected against subsequent reinfection, indicating that infection can result in protective immunity [ 17,18]. Vaccination of primates also protected against viral challenge; development of functional neutralizing antibodies correlated with protection [ 19-21]. Epidemiologic studies in humans have also suggested that neutralizing antibodies are associated with protection from infection, as illustrated in an outbreak on a fishing vessel [ 22]. Thus, vaccines that elicit a sufficient neutralizing response should be able to offer protection against COVID-19. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Immune responses following infection'.)

* Inactivated virus vector vaccines - Inactivated virus vectors are engineered to express the target protein but have been inactivated and are thus safer since they cannot replicate, even in the immunocompromised host.

● DNA vaccines - DNA vaccines consist of plasmid DNA that contain mammalian expression promotors and the target gene, so that the target protein is expressed in the vaccine recipient. Large quantities of stable plasmid DNA can be generated in Escherichia coli, which is a major production advantage. However, DNA vaccines are often of low immunogenicity and need special delivery devices, such as electroporators, which limit their use. Further, DNA vaccines must reach the nucleus to be transcribed to messenger RNA (mRNA) so proteins can be generated to stimulate an immune response.

● RNA vaccines - RNA vaccines were the first vaccines for SARS-CoV-2 to be produced and represent an entirely new vaccine approach. Once administered, the RNA is translated into the target protein, which is intended to elicit an immune response. The mRNA remains in the cell cytoplasm and does not enter into the nucleus; mRNA vaccines do not interact with or integrate into the recipient's DNA. These vaccines are produced completely in vitro, which facilitates production. However, some of the vaccines must be maintained at very low temperatures, complicating storage.

APPROACH TO VACCINATION

United States

●BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) is indicated for individuals aged 5 years or older.

●mRNA-1273 (Moderna COVID-19 vaccine) is indicated for individuals aged 18 years or older.

●Ad26.COV2.S (Janssen COVID-19 vaccine) is indicated for individuals aged 18 years or older.

The choice between these COVID-19 vaccines is based on availability, patient preference (eg, regarding number of doses in the primary series), and the possibility of rare adverse events. Ad26.COV2.S has been associated with thrombosis with thrombocytopenia and possibly Guillain-Barre syndrome, and the mRNA vaccines (BNT162b2 and mRNA-1273) have been associated with myocarditis. The risks of these events are extremely small, and the benefits of the vaccine outweigh them. Nevertheless, potential recipients should be aware of the risks (see 'Specific safety concerns' below). Individuals who have a contraindication to a vaccine in one class (eg, an mRNA vaccine) should not receive other vaccines in that same class but can receive a vaccine in the other class with precautions. (See 'Contraindications and precautions (including allergies)' below.)

All the available vaccines are highly effective and substantially reduce the risk of COVID-19, especially severe/critical disease. However, they have not been compared directly in trials, so comparative efficacy is uncertain. Limited observational data suggest that vaccine effectiveness may be greater with two doses of the mRNA vaccines than with one dose of Ad26.COV2.S [ 33-35]. As an example, in a case control study of 3689 immunocompetent adults hospitalized for COVID-19, estimated effectiveness against COVID-19-related hospitalization was 93 and 88 percent for mRNA-1273 and BNT162b2, respectively, compared with 71 percent for Ad26.COV2.S [ 33]. Although the analysis adjusted for age, sex, admission date, geographic region, and race, the contribution of these and other unmeasured confounders, such as variable exposure risk, to the apparent differences in effectiveness is uncertain.

In addition to direct reductions in COVID-19-associated morbidity and mortality, vaccination (with any of the three vaccines authorized or licensed in the United States) has been associated with lower non-COVID-19 mortality rates, supporting evidence that COVID-19 vaccination does not increase the risk of death [ 36]. Details on the efficacy and safety of the individual vaccines are discussed elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)

Administration

Dose and interval

● BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)

For adults and adolescents ≥12 years of age:

*Primary series - Two intramuscular doses of 0.3 mL (30 mcg) each are given three weeks (21 days) apart. For individuals with certain immunocompromising conditions ( table 1), a third dose is given at least 28 days after the second [ 30]. (See 'Immunocompromised individuals' below.)

*Booster dose for select individuals - One intramuscular dose of 0.3 mL (30 mcg), given at least six months after the last dose in the primary series, is suggested for adults who are 65 years or older, are at risk for severe COVID-19 because of medical comorbidities ( table 2), or have frequent occupational or institutional exposure to SARS-CoV-2 [ 30,37]. (See 'Role of booster vaccinations' below.)

For children 5 to 11 years of age:

*Primary series - Two intramuscular doses of 0.1 mL (10 mcg) each are given three weeks (21 days) apart. Clinicians should be aware that this is a lower dose and a different formulation than those used for older individuals.

● mRNA-1273 (Moderna COVID-19 vaccine)

*Primary series - Two intramuscular doses of 0.5 mL (100 mcg) each are given one month (28 days) apart. For individuals with certain immunocompromising conditions ( table 1), a third dose is given at least 28 days after the second [ 31]. (See 'Immunocompromised individuals' below.)

*Booster dose for select individuals - One intramuscular dose of 0.25 mL (50 mcg), given at least six months after the last dose in the primary series, is suggested for adults who are 65 years or older, are at risk for severe COVID-19 because of medical comorbidities ( table 2), or have frequent occupational or institutional exposure to SARS-CoV-2 [ 31,37]. (See 'Role of booster vaccinations' below.)

● Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine)

*Primary series - One intramuscular dose of 0.5 mL (5x10 ¹⁰ viral particles) is given [ 32].

*Booster dose - One intramuscular dose of 0.5 mL (5x10 ¹⁰ viral particles) is given at least two months after the primary series. (See 'Role of booster vaccinations' below.)

The same vaccine, if available, is generally used to complete the primary series. A different vaccine can be used for the booster dose; the interval and indications for the booster dose depend on the vaccine given for the primary series. As an example, an individual who received a primary series with one dose of Ad26.COV2.S can receive a booster dose at least two months later with another Ad26.COV2.S dose or with one of the other two authorized vaccines. This is discussed in detail elsewhere. (See 'Mixing vaccine types' below.)

In adults and adolescents, intramuscular vaccines are typically injected into the deltoid. Proper injection technique to reduce the risk of shoulder injury involves injection at a 90° angle into the central, thickest part of the deltoid ( figure 4). (See "Standard immunizations for nonpregnant adults", section on 'Technique'.)

Additional details on administration can be found on the Centers for Disease Control and Prevention (CDC) website. The following table details CDC recommendations on the management of vaccine administration errors ( table 3).

Mixing vaccine types

For individuals who received a first dose of an mRNA vaccine but cannot receive either mRNA vaccine for the second dose (eg, because of contraindications), Ad26.COV2.S can be given as long as there is not also a contraindication to Ad26.COV2.S (see 'Contraindications and precautions (including allergies)' below). The CDC suggests giving Ad26.COV2.S at least 28 days after the mRNA vaccine dose [ 38]. Such individuals should be considered to have received a complete AD26.COV2.S vaccine regimen.

Support for use of a different vaccine for the booster dose comes from an unpublished, nonrandomized, open-label trial presented to the FDA [ 40,41]. Participants who had received a primary series of one of the three vaccines authorized in the United States were given a booster dose with the same vaccine or one of the other two. In all groups, binding and neutralizing antibody titers (targeting wild-type virus and variants) following the booster dose rose at least fourfold compared with pre-boost levels, and heterologous boost resulted in similar or higher antibody responses as using the same vaccine to boost. Among those who received a primary Ad26.COV2.S vaccine, receipt of an mRNA vaccine boost rather than an Ad26.COV2.S boost was associated with a greater rise in antibody titers; however, the trial was not designed to compare immunogenicity across groups, and other differences between groups (eg, the interval at which the booster dose was provided varied from 11 to 41 weeks) may have contributed to the apparent immunogenicity difference. No safety concerns were identified; the pattern of systemic symptoms was largely similar across all groups.

Studies from other countries using different vaccines to complete a series (eg, ChAdOx1 nCoV-19/ADZ122 followed by BNT162b2) suggests a more robust and broad immune response with certain heterologous vaccine combinations, although in some cases there is a higher rate of systemic reactions (fever, fatigue, headaches, myalgias) compared with using the same vaccine for both doses [ 42-44].

Some side effects of vaccination overlap with symptoms of COVID-19. Systemic reactions (eg, fever, chills, fatigue, headache) that occur within the first day or two after vaccination and resolve within a day or two are consistent with a reaction to the vaccine. However, respiratory symptoms or systemic symptoms that occur after the first couple days following vaccination or that last several days could be indicative of COVID-19 and warrant testing. (See "COVID-19: Diagnosis", section on 'Preferred initial test and specimen collection'.)

Special populations

Individuals with recent, documented SARS-CoV-2 infection (including those who are diagnosed following the first vaccine dose) should have recovered from acute infection and met criteria for discontinuation of isolation precautions before receiving the vaccine (either the initial dose or the second dose of a two-dose series) (see 'Administration' above). It is also reasonable for such individuals to delay any vaccine receipt for a few months after infection to allow others to get vaccinated sooner, as the risk of reinfection appears extremely low in this period. The CDC also suggests that individuals who received monoclonal antibodies or convalescent plasma for COVID-19 should delay vaccination for at least 90 days from the time of treatment [ 38]. This delay also applies to receipt of the second vaccine dose of a two-dose series if antibody-based COVID-19 therapy was administered after the initial vaccine dose.

For individuals who had SARS-CoV-2 infection complicated by multisystem inflammatory syndrome (MIS), the decision to vaccinate should weigh the risk of exposure, reinfection, and severe disease with infection against the uncertain safety of vaccination in such individuals. Given the hypothesis that MIS is associated with immune dysregulation precipitated by SARS-CoV-2 infection, it is unknown if a SARS-CoV-2 vaccine could trigger a similar dysregulated response.

Vaccination is likely still beneficial in many patients with a history of SARS-CoV-2 infection. Although reinfection appears uncommon in individuals who develop detectable antibodies after SARS-CoV-2 infection, ascertainment of prior infection can be unreliable or impractical in some cases, and the duration of protection from prior infection is unknown. Furthermore, vaccination is associated with greater protection against hospitalization for COVID-19 compared with prior infection [ 45]. Vaccination appears to further boost antibody levels in those with past infection and might improve the durability and breadth of protection [ 46]. In observational studies, vaccination following SARS-CoV-2 infection has been associated with a lower risk of subsequent reinfection [ 47,48]; it has also been associated with a lower risk of breakthrough infection compared with vaccination in individuals without prior infection [ 49]. Several small studies have also suggested that after a single mRNA vaccine dose, individuals with evidence of prior SARS-CoV-2 infection mount substantially higher binding and neutralizing antibody responses compared with SARS-CoV-2-naïve individuals [ 50-56]. Furthermore, studies suggest that in individuals with prior infection, a single mRNA vaccine dose augments neutralizing antibody levels as well as cell-mediated responses against other SARS-CoV-2 variants (Alpha [B.1.1.7] and Beta [B.1.351]) [ 57,58].

Despite the promising data, until there is longer follow-up of single-dose mRNA vaccination in a broader population of individuals with prior infection, the full two-dose series is recommended when mRNA vaccines are used.

Individuals with a history of SARS-CoV-2 may be more likely to experience local and systemic adverse effects (eg, fevers, chills, myalgias, fatigue) after a first vaccine dose than SARS-CoV-2-naïve individuals [ 38,53,59]. This is not a contraindication or precaution to a second dose (if receiving a vaccine given as two doses). In published reports of individuals with persistent symptoms following acute COVID-19, vaccination has not been associated with exacerbation of these symptoms [ 60].

Immunocompromised individuals - We suggest that eligible individuals who have an immunocompromising condition or are taking immunosuppressive agents undergo COVID-19 vaccination. Immunogenicity and effectiveness of COVID-19 vaccines appear lower in such individuals compared with the general population; nevertheless, the potential for severe COVID-19 in this population outweighs the uncertainties. Considerations for immunocompromised patients given the potential for reduced vaccine response include the following:

● Additional vaccine dose - We agree with recommendations from the ACIP that individuals with certain immunocompromising conditions who received a two-dose mRNA vaccine series receive a third dose (if possible, the same vaccine formulation should be used) as part of the primary vaccine series [ 61]; authorization for the mRNA vaccines was updated to include a third dose, to be given at least 28 days after the second dose, for such individuals [ 30,31]. Immunocompromising conditions that would warrant a third dose include active use of chemotherapy for cancer, hematologic malignancies, hematopoietic stem cell or solid organ transplant, advanced or untreated HIV infection with CD4 cell count <200 cells/microL, moderate or severe primary immunodeficiency disorder, and use of immunosuppressive medications (eg, mycophenolate mofetil, rituximab, prednisone >20 mg/day for >14 days) ( table 1) [ 62]. Several other countries, including France, Germany, and Israel, have made similar recommendations [ 63]. Patients with immunocompromising conditions should be advised to continue other protective measures regardless of the number of vaccine doses received, as immune response may not be optimal even with three doses.

Administering a three-dose primary mRNA vaccine series for certain immunocompromised patients is a distinct issue from booster vaccines following a primary series. Immunocompromised individuals who received three doses of a primary mRNA vaccine series may also receive a booster dose six months later [ 38]. (See 'Role of booster vaccinations' below.)

In studies of transplant recipients who received a third dose of mRNA vaccines, seroconversion rates were higher after the additional dose, although approximately 50 to 70 percent who were seronegative after two doses remained seronegative; adverse effects were similar to those reported after prior doses [ 64-68]. Longitudinal follow-up and evaluation of cellular immune responses are needed to more completely characterize the impact of additional vaccine doses.

● Continued use of protective measures - We advise immunocompromised patients to maintain personal measures to try to minimize exposure to SARS-CoV-2 (eg, masking, distancing, avoiding crowds when possible) even after they are fully vaccinated because of the potential for reduced vaccine effectiveness. Household and other close contacts of immunocompromised patients should be vaccinated.

Issues related to vaccination of specific immunocompromised populations are discussed in detail elsewhere:

●(See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected patients during the pandemic, and issues related to COVID-19 vaccination in cancer patients", section on 'Vaccination to prevent SARS-CoV-2 infection'.)

●(See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'COVID-19 vaccination while on immunosuppressive therapy'.)

●(See "COVID-19: Issues related to solid organ transplantation", section on 'Vaccination'.)

●(See "Immunizations in patients with primary immunodeficiency", section on 'Issues related to SARS-CoV-2 vaccination'.)

The individual benefit of COVID-19 vaccination in young children may be somewhat less than in adults because COVID-19 tends to be less severe in children than in adults. Nevertheless, the risk of the multisystem inflammatory syndrome in children (MIS-C) following acute infection, the potential for other sequelae of SARS-CoV-2 infection (eg, "long-COVID-19" and indirect effects on mental health and education), the risk of severe disease in children with underlying medical conditions, and the desire to prevent COVID-19 of any severity in children remain compelling reasons for vaccination of children [ 84]. Furthermore, even with the lower risk of severe disease among children, the number of COVID-19 deaths among those 5 to 11 years old from 2020 to 2021 exceeds the prevaccination era mortality rates of infections for which childhood vaccines are routinely provided (eg, rotavirus, meningococcal disease, varicella) [ 85].

Given the hypothesis that MIS-C is associated with immune dysregulation precipitated by SARS-CoV-2 infection, similar immune-related side effects following vaccination in children are another concern. Vaccine trials in this age group have not identified a potential signal, although rare case reports of MIS in adults following vaccination highlight the importance of monitoring for this possible adverse effect [ 87]. (See "COVID-19: Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis".)

Most vaccines for children are delivered by private health care providers, although many are purchased using federal or other government funds. The Vaccines for Children (VFC) program is an entitlement program for all ACIP-approved vaccines for eligible children through 18 years of age [ 88,89]. Eligible children include those on Medicaid, those who are completely uninsured, and American Indian/Alaskan Natives. Approximately 50 percent of children are covered by the VFC. In addition, federal grants to states can be used to purchase vaccines to cover other children. Since COVID-19 vaccines are free to all persons for whom the vaccines are recommended, these funding mechanisms may be used with the COVID-19 vaccines that are licensed in children in addition to other funding sources.

Patient counseling

Expected adverse effects and their management

● Common local and systemic reactions - Vaccine recipients should be advised that side effects are common and include local and systemic reactions, including pain at the injection site, ipsilateral axillary lymph node enlargement, fever, fatigue, and headache. Among mRNA vaccines, BNT162b2 may be associated with slightly lower rates of local and systemic reactions compared with mRNA-1273 [ 90]. Rates of reactions for the distinct vaccines are discussed in detail elsewhere. (See 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' below and 'mRNA-1273 (Moderna COVID-19 vaccine)' below and 'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)' below.)

Because of the risk of axillary lymph node enlargement following vaccination, some expert societies suggest postponing breast cancer screening mammography for several weeks post-vaccination if it cannot be performed beforehand. (See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected patients during the pandemic, and issues related to COVID-19 vaccination in cancer patients", section on 'COVID-19 vaccine-related adenopathy and implications for radiologic imaging'.)

Other complications (including more common venous thromboembolic events without thrombocytopenia such as deep vein thrombosis or pulmonary embolism, Bell's palsy, tinnitus) have been reported in vaccine recipients but have not been identified as causally related vaccine-associated adverse events. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)

Post-vaccine public health precautions - Although SARS-CoV-2 infection might still occur despite vaccination, the risk is substantially lower, and certain public health precautions may be relaxed for individuals who have been fully vaccinated. However, recommendations have evolved with new developments in the pandemic (eg, emergence of the highly transmissible Delta variant), and the approach should be tailored to the overall rate of transmission in the community. Individuals are considered fully vaccinated once two weeks have elapsed following receipt of the primary vaccination series.

The CDC suggests waiving post-travel quarantine and testing requirements for fully vaccinated individuals in the community who remain asymptomatic. Vaccinated individuals do not have to quarantine following exposure to SARS-CoV-2 but should undergo testing five to seven days after exposure and wear a mask in public spaces for 14 days or until receiving a negative SARS-CoV-2 test. Symptoms consistent with COVID-19 should prompt testing, regardless of vaccination history.

Because individuals with immunocompromising conditions may have suboptimal responses to COVID-19 vaccination, we counsel such individuals to maintain personal preventive measures even if they have been vaccinated, particularly when contact with unvaccinated individuals is possible, to minimize exposure to SARS-CoV-2. (See 'Immunocompromised individuals' above.)

Recommendations on masking, distancing, and post-exposure management for individuals who have not been fully vaccinated are discussed in detail elsewhere. (See "COVID-19: Epidemiology, virology, and prevention", section on 'Prevention' and "COVID-19: Epidemiology, virology, and prevention", section on 'Post-exposure management'.)

Contraindications and precautions (including allergies)

*Severe allergic reaction (eg, anaphylaxis) to a previous COVID-19 vaccine dose or to a component of the vaccine.

*Immediate allergic reaction of any severity (including hives) developing within four hours of a previous COVID-19 vaccine dose or known (diagnosed) allergy to a component of the vaccine. Symptoms of immediate reactions are listed on the CDC website. Isolated hives that develop more than four hours after vaccine receipt are unlikely to represent an allergic reaction to the vaccine. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Delayed urticarial reactions'.)

The mRNA vaccines, BNT162b2 (Pfizer-BioNTech COVID-19 vaccine) and mRNA-1273 (Moderna COVID-19 vaccine), each contain polyethylene glycol, and Ad26.COV2.S (Janssen COVID-19 vaccine, also known as the Johnson & Johnson vaccine) contains polysorbate. Allergic reaction to polysorbate is not a contraindication to mRNA vaccines, but it is a contraindication to Ad26.COV2.S. Other components of COVID-19 vaccines are listed on the CDC website.

*Immediate allergic reaction to any other (non-COVID-19) vaccine or injectable therapy.

*Contraindication to an mRNA COVID-19 vaccine is a precaution to Ad26.COV2.S because of potential cross-reactive hypersensitivity.

*Contraindication to AD26.COV2.S is a precaution to an mRNA vaccine because of potential cross-reactive hypersensitivity.

Allergy consultation can be helpful to evaluate suspected allergic reactions to a COVID-19 vaccine or its components and assess the risk of future COVID-19 vaccination. This is discussed in detail elsewhere. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Possible anaphylaxis'.)

Other reactions or conditions that are neither precautions nor contraindications include:

●Late local reactions characterized by a well-demarcated area of erythema appearing at the injection site approximately a week after mRNA COVID-19 vaccination have been reported, with recurrence occurring in some individuals after repeat vaccination [ 99]. This may occur more frequently with mRNA-1273 than with BNT162b2 [ 100]. This type of reaction is not a contraindication to vaccination, and individuals who experience this after the initial mRNA vaccine dose can proceed with the second dose as scheduled [ 38]. (See "COVID-19: Allergic reactions to SARS-CoV-2 vaccines", section on 'Late local reactions'.)

●Facial swelling in areas previously injected with cosmetic dermal fillers has also been rarely reported following vaccination with the mRNA COVID-19 vaccines. Dermal fillers are not a contraindication to COVID-19 vaccination, and no specific precautions are recommended [ 38]. However, it is reasonable to advise individuals with dermal fillers of the possibility of post-vaccination swelling. This is discussed elsewhere. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Soft tissue fillers'.)

●Anticoagulation is not a contraindication to vaccination; excess bleeding is unlikely with intramuscular vaccines in patients taking anticoagulants [ 101]. Such patients can be instructed to hold pressure over the injection site to reduce the risk of hematoma. (See "Standard immunizations for nonpregnant adults", section on 'Patients on anticoagulation'.)

Monitoring for immediate reactions to vaccine - All individuals should be monitored for immediate vaccine reactions following receipt of any COVID-19 vaccine.

The following warrant monitoring for 30 minutes:

●Precautions to the administered vaccine (immediate reaction to any vaccine or injectable therapy; contraindication to the other vaccine type) (see 'Contraindications and precautions (including allergies)' above)

●History of anaphylaxis due to any cause

All other individuals are monitored for 15 minutes.

Details on the efficacy and safety of available COVID-19 vaccines are discussed elsewhere. (See 'Immunogenicity, efficacy, and safety of select vaccines' below.)

Dosing schedules vary by vaccine. Additionally, different countries may have specific recommendations for vaccine use. As an example, Canadian national guidelines allow administration of an mRNA vaccine to complete a two-dose series following receipt of the adenovirus vector vaccine, ChAdOx1 nCoV-19/AZD1222 (University of Oxford/AstraZeneca COVID-19 vaccine), as studies suggest the combination results in a more robust and broader immune response than a two-dose ChAdOx1 nCOV-19/AZD1222 series without major safety concerns [ 44,106-108]. (See 'Mixing vaccine types' above.)

Different countries may also have specific allocation priorities for distributing the initial vaccine supplies. As an example, the Joint Committee on Vaccination and Immunisation in the United Kingdom recommends prioritizing a first vaccine dose for all eligible individuals prior to securing a second vaccine dose for recipients [ 109]. However, both mRNA vaccines were studied with two-dose schedules, and the efficacy estimates from those schedules are difficult, if not impossible, to extrapolate to a single-dose schedule. Clinicians should refer to local guidelines for vaccine recommendations in their location. (See 'Society guideline links' below.)

Several countries had paused use of ChAdOx1 nCoV-19/AZD1222 to investigate scattered reports of thromboembolic events; many have since resumed use, in some cases with age restrictions. This is discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia' below.)

Immunogenicity, efficacy, and safety of specific vaccines are discussed below. General issues related to breakthrough infections, impact on transmission, effectiveness against variants of concern, and duration of effect are discussed elsewhere. (See 'Ongoing safety assessment' below.)

Observational data from various countries following their national roll-outs of BNT162b2 support the trial findings in adults and adolescents [ 34,124-137]. In a study from Israel using national surveillance data from more than 6.5 million individuals, of whom 72 percent had received BNT162b2, estimated vaccine effectiveness seven days or more following the second dose was 92 percent for documented SARS-CoV-2 infection, 97 percent for symptomatic COVID-19, 97 percent for COVID-19-related hospitalization, and 97 percent for COVID-19-related death [ 124]. In a study of 464 individuals aged 12 to 18 years old who were hospitalized in the United States during the summer of 2021, vaccine effectiveness against COVID-19-related hospitalization was estimated at 93 percent [ 137]. The vaccine also appears effective against SARS-CoV-2 variants that have become prevalent since the initial trial. In a study from the United Kingdom, estimated effectiveness against symptomatic infection caused by Delta (B.1.617.2) was 88 percent (95% CI 85-90) compared with 94 percent (95% CI 92-95) for Alpha [ 138]. However, unpublished data from Israel have suggested that the emergence of Delta as the predominant variant in the country was temporally associated with lower effectiveness rates (64 percent) against symptomatic infection; effectiveness against hospitalization remained very high [ 139].

Vaccine efficacy may wane over time. In a follow-up report of the phase III trial participants, vaccine efficacy against symptomatic disease remained high over six months but slightly decreased from 96 percent up to two months, to 90 percent between two and four months, to 84 percent from four to six months [ 140]. Of 30 severe infections, only one occurred in a vaccinated individual. (See 'Role of booster vaccinations' below.)

● Safety and side effects - Local and systemic adverse effects are relatively common, particularly after the second dose; most are of mild or moderate severity (ie, do not prevent daily activities) and are limited to the first two days after vaccination [ 90,105,122]. Among 1.6 million vaccine recipients (16 years or older) in the United States who responded to post-vaccination surveys, an injection site reaction (mainly pain, but also redness, swelling, and pruritus) was reported in approximately 65 percent after each dose; fatigue, headache, and myalgias were reported in 29, 25, and 17 percent after the first dose and in 48, 40, and 37 percent after the second, respectively [ 90]. After the second dose, fevers, chills, and joint pain each occurred in approximately 20 percent. Reactions were most frequently reported on the day following vaccination. These reactions were also commonly reported among adolescents aged 12 through 15 years following the second dose (fatigue, headache, chills, and myalgia in 66, 65, 42, and 32 percent, respectively) [ 114]; systemic reactions among children aged 5 through 11 years were reported at slightly lower rates and were milder [ 115]. Local and systemic reactions occur less frequently among recipients 65 years or older but are still relatively common.

Although not identified in the clinical trials, myocarditis and pericarditis, mainly in male adolescents and young adults, have subsequently been reported more frequently than expected following receipt of BNT162b2. This is discussed in detail elsewhere. (See 'Myocarditis' below.)

Anaphylaxis following vaccination has been reported at an approximate rate of 5 events per 1 million doses; 80 percent of anaphylaxis cases have occurred in individuals with a history of allergic reactions and 90 percent occurred within 30 minutes [ 103]. Other reported allergic reactions included pruritus, rash, scratchy sensations in the throat, and mild respiratory symptoms [ 141].

Other major adverse events have not been consistently associated with BNT162b2 receipt [ 142]. Rare cases of Bell's palsy were noted in the phase III trial (four in vaccine and zero in placebo recipients) [ 122]; however, the rate did not exceed background rates found in the general population (15 to 30 cases per 100,000 people per year), and post-vaccine monitoring has not identified an association between vaccination and Bell's palsy [ 103]. As of April 12, 2021, there had been no reports in the United States of cerebral venous sinus thrombosis with thrombocytopenia following nearly 98 million doses of BNT162b2 administered [ 143]. In a large cohort study from Israel, BNT162b2 receipt was most strongly associated with myocarditis, lymphadenopathy, appendicitis, and herpes zoster [ 144].

● Immunogenicity - A phase I open-label trial demonstrated binding and neutralizing antibody responses comparable to those seen in convalescent plasma with vaccination in healthy individuals 18 to 55 years of age [ 146]. CD4 cell responses with a Th1 bias were also detected. Vaccination in adults older than 55 years also elicited immune responses that were comparable to those seen in the younger populations [ 147]. Binding and neutralizing antibody responses declined slightly over six months in participants from all age groups but antibody titers remained high and neutralizing activity persisted over this time [ 148]. Immunogenicity in adolescents aged 12 to 17 years is comparable to or higher than that seen in young adults [ 149]. Vaccination with mRNA-1273 is associated with higher antibody titers after the second dose compared with BNT162b2 [ 150,151].

Myocarditis and pericarditis, mainly in male adolescents and young adults, have been reported more frequently than expected following receipt of mRNA-1273. This is discussed in detail elsewhere. (See 'Myocarditis' below.)

Anaphylaxis following vaccination has been reported at an approximate rate of 2.8 events per one million doses; 86 percent of anaphylaxis cases have occurred in individuals with a history of allergic reactions, and 90 percent occurred within 30 minutes [ 103,141]. There were rare cases of Bell's palsy that were considered potentially related to vaccination (three in the vaccine and one in the placebo group). However, the rate did not exceed the background rate in the general population (15 to 30 cases per 100,000 people per year), and post-vaccine monitoring has not identified an association between vaccination and Bell's palsy [ 103].

No other major vaccine-associated adverse events have been identified in post-vaccine surveillance [ 142]. As of June 29, 2021, a single case of cerebral venous sinus thrombosis with thrombocytopenia following mRNA-1273 receipt had been reported in the United States. Given only one case, it is difficult to determine whether the relation is causal or coincidental; regardless, it is extremely rare [ 160].

Baseline seroprevalence to adenovirus 26 is low in North America and Europe; it is moderately high in sub-Saharan Africa and Southeast Asia, although most seropositive individuals have low neutralizing titers [ 165]. Nonhuman primate studies suggest that these low titers do not suppress responses to adenovirus 26 vector vaccines.

● Efficacy - Ad26.COV2.S has been studied as both one- and two-dose regimens:

Reported overall efficacy varied by region: 74 percent in the United States, 66 percent in Brazil, where the Gamma (P.2) variant was prevalent, and 52 percent in South Africa, where most infections were caused by the variant Beta (B.1.351). Nevertheless, vaccine efficacy against severe/critical disease was similar across regions (and in South Africa was 73 and 82 percent after 14 and 28 days post-vaccination).

Observational data evaluating vaccine effectiveness largely support the trial findings [ 33,34]. In a study that compared the odds of a positive SARS-CoV-2 test between vaccinated and unvaccinated individuals who were tested in the context of 11,000 hospital admissions and 9000 urgent care or emergency department visits, Ad26.COV2.S vaccine effectiveness was 73 and 68 percent against COVID-19-related emergency care and hospitalization, respectively [ 34].

ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India) - This vaccine is based on a replication-incompetent chimpanzee adenovirus vector that expresses the spike protein ( table 5). It is given intramuscularly and is being evaluated as two doses 4 to 12 weeks apart. The World Health Organization (WHO) recommends that the two doses be given 8 to 12 weeks apart [ 172]. ChAdOx1 nCoV-19/AZD1222 has been authorized for use in the European Union and several other countries, including the United Kingdom, Canada, and India. Although there is some concern about vaccine efficacy against certain SARS-CoV-2 variants, as discussed below, WHO recommends use of this vaccine even if those variants are circulating in a country [ 172]. Because of an extremely rare side effect, several countries have suspended use of the vaccine pending additional data, and some are limiting the vaccine to individuals over a certain age; this is discussed in detail elsewhere. (See 'Thrombosis with thrombocytopenia' below.)

● Immunogenicity - In a single-blind, randomized controlled phase I/II trial in healthy individuals 18 to 55 years old, in which most of the vaccine recipients received a single dose and a small cohort received an additional booster dose, neutralizing antibody titers 28 days after the last dose were comparable to those detected in convalescent plasma [ 173]. The levels of antibody titers achieved were higher following two doses, and a third dose is associated with even higher antibody titers [ 174]. Cellular immune responses were also detected. In a study that included older vaccine recipients (>70 years), the vaccine resulted in similar antibody responses after the second dose as in younger adults [ 175]. However, the Beta (B.1.351) and Delta (B.1.617.2) variants may evade immune responses in some vaccinated individuals [ 118,176]; in one study of 63 ChAdOx1 nCoV-19/AZD1222 recipients, approximately 60 percent had detectable neutralizing activity against those variants [ 176].

In a subsequent analysis of this trial, vaccine efficacy for symptomatic COVID-19 was 76 percent from 21 days after receipt of the first dose until receipt of the second dose or day 90, whichever came first, suggesting protection with a single dose [ 178]. Additionally, receipt of the second dose at 12 weeks or later was associated with higher vaccine efficacy than receipt at <6 weeks (81 versus 55 percent). These findings lend support to extending the time interval for the second dose to 12 weeks.

Efficacy against variants of concern may be reduced. In an unpublished study from the United Kingdom, estimated effectiveness against symptomatic infection caused by Delta (B.1.617.2) was 67 percent (95% CI 61-72) compared with 75 percent (95% CI 68-79) for Alpha [ 138].

In an open-label, nonrandomized phase I/II trial, SARS-CoV-2 humoral and cellular immune responses were detected in the participants [ 185].

According to interim analysis of a phase III trial that included over 20,000 participants without serologic evidence of prior SARS-CoV-2 infection, this vaccine had 91.6 percent (95% CI 85.6-95.2) efficacy in preventing symptomatic COVID-19 starting at 21 days following the first dose (at the time of the second dose) [ 185]. This effect was assessed after 78 cases of COVID-19 (16 of 14,964 participants who received vaccine and 62 of 4902 participants who received placebo). All 20 cases of severe COVID-19 that occurred 21 days after the first dose were in the placebo group. Median follow-up time was 48 days after the first dose. Local and systemic flu-like reactions were more common in the vaccine group, at rates of 15 and 5 percent, respectively. No serious adverse events were deemed related to vaccine.

● CoronaVac (Sinovac) - This inactivated COVID-19 vaccine was developed in China; it has an aluminum hydroxide adjuvant. The vaccine is given intramuscularly in two doses 28 days apart. In phase I/II randomized, placebo-controlled trials, the vaccine appeared safe and immunogenic in healthy individuals aged 18 to 59 years [ 190] as well as those 60 years or older [ 191]. Neutralizing activity against the variant B.1.351 (Beta) is reduced [ 188]. According to interim results of a phase III trial of 10,000 participants in Turkey without evidence of prior SARS-CoV-2 infection, vaccine efficacy starting 14 days after full vaccination was 83.5 percent (95% CI 65.4-92.1) [ 192]; however, lower efficacy rates have been reported in press releases of trials in different countries [ 183]. In an observational study that included over 10 million individuals in Chile, estimated vaccine effectiveness was 70 percent for preventing COVID-19 and 86 to 88 percent for preventing hospital admission or death [ 193]; a subsequent study in Brazil reported lower vaccine effectiveness among adults older than 70 years in the context of prevalent Gamma variant (47, 56, and 61 percent against COVID-19, hospitalization, and death, respectively) [ 194]. This vaccine is available in China and some other countries, including Brazil, Chile, Indonesia, Mexico, and Turkey.

GENERAL EFFICACY ISSUES

Impact on transmission risk - Widespread vaccination reduces the overall transmission risk, since vaccinated individuals are less likely to get infection. Previous data had also suggested that individuals who developed infection despite vaccination may be less likely to transmit to others, thereby further decreasing transmission risk. However, with the emergence of the Delta variant, which appears more transmissible than other variants, individuals with breakthrough infection following vaccination appear to have a substantial risk of transmission that may be comparable to that of unvaccinated individuals.

● Delta - Observational evidence suggests that vaccine effectiveness against symptomatic infection with the Delta variant is lower than that with Alpha [ 138,214-217]. However, data from the United States, the United Kingdom, Canada, and Israel suggest that vaccine effectiveness against severe disease, hospitalization, and death remains high with Delta and is comparable to that with Alpha [ 35,139,210,214,218-222]. As an example, in an analysis of SARS-CoV-2 infections in Los Angeles, California from May to July 2021, over which time Delta became the dominant variant, the age-adjusted rate of hospitalization among unvaccinated individuals was 29 times that among fully vaccinated individuals [ 210]. Another study of over 30,000 hospital, emergency, or urgent care encounters in the United States over a period when Delta predominated estimated vaccine effectiveness of 86 percent against COVID-19-associated hospitalization and 82 percent against emergency or urgent care [ 35]. (See 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' above and 'ChAdOx1 nCoV-19/AZD1222 (University of Oxford, AstraZeneca, and the Serum Institute of India)' above.)

There have also been reports of breakthrough infections in fully vaccinated individuals caused by other SARS-CoV-2 variants that share some mutations with variants of concern (such as E484K, which is associated with reduced neutralization by convalescent plasma from individuals with wild-type infection) [ 225,226]; however, in at least one report, the risk of infection with a variant that contained E484K was still lower among vaccinated compared with unvaccinated individuals [ 225].

●Among individuals who received a primary mRNA vaccine series (BNT162b2 [Pfizer COVID-19 vaccine] or mRNA-1273 [Moderna COVID-19 vaccine]), the CDC recommends a booster dose six months after the primary series for certain high-risk adults [ 30,31,37,39]:

*Adults 65 years or older should receive a booster dose.

*Adults 50 years or older at risk for severe COVID-19 because of comorbidities ( table 2) should receive a booster dose.

*Adults 18 years or older in long-term care settings should receive a booster dose.

*Adults aged 18 to 49 years and at risk for severe COVID-19 because of comorbidities ( table 2) may receive a booster dose after weighing the individual risks and benefits.

*Adults aged 18 to 64 years who have occupational or institutional risk of exposure to SARS-CoV-2 (eg, health care workers or those living in congregate settings) may receive a booster dose after weighing the individual risks and benefits.

●Among individuals who received a primary vaccine series with Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine), the CDC recommends a booster dose at least two months after the primary series [ 32,39].

Booster doses following a primary vaccine series are a distinct issue from administering a third dose of an mRNA vaccine for the primary series in certain immunocompromised patients. Such individuals who received three doses of a primary mRNA vaccine series may also receive a booster dose six months later [ 38]. (See 'Immunocompromised individuals' above.)

Although overall vaccine effectiveness against severe disease and hospitalization remains high over time, some observational data suggest that there may be a relative decline in effectiveness [ 35,221,232,233].

Observational data suggest that a booster vaccine may improve vaccine effectiveness, at least in the short term. As an example, in an observational study from Israel of over one million individuals aged 60 years or older who had received two doses of BNT162b2 at least five months previously, receipt of a booster dose was associated with an 11-times lower rate of infection compared with those who did not receive a booster (absolute difference 87 infections per 100,000 days) and a 20-times lower rate of severe illness (absolute difference 7.5 cases per 100,000 days) [ 234]. In a similar study from Israel, receipt of a booster BNT162b2 dose was associated with vaccine effectiveness of 92, 93, and 81 percent for severe COVID-19, hospitalization, and death, respectively, compared with two doses [ 235]. Given the observational design, it is uncertain whether some of these differences could have been related to other variables (eg, exposure risk or testing differences); there was also limited follow-up time following receipt of the booster.

Data on immunogenicity are consistent with the observational data [ 236,237]. In a small trial of 23 individuals who had received two doses of BNT162b2 (Pfizer COVID-19 vaccine), neutralizing antibody titers against wild-type virus, the Beta variant, and the Delta variant following receipt of a third dose eight to nine months later were higher than those detected following the initial two vaccine series [ 237]. The rate and severity of adverse reactions following the booster dose were similar to those following the second dose in prior trials. Similar findings from a larger trial were included in a report to the FDA [ 238]. Data presented to that FDA indicate that booster doses of mRNA-1273 and AD26.COV2.S also result in increases in binding and neutralizing antibody titers compared with pre-boost with similar reactogenicity profiles to those with the primary series [ 239,240]. Efficacy data from trials evaluating two doses of AD26.COV2.S also support use of a booster for this vaccine. (See 'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)' above.)

Data informing the use of heterologous booster vaccines are discussed elsewhere. (See 'Mixing vaccine types' above.)

SPECIFIC SAFETY CONCERNS

The incidence, risk factors, clinical features, evaluation, and management of VITT/TTS are discussed in detail elsewhere. (See "COVID-19: Vaccine-induced immune thrombotic thrombocytopenia (VITT)".)

In a review of the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system in the United States to which patients and providers can submit reports of events, there were 267 reported cases of myocarditis/pericarditis following one dose of an mRNA vaccine, 827 following two doses, and 132 without the number of doses specified as of June 11, 2021 [ 255]. The median ages for events after one and two doses were 30 and 24 years, respectively. Approximately three-quarters of the cases occurred in males. Among individuals aged 12 to 39 years, the number of events observed within a 21-day post-vaccine window exceeded the expected number. The estimated rate of myocarditis/pericarditis among males 12 to 29 years of age was 41 cases per million following a second dose of an mRNA. The estimated rates among females of the same age range was 4.2 cases per million and among males ≥30 years was 2.4 cases per million. Studies from Israel have also suggested an increased rate of myocarditis following BNT162b2 vaccination compared with the expected background rate, with the highest rates reported in males aged 16 to 29 years old [ 256,257].

Among the cases that have been reported, most were mild [ 255-257]. Onset was generally within the first week after vaccine receipt, more commonly after the second dose. Most patients who presented for care responded well to medical treatment and had rapid symptom improvement. There have been very rare reports of fulminant myocarditis in individuals who had received an mRNA vaccine within the preceding weeks, although a causal relationship is difficult to establish [ 258].

●In the United States, as of July 24, 2021, there had been 132 preliminary reports of GBS among Ad26.COV2.S recipients after approximately 13.2 million doses [ 266]. The estimated rate was 9.8 cases per million doses, a rate that is approximately four times the background rate. The median age was 56 years (interquartile range 45 to 62 years), the median time to onset was 13 days following vaccination, 35 percent had a life-threatening case, and 1 patient died. In an earlier report of 100 cases, a quarter of the patients reported bilateral facial weakness [ 248].

●In Europe, a total of 227 cases of GBS in ChAdOx1 nCoV-19/AZD1222 recipients had been reported to regulators as of June 27, 2021, at which point approximately 51 million doses had been administered [ 263]. Other scattered reports have also described GBS, including variant GBS with bilateral facial weakness, following ChAdOx1 nCoV-19/AZD1222 vaccination [ 267,268].

STEPS TO VACCINE AVAILABILITY AND DELIVERY

Once safety and efficacy meeting the criteria have been demonstrated, the FDA makes decisions on vaccine licensure, relying on guidance from the Vaccines and Related Biologic Products Advisory Committee (VRBPAC), a standing advisory group of experienced clinicians, vaccine experts, epidemiologists, and other subject matter experts. Similar approaches are taken by regulatory bodies in Canada and European countries for the licensure of their vaccines.

In addition to the traditional process to issue a license for a vaccine, the FDA can issue an emergency use authorization (EUA), which is designed to make products available during public health emergencies [ 271]. For a COVID-19 vaccine to receive EUA, it must meet the prespecified efficacy criteria defined for the primary endpoint with a median of two months of follow-up for half of the trial participants [ 272].

POST-LICENSURE ISSUES

Based on evidence from other vaccines, health care providers can improve vaccine acceptance in individual patients by making direct recommendations for vaccination, identifying concerns, educating patients on vaccine risks and benefits, and dispelling misconceptions about the disease and the vaccine. (See "Standard childhood vaccines: Parental hesitancy or refusal", section on 'Target education'.)

Willingness to accept a COVID-19 vaccine varies by country. In an online survey of 13,426 participants from 19 countries who were asked if they would accept a "proven, safe and effective vaccine," 72 percent overall said they completely or somewhat agreed [ 281]. The highest proportion of positive responses were from China, South Korea, and Singapore (over 80 percent), whereas the lowest were from Russia (55 percent).

In the United States, rates of vaccine hesitancy appear to have decreased since the availability of COVID-19 vaccines but remain substantial. In an internet survey of approximately 3500 adults conducted by the CDC in September and December 2020, the proportion who reported that they were very likely or absolutely certain to receive a COVID-19 vaccine increased from 39 to 49 percent, and the proportion who were unlikely to receive one decreased from 38 to 32 percent [ 282]. In another survey of approximately 7200 adults, rates of vaccine hesitancy also decreased from 46 percent in October 2020 to 35 percent in March 2021 [ 283-286].

COVID-19 vaccine hesitancy has been associated with younger age (eg, <60 years old), lower levels of education, lower household income, rural residence, and lack of health insurance [ 282,283,287]. In the CDC survey, the main reasons for reporting non-intent to receive vaccine were concerns about vaccine side effects and safety and lack of trust in the process [ 282].

Ongoing safety assessment - Adequately assessing vaccine safety is critical to the success of immunization programs. Although existing comprehensive systems to monitor vaccine safety are in place, they are being enhanced for the rollout of the COVID-19 vaccine program. It is particularly important to identify rare adverse events that are causally related to vaccine administration and assess their incidence and risk factors to inform potential vaccine contraindications.

In the United States, there are several systems in place to assess safety in the post-licensure setting; some are passive (ie, rely on others reporting the event) and others are active (ie, review databases or conduct studies to identify events) [ 288]. These include the Vaccine Adverse Event Reporting System (VAERS), a passive surveillance system in which providers, parents, and patients report adverse events. VAERS is intended to raise hypotheses about whether receipt of a vaccine could cause the adverse event rather than evaluate causation. The Vaccine Safety Datalink (VSD) is a collaborative project between the CDC's Immunization Safety Office and eight health care organizations to actively monitor the safety of vaccines and conduct studies about rare and serious post-vaccination adverse events. The Clinical Immunization Safety Assessment project (CISA) is a national network of vaccine safety experts from the CDC's Immunization Safety Office, seven academic medical research centers, and subject matter experts, and it provides a comprehensive vaccine safety public health service to the nation.

In addition, specific post-licensure vaccine safety systems have been implemented for the introduction of COVID-19 vaccines, similar to those established during the 2009 H1N1 influenza pandemic [ 289,290]. These systems will be coordinated through the CDC and will enlist multiple other health care groups to provide ongoing data on vaccine safety. These systems and information sources add an additional layer of safety monitoring [ 291,292].

● V-SAFE is a new smartphone-based health checker for people who have received a COVID-19 vaccine. The CDC will send text messages and web-based surveys to vaccine recipients through V-SAFE to check in regarding health problems following vaccination. The system will also provide telephone follow-up to anyone who reports clinically significant adverse events.

● Enhanced reporting through National Healthcare Safety Network (NHSN) sites - A monitoring system for health care workers and long-term care facility residents that reports to the VAERS.

● Monitoring of larger insurer/payer databases through the US Food and Drug Administration - A system of administrative and claims-based data for surveillance and research.

INFORMATION FOR PATIENTS - UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: COVID-19 vaccines (The Basics)" and "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Antigenic target - The primary antigenic target for COVID-19 vaccines is the large surface spike protein ( figure 1), which binds to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells ( figure 2). (See 'Overview of vaccine development' above and 'Antigenic target' above.)

*Two mRNA vaccines:

-BNT162b2 (Pfizer COVID-19 vaccine): The primary series includes two intramuscular injections given three weeks apart for individuals aged five years or older. This vaccine is associated with a rare risk of myocarditis. (See 'BNT162b2 (Pfizer-BioNTech COVID-19 vaccine)' above.)

-mRNA-1273 (Moderna COVID-19 vaccine): The primary series includes two intramuscular injections given one month apart for individuals 18 years or older. This vaccine is associated with a rare risk of myocarditis. (See 'mRNA-1273 (Moderna COVID-19 vaccine)' above.)

*An adenovirus-vector vaccine Ad26.COV2.S (Janssen COVID-19 vaccine, also referred to as the Johnson & Johnson vaccine): The primary series includes a single intramuscular injection for individuals 18 years or older. This vaccine is associated with a rare risk of thrombosis with thrombocytopenia and possibly Guillain-Barre syndrome. (See 'Ad26.COV2.S (Janssen/Johnson & Johnson COVID-19 vaccine)' above.)

Selection among vaccines depends on local availability and patient preference (eg, for a single dose). All three are highly effective, but limited observational data suggest that the mRNA vaccines may have slightly higher effectiveness against severe disease. The benefits of any of these vaccines greatly outweigh the rare risks of specific adverse events. (See 'Specific safety concerns' above.)

Different vaccines are available elsewhere; a list of vaccines that have been authorized in at least one country can be found at covid19.trackvaccines.org/vaccines. Clinicians outside the United States should refer to local guidelines for vaccine recommendations in their location. (See 'Other countries' above.)

REFERENCES

1. World Health Organization. Director-General's remarks at the media briefing on 2019-nCoV on 11 February 2020. http://www.who.int/dg/speeches/detail/who-director-general-s-remarks-at-the-media-briefing-on-2019-ncov-on-11-february-2020 (Accessed on February 12, 2020).

2. World Health Organization. Draft landscape of COVID-19 candidate vaccines. https://www.who.int/publications/m/item/draft-landscape-of-covid-19-candidate-vaccines (Accessed on October 20, 2020).

3. College of Physicians of Philadelphia. The History of Vaccines: Vaccine Development, Testing, and Regulation. https://www.historyofvaccines.org/content/articles/vaccine-development-testing-and-regulation (Accessed on October 20, 2020).

4. Martin JE, Louder MK, Holman LA, et al. A SARS DNA vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a Phase I clinical trial. Vaccine 2008; 26:6338.

5. Lin JT, Zhang JS, Su N, et al. Safety and immunogenicity from a phase I trial of inactivated severe acute respiratory syndrome coronavirus vaccine. Antivir Ther 2007; 12:1107.

6. Modjarrad K, Roberts CC, Mills KT, et al. Safety and immunogenicity of an anti-Middle East respiratory syndrome coronavirus DNA vaccine: a phase 1, open-label, single-arm, dose-escalation trial. Lancet Infect Dis 2019; 19:1013.

7. Yong CY, Ong HK, Yeap SK, et al. Recent Advances in the Vaccine Development Against Middle East Respiratory Syndrome-Coronavirus. Front Microbiol 2019; 10:1781.

8. Graham RL, Donaldson EF, Baric RS. A decade after SARS: strategies for controlling emerging coronaviruses. Nat Rev Microbiol 2013; 11:836.

9. Tortorici MA, Veesler D. Structural insights into coronavirus entry. Adv Virus Res 2019; 105:93.

10. Pallesen J, Wang N, Corbett KS, et al. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A 2017; 114:E7348.

11. Zhou P, Yang XL, Wang XG, et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579:270.

12. Krammer F. SARS-CoV-2 vaccines in development. Nature 2020; 586:516.

13. Graepel KW, Kochhar S, Clayton EW, Edwards KE. Balancing Expediency and Scientific Rigor in Severe Acute Respiratory Syndrome Coronavirus 2 Vaccine Development. J Infect Dis 2020; 222:180.

14. Graham BS. Rapid COVID-19 vaccine development. Science 2020; 368:945.

15. Halstead SB, Katzelnick L. COVID-19 Vaccines: Should We Fear ADE? J Infect Dis 2020; 222:1946.

16. Brighton Collaboration. Accelerated Assessment of the Risk of Disease Enhancement with COVID-19 Vaccines​, March 2020. https://brightoncollaboration.us/brighton-collaboration-cepi-covid-19-web-conference/ (Accessed on October 20, 2020).

17. Deng W, Bao L, Liu J, et al. Primary exposure to SARS-CoV-2 protects against reinfection in rhesus macaques. Science 2020; 369:818.

18. Chandrashekar A, Liu J, Martinot AJ, et al. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 2020; 369:812.

19. Gao Q, Bao L, Mao H, et al. Development of an inactivated vaccine candidate for SARS-CoV-2. Science 2020; 369:77.

20. Yu J, Tostanoski LH, Peter L, et al. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 2020; 369:806.

21. Mercado NB, Zahn R, Wegmann F, et al. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 2020; 586:583.

22. Addetia A, Crawford KHD, Dingens A, et al. Neutralizing Antibodies Correlate with Protection from SARS-CoV-2 in Humans during a Fishery Vessel Outbreak with a High Attack Rate. J Clin Microbiol 2020; 58.

23. Edwards KM, Dupont WD, Westrich MK, et al. A randomized controlled trial of cold-adapted and inactivated vaccines for the prevention of influenza A disease. J Infect Dis 1994; 169:68.

24. Ohmit SE, Victor JC, Rotthoff JR, et al. Prevention of antigenically drifted influenza by inactivated and live attenuated vaccines. N Engl J Med 2006; 355:2513.

25. Plotkin S, Robinson JM, Cunningham G, et al. The complexity and cost of vaccine manufacturing - An overview. Vaccine 2017; 35:4064.

26. Gomez PL, Robinson JM. Vaccine Manufacturing. In: Plotkin's Vaccines, 7th, Plotkin S, Orenstein W, Offit P, Edwards K (Eds), Elsevier, 2018. p.51.

27. Zhu FC, Li YH, Guan XH, et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 2020; 395:1845.

28. Case JB, Rothlauf PW, Chen RE, et al. Replication-Competent Vesicular Stomatitis Virus Vaccine Vector Protects against SARS-CoV-2-Mediated Pathogenesis in Mice. Cell Host Microbe 2020; 28:465.

29. Sun W, Leist SR, McCroskery S, et al. Newcastle disease virus (NDV) expressing the spike protein of SARS-CoV-2 as vaccine candidate. bioRxiv 2020.

30. Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 Vaccine to Prevent Coronavirus. Fact sheet for healthcare providers administering vaccine. https://www.fda.gov/media/144413/download (Accessed on October 21, 2021).

31. Emergency Use Authorization (EUA) of the Moderna COVID-19 Vaccine to prevent Coronavirus Disease 2019 (COVID-19). Factsheet for healthcare providers administering vaccine. https://www.fda.gov/media/144637/download?utm_medium=email&utm_source=govdelivery (Accessed on October 21, 2021).

32. US FDA. Emergency use authorization (EUA) of the Janssen COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19). https://www.fda.gov/media/146304/download (Accessed on October 21, 2021).

33. Self WH, Tenforde MW, Rhoads JP, et al. Comparative Effectiveness of Moderna, Pfizer-BioNTech, and Janssen (Johnson & Johnson) Vaccines in Preventing COVID-19 Hospitalizations Among Adults Without Immunocompromising Conditions - United States, March-August 2021. MMWR Morb Mortal Wkly Rep.

34. Thompson MG, Stenehjem E, Grannis S, et al. Effectiveness of Covid-19 Vaccines in Ambulatory and Inpatient Care Settings. N Engl J Med 2021; 385:1355.

35. Grannis SJ, Rowley EA, Ong TC, et al. Interim Estimates of COVID-19 Vaccine Effectiveness Against COVID-19-Associated Emergency Department or Urgent Care Clinic Encounters and Hospitalizations Among Adults During SARS-CoV-2 B.1.617.2 (Delta) Variant Predominance - Nine States, June-August 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1291.

36. Xu S, Huang R, Sy LS, et al. COVID-19 Vaccination and Non-COVID-19 Mortality Risk - Seven Integrated Health Care Organizations, United States, December 14, 2020-July 31, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1520.

37. CDC Statement on ACIP Booster Recommendations. Available at: https://www.cdc.gov/media/releases/2021/p0924-booster-recommendations-.html (Accessed on September 26, 2021).

38. Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html (Accessed on November 03, 2021).

39. CDC Expands Eligibility for COVID-19 Booster Shots https://www.cdc.gov/media/releases/2021/p1021-covid-booster.html (Accessed on October 22, 2021).

40. DMID 21-0012 - Heterologous Platform Boost Study. Presented at the Vaccines and Related Biological Products Advisory Committee October 14-15, 2021 Meeting Presentation. https://www.fda.gov/media/153128/download (Accessed on October 21, 2021).

41. Atmar RL, Lyke KE, Deming ME, et al. Heterologous SARS-CoV-2 Booster Vaccinations - Preliminary Report. UNPUBLISHED. https://www.medrxiv.org/content/10.1101/2021.10.10.21264827v2 (Accessed on October 21, 2021).

42. Borobia AM, Carcas AJ, Pérez-Olmeda M, et al. Immunogenicity and reactogenicity of BNT162b2 booster in ChAdOx1-S-primed participants (CombiVacS): a multicentre, open-label, randomised, controlled, phase 2 trial. Lancet 2021; 398:121.

43. Shaw RH, Stuart A, Greenland M, et al. Heterologous prime-boost COVID-19 vaccination: initial reactogenicity data. Lancet 2021; 397:2043.

44. Normark J, Vikström L, Gwon YD, et al. Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination. N Engl J Med 2021; 385:1049.

45. Bozio CH, Grannis SJ, Naleway AL, et al. Laboratory-Confirmed COVID-19 Among Adults Hospitalized with COVID-19-Like Illness with Infection-Induced or mRNA Vaccine-Induced SARS-CoV-2 Immunity - Nine States, January-September 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1539.

46. Zhong D, Xiao S, Debes AK, et al. Durability of Antibody Levels After Vaccination With mRNA SARS-CoV-2 Vaccine in Individuals With or Without Prior Infection. JAMA 2021.

47. Cavanaugh AM, Spicer KB, Thoroughman D, et al. Reduced Risk of Reinfection with SARS-CoV-2 After COVID-19 Vaccination - Kentucky, May-June 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1081.

48. Chin ET, Leidner D, Zhang Y, et al. Effectiveness of the mRNA-1273 Vaccine during a SARS-CoV-2 Delta Outbreak in a Prison. N Engl J Med 2021.

49. Abu-Raddad LJ, Chemaitelly H, Ayoub HH, et al. Association of Prior SARS-CoV-2 Infection With Risk of Breakthrough Infection Following mRNA Vaccination in Qatar. JAMA 2021.

50. Manisty C, Otter AD, Treibel TA, et al. Antibody response to first BNT162b2 dose in previously SARS-CoV-2-infected individuals. Lancet 2021; 397:1057.

51. Prendecki M, Clarke C, Brown J, et al. Effect of previous SARS-CoV-2 infection on humoral and T-cell responses to single-dose BNT162b2 vaccine. Lancet 2021; 397:1178.

52. Saadat S, Rikhtegaran Tehrani Z, Logue J, et al. Binding and Neutralization Antibody Titers After a Single Vaccine Dose in Health Care Workers Previously Infected With SARS-CoV-2. JAMA 2021; 325:1467.

53. Krammer F, Srivastava K, Alshammary H, et al. Antibody Responses in Seropositive Persons after a Single Dose of SARS-CoV-2 mRNA Vaccine. N Engl J Med 2021; 384:1372.

54. Bradley T, Grundberg E, Selvarangan R, et al. Antibody Responses after a Single Dose of SARS-CoV-2 mRNA Vaccine. N Engl J Med 2021; 384:1959.

55. Blain H, Tuaillon E, Gamon L, et al. Spike Antibody Levels of Nursing Home Residents With or Without Prior COVID-19 3 Weeks After a Single BNT162b2 Vaccine Dose. JAMA 2021.

56. Anderson M, Stec M, Rewane A, et al. SARS-CoV-2 Antibody Responses in Infection-Naive or Previously Infected Individuals After 1 and 2 Doses of the BNT162b2 Vaccine. JAMA Netw Open 2021; 4:e2119741.

57. Reynolds CJ, Pade C, Gibbons JM, et al. Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose. Science 2021.

58. Stamatatos L, Czartoski J, Wan YH, et al. mRNA vaccination boosts cross-variant neutralizing antibodies elicited by SARS-CoV-2 infection. Science 2021.

59. Menni C, Klaser K, May A, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis 2021; 21:939.

60. Arnold DT, Milne A, Samms E, et al. Symptoms After COVID-19 Vaccination in Patients With Persistent Symptoms After Acute Infection: A Case Series. Ann Intern Med 2021; 174:1334.

61. CDC - An Additional Dose of mRNA COVID-19 Vaccine Following a Primary Series in Immunocompromised People. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-08-13/02-COVID-Dooling-508.pdf (Accessed on August 14, 2021).

62. Centers for Disease Control and Prevention. Updated healthcare infection prevention and control recommendations in response to COVID-19 vaccination. Available at: https://www.cdc.gov/coronavirus/2019-ncov/hcp/infection-control-after-vaccination.html (Accessed on May 05, 2021).

63. CDC Data and clinical considerations for additional doses in immunocompromised people. Available at: https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/07-COVID-Oliver-508.pdf (Accessed on July 23, 2021).

64. Kamar N, Abravanel F, Marion O, et al. Three Doses of an mRNA Covid-19 Vaccine in Solid-Organ Transplant Recipients. N Engl J Med 2021; 385:661.

65. Werbel WA, Boyarsky BJ, Ou MT, et al. Safety and Immunogenicity of a Third Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: A Case Series. Ann Intern Med 2021; 174:1330.

66. Longlune N, Nogier MB, Miedougé M, et al. High immunogenicity of a messenger RNA-based vaccine against SARS-CoV-2 in chronic dialysis patients. Nephrol Dial Transplant 2021; 36:1704.

67. Benotmane I, Gautier G, Perrin P, et al. Antibody Response After a Third Dose of the mRNA-1273 SARS-CoV-2 Vaccine in Kidney Transplant Recipients With Minimal Serologic Response to 2 Doses. JAMA 2021.

68. Hall VG, Ferreira VH, Ku T, et al. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients. N Engl J Med 2021; 385:1244.

69. American College of Rheumatology. COVID-19 Vaccine Clinical Guidance Summary for Patients with Rheumatic and Musculoskeletal Diseases. https://www.rheumatology.org/Portals/0/Files/COVID-19-Vaccine-Clinical-Guidance-Rheumatic-Diseases-Summary.pdf (Accessed on March 04, 2021).

70. Chodick G, Tene L, Rotem RS, et al. The effectiveness of the TWO-DOSE BNT162b2 vaccine: analysis of real-world data. Clin Infect Dis 2021.

71. Tenforde MW, Patel MM, Ginde AA, et al. Effectiveness of SARS-CoV-2 mRNA Vaccines for Preventing Covid-19 Hospitalizations in the United States. Clin Infect Dis 2021.

72. Brosh-Nissimov T, Orenbuch-Harroch E, Chowers M, et al. BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully vaccinated hospitalized COVID-19 patients in Israel. Clin Microbiol Infect 2021.

73. Herishanu Y, Avivi I, Aharon A, et al. Efficacy of the BNT162b2 mRNA COVID-19 vaccine in patients with chronic lymphocytic leukemia. Blood 2021; 137:3165.

74. Boyarsky BJ, Werbel WA, Avery RK, et al. Antibody Response to 2-Dose SARS-CoV-2 mRNA Vaccine Series in Solid Organ Transplant Recipients. JAMA 2021; 325:2204.

75. Monin L, Laing AG, Muñoz-Ruiz M, et al. Safety and immunogenicity of one versus two doses of the COVID-19 vaccine BNT162b2 for patients with cancer: interim analysis of a prospective observational study. Lancet Oncol 2021; 22:765.

76. Goupil R, Benlarbi M, Beaubien-Souligny W, et al. Short-term antibody response after 1 dose of BNT162b2 vaccine in patients receiving hemodialysis. CMAJ 2021; 193:E793.

77. Marion O, Del Bello A, Abravanel F, et al. Safety and Immunogenicity of Anti-SARS-CoV-2 Messenger RNA Vaccines in Recipients of Solid Organ Transplants. Ann Intern Med 2021; 174:1336.

78. Connolly CM, Boyarsky BJ, Ruddy JA, et al. Absence of Humoral Response After Two-Dose SARS-CoV-2 Messenger RNA Vaccination in Patients With Rheumatic and Musculoskeletal Diseases: A Case Series. Ann Intern Med 2021; 174:1332.

79. Redjoul R, Le Bouter A, Beckerich F, et al. Antibody response after second BNT162b2 dose in allogeneic HSCT recipients. Lancet 2021; 398:298.

80. Mazzola A, Todesco E, Drouin S, et al. Poor Antibody Response after Two Doses of SARS-CoV-2 vaccine in Transplant Recipients. Clin Infect Dis 2021.

81. Deepak P, Kim W, Paley MA, et al. Effect of Immunosuppression on the Immunogenicity of mRNA Vaccines to SARS-CoV-2 : A Prospective Cohort Study. Ann Intern Med 2021.

82. Shimabukuro TT, Kim SY, Myers TR, et al. Preliminary Findings of mRNA Covid-19 Vaccine Safety in Pregnant Persons. N Engl J Med 2021; 384:2273.

83. Food and Drug Administration. Emergency Use Authorization letter for Pfizer-BioNTech COVID‑19 Vaccine. May 10, 2021. https://www.fda.gov/media/144412/download (Accessed on May 12, 2021).

84. Anderson EJ, Campbell JD, Creech CB, et al. Warp Speed for Coronavirus Disease 2019 (COVID-19) Vaccines: Why Are Children Stuck in Neutral? Clin Infect Dis 2021; 73:336.

85. Olivier S. Evidence to Recommendations (EtR) Framework:Pfizer-BioNTech COVID-19 vaccine in children aged 5-11 years. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-11-2-3/08-COVID-Oliver-508.pdf (Accessed on November 03, 2021).

86. Yang H. Benefits-Risks of Pfizer-BioNTech COVID-19 Vaccine for Ages 5 to 11 Years. https://www.fda.gov/media/153507/download (Accessed on November 02, 2021).

87. Salzman MB, Huang CW, O'Brien CM, Castillo RD. Multisystem Inflammatory Syndrome after SARS-CoV-2 Infection and COVID-19 Vaccination. Emerg Infect Dis 2021; 27:1944.

88. Centers for Disease Control and Prevention. Vaccines for Children Program (VFC). https://www.cdc.gov/vaccines/programs/vfc/ (Accessed on November 05, 2020).

89. Whitney CG, Zhou F, Singleton J, et al. Benefits from immunization during the vaccines for children program era - United States, 1994-2013. MMWR Morb Mortal Wkly Rep 2014; 63:352.

90. Chapin-Bardales J, Gee J, Myers T. Reactogenicity Following Receipt of mRNA-Based COVID-19 Vaccines. JAMA 2021; 325:2201.

91. Prymula R, Siegrist CA, Chlibek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomised controlled trials. Lancet 2009; 374:1339.

92. Doedée AM, Boland GJ, Pennings JL, et al. Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials. PLoS One 2014; 9:e98175.

93. Centers for Disease Control and Prevention (CDC). Syncope after vaccination--United States, January 2005-July 2007. MMWR Morb Mortal Wkly Rep 2008; 57:457.

94. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/fully-vaccinated-guidance.html#anchor_1619526673330 (Accessed on July 29, 2021).

95. Brown CM, Vostok J, Johnson H, et al. Outbreak of SARS-CoV-2 Infections, Including COVID-19 Vaccine Breakthrough Infections, Associated with Large Public Gatherings - Barnstable County, Massachusetts, July 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1059.

96. Maayan H, Kirgner I, Gutwein O, et al. Acquired thrombotic thrombocytopenic purpura: A rare disease associated with BNT162b2 vaccine. J Thromb Haemost 2021; 19:2314.

97. Matheny M, Maleque N, Channell N, et al. Severe Exacerbations of Systemic Capillary Leak Syndrome After COVID-19 Vaccination: A Case Series. Ann Intern Med 2021; 174:1476.

98. American Society of Hematology. Thrombosis with Thrombocytopenia Syndrome (also termed Vaccine-induced Thrombotic Thrombocytopenia). https://www.hematology.org/covid-19/vaccine-induced-immune-thrombotic-thrombocytopenia (Accessed on April 24, 2021).

99. Blumenthal KG, Freeman EE, Saff RR, et al. Delayed Large Local Reactions to mRNA-1273 Vaccine against SARS-CoV-2. N Engl J Med 2021; 384:1273.

100. Blumenthal KG, Saff RR, Freeman EE. Delayed Large Local Reactions to mRNA Vaccines. Reply. N Engl J Med 2021; 384:e98.

101. Casajuana J, Iglesias B, Fàbregas M, et al. Safety of intramuscular influenza vaccine in patients receiving oral anticoagulation therapy: a single blinded multi-centre randomized controlled clinical trial. BMC Blood Disord 2008; 8:1.

102. Banerji A, Wickner PG, Saff R, et al. mRNA Vaccines to Prevent COVID-19 Disease and Reported Allergic Reactions: Current Evidence and Suggested Approach. J Allergy Clin Immunol Pract 2021; 9:1423.

103. Shimabukuro T. COVID-19 vaccine safety update, Advisory Committee on Immunization Practices (ACIP) meeting, January 27, 2021. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-01/06-COVID-Shimabukuro.pdf (Accessed on January 28, 2021).

104. Shimabukuro T. Allergic reactions including anaphylaxis after receipt of the first dose of Moderna COVID-19 vaccine - United States, December 21, 2020-January 10, 2021. Am J Transplant 2021; 21:1326.

105. Gee J, Marquez P, Su J, et al. First Month of COVID-19 Vaccine Safety Monitoring - United States, December 14, 2020-January 13, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:283.

106. Government of Canada National Advisory Committee on Immunization. NACI rapid response: Interchangeability of authorized COVID-19 vaccines. https://www.canada.ca/en/public-health/services/immunization/national-advisory-committee-on-immunization-naci/recommendations-use-covid-19-vaccines/rapid-response-interchangeability.html (Accessed on June 25, 2021).

107. Behrens GM, Cossmann A, Stankov MV, et al. SARS-CoV-2 delta variant neutralisation after heterologous ChAdOx1-S/BNT162b2 vaccination. Lancet 2021; 398:1041.

108. Liu X, Shaw RH, Stuart ASV, et al. Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial. Lancet 2021; 398:856.

109. United Kingdom Department of Health and Social Care. Joint Committee on Vaccination and Immunisation: advice on priority groups for COVID-19 vaccination. https://www.gov.uk/government/publications/priority-groups-for-coronavirus-covid-19-vaccination-advice-from-the-jcvi-30-december-2020/joint-committee-on-vaccination-and-immunisation-advice-on-priority-groups-for-covid-19-vaccination-30-december-2020 (Accessed on January 04, 2021).

110. United Kingdom Medicines and Healthcare products Regulatory Agency. UK medicines regulator gives approval for first UK COVID-19 vaccine. https://www.gov.uk/government/news/uk-medicines-regulator-gives-approval-for-first-uk-covid-19-vaccine (Accessed on December 02, 2020).

111. Canada. Pfizer-BioNTech COVID-19 vaccine: Authorization information. https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry/drugs-vaccines-treatments/vaccines/pfizer-biontech/authorization.html (Accessed on December 09, 2020).

112. European Medicines Agency. EMA recommends first COVID-19 vaccine for authorisation in the EU. https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu (Accessed on January 04, 2021).

113. Walsh EE, Frenck RW Jr, Falsey AR, et al. Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med 2020; 383:2439.

114. Frenck RW Jr, Klein NP, Kitchin N, et al. Safety, Immunogenicity, and Efficacy of the BNT162b2 Covid-19 Vaccine in Adolescents. N Engl J Med 2021; 385:239.

115. US FDA. Emergency Use Authorization (EUA) of the Pfizer-BioNTech COVID-19 vaccine to prevent coronavirus disease 2019 (COVID-19) for 5 through 11 years of age. https://www.fda.gov/media/153714/download (Accessed on November 02, 2021).

116. Zhou D, Dejnirattisai W, Supasa P, et al. Evidence of escape of SARS-CoV-2 variant B.1.351 from natural and vaccine-induced sera. Cell 2021; 184:2348.

117. Wall EC, Wu M, Harvey R, et al. Neutralising antibody activity against SARS-CoV-2 VOCs B.1.617.2 and B.1.351 by BNT162b2 vaccination. Lancet 2021; 397:2331.

118. Planas D, Veyer D, Baidaliuk A, et al. Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization. Nature 2021; 596:276.

119. Tada T, Dcosta BM, Samanovic MI, et al. Convalescent-Phase Sera and Vaccine-Elicited Antibodies Largely Maintain Neutralizing Titer against Global SARS-CoV-2 Variant Spikes. mBio 2021; 12:e0069621.

120. Edara VV, Pinsky BA, Suthar MS, et al. Infection and Vaccine-Induced Neutralizing-Antibody Responses to the SARS-CoV-2 B.1.617 Variants. N Engl J Med 2021; 385:664.

121. Levin EG, Lustig Y, Cohen C, et al. Waning Immune Humoral Response to BNT162b2 Covid-19 Vaccine over 6 Months. N Engl J Med 2021.

122. FDA Briefing Document. Pfizer-BioNTech COVID-19 Vaccine. Vaccines and Related Biological Products Advisory Committee Meeting. December 10, 2020 https://www.fda.gov/media/144245/download (Accessed on December 09, 2020).

123. Polack FP, Thomas SJ, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med 2020; 383:2603.

124. Haas EJ, Angulo FJ, McLaughlin JM, et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet 2021; 397:1819.

125. Vasileiou E, Simpson CR, Shi T, et al. Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study. Lancet 2021; 397:1646.

126. Dagan N, Barda N, Kepten E, et al. BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting. N Engl J Med 2021; 384:1412.

127. Hall VJ, Foulkes S, Saei A, et al. COVID-19 vaccine coverage in health-care workers in England and effectiveness of BNT162b2 mRNA vaccine against infection (SIREN): a prospective, multicentre, cohort study. Lancet 2021; 397:1725.

128. Amit S, Regev-Yochay G, Afek A, et al. Early rate reductions of SARS-CoV-2 infection and COVID-19 in BNT162b2 vaccine recipients. Lancet 2021; 397:875.

129. Rinott E, Youngster I, Lewis YE. Reduction in COVID-19 Patients Requiring Mechanical Ventilation Following Implementation of a National COVID-19 Vaccination Program - Israel, December 2020-February 2021. MMWR Morb Mortal Wkly Rep 2021; 70:326.

130. Britton A, Jacobs Slifka KM, Edens C, et al. Effectiveness of the Pfizer-BioNTech COVID-19 Vaccine Among Residents of Two Skilled Nursing Facilities Experiencing COVID-19 Outbreaks - Connecticut, December 2020-February 2021. MMWR Morb Mortal Wkly Rep 2021; 70:396.

131. Benenson S, Oster Y, Cohen MJ, Nir-Paz R. BNT162b2 mRNA Covid-19 Vaccine Effectiveness among Health Care Workers. N Engl J Med 2021; 384:1775.

132. Tenforde MW, Olson SM, Self WH, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥65 Years - United States, January-March 2021. MMWR Morb Mortal Wkly Rep 2021; 70:674.

133. Butt AA, Omer SB, Yan P, et al. SARS-CoV-2 Vaccine Effectiveness in a High-Risk National Population in a Real-World Setting. Ann Intern Med 2021; 174:1404.

134. Chodick G, Tene L, Patalon T, et al. Assessment of Effectiveness of 1 Dose of BNT162b2 Vaccine for SARS-CoV-2 Infection 13 to 24 Days After Immunization. JAMA Netw Open 2021; 4:e2115985.

135. Chung H, He S, Nasreen S, et al. Effectiveness of BNT162b2 and mRNA-1273 covid-19 vaccines against symptomatic SARS-CoV-2 infection and severe covid-19 outcomes in Ontario, Canada: test negative design study. BMJ 2021; 374:n1943.

136. Reis BY, Barda N, Leshchinsky M, et al. Effectiveness of BNT162b2 Vaccine against Delta Variant in Adolescents. N Engl J Med 2021.

137. Olson SM, Newhams MM, Halasa NB, et al. Effectiveness of Pfizer-BioNTech mRNA Vaccination Against COVID-19 Hospitalization Among Persons Aged 12-18 Years - United States, June-September 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1483.

138. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant. N Engl J Med 2021; 385:585.

139. https://www.gov.il/en/departments/news/06072021-04 (Accessed on July 29, 2021).

140. Thomas SJ, Moreira ED Jr, Kitchin N, et al. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine through 6 Months. N Engl J Med 2021.

141. CDC COVID-19 Response Team, Food and Drug Administration. Allergic Reactions Including Anaphylaxis After Receipt of the First Dose of Pfizer-BioNTech COVID-19 Vaccine - United States, December 14-23, 2020. MMWR Morb Mortal Wkly Rep 2021; 70:46.

142. Klein NP, Lewis N, Goddard K, et al. Surveillance for Adverse Events After COVID-19 mRNA Vaccination. JAMA 2021; 326:1390.

143. Centers for Disease Control and Prevention. Thrombosis with thrombocytopenia syndrome (TTS) following Janssen COVID-19 vaccine. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-04-23/03-COVID-Shimabukuro-508.pdf (Accessed on April 23, 2021).

144. Barda N, Dagan N, Ben-Shlomo Y, et al. Safety of the BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting. N Engl J Med 2021; 385:1078.

145. European Medicines Agency. EMA recommends COVID-19 Vaccine Moderna for authorisation in the EU. https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu (Accessed on January 06, 2021).

146. Jackson LA, Anderson EJ, Rouphael NG, et al. An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med 2020; 383:1920.

147. Anderson EJ, Rouphael NG, Widge AT, et al. Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults. N Engl J Med 2020; 383:2427.

148. Doria-Rose N, Suthar MS, Makowski M, et al. Antibody Persistence through 6 Months after the Second Dose of mRNA-1273 Vaccine for Covid-19. N Engl J Med 2021; 384:2259.

149. Ali K, Berman G, Zhou H, et al. Evaluation of mRNA-1273 SARS-CoV-2 Vaccine in Adolescents. N Engl J Med 2021.

150. Steensels D, Pierlet N, Penders J, et al. Comparison of SARS-CoV-2 Antibody Response Following Vaccination With BNT162b2 and mRNA-1273. JAMA 2021; 326:1533.

151. Richards NE, Keshavarz B, Workman LJ, et al. Comparison of SARS-CoV-2 Antibody Response by Age Among Recipients of the BNT162b2 vs the mRNA-1273 Vaccine. JAMA Netw Open 2021; 4:e2124331.

152. Wu K, Werner AP, Koch M, et al. Serum Neutralizing Activity Elicited by mRNA-1273 Vaccine. N Engl J Med 2021; 384:1468.

153. Shen X, Tang H, Pajon R, et al. Neutralization of SARS-CoV-2 Variants B.1.429 and B.1.351. N Engl J Med 2021; 384:2352.

154. Baden LR, El Sahly HM, Essink B, et al. Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med 2021; 384:403.

155. El Sahly HM, Baden LR, Essink B, et al. Efficacy of the mRNA-1273 SARS-CoV-2 Vaccine at Completion of Blinded Phase. N Engl J Med 2021.

156. Pilishvili T, Fleming-Dutra KE, Farrar JL, et al. Interim Estimates of Vaccine Effectiveness of Pfizer-BioNTech and Moderna COVID-19 Vaccines Among Health Care Personnel - 33 U.S. Sites, January-March 2021. MMWR Morb Mortal Wkly Rep 2021; 70:753.

157. Thompson MG, Burgess JL, Naleway AL, et al. Prevention and Attenuation of Covid-19 with the BNT162b2 and mRNA-1273 Vaccines. N Engl J Med 2021; 385:320.

158. Pilishvili T, Gierke R, Fleming-Dutra KE, et al. Effectiveness of mRNA Covid-19 Vaccine among U.S. Health Care Personnel. N Engl J Med 2021.

159. FDA Briefing Document. Moderna COVID-19 Vaccine. https://www.fda.gov/media/144434/download (Accessed on December 16, 2020).

160. Sangli S, Virani A, Cheronis N, et al. Thrombosis With Thrombocytopenia After the Messenger RNA-1273 Vaccine. Ann Intern Med 2021; 174:1480.

161. Sadoff J, Le Gars M, Shukarev G, et al. Interim Results of a Phase 1-2a Trial of Ad26.COV2.S Covid-19 Vaccine. N Engl J Med 2021; 384:1824.

162. Stephenson KE, Le Gars M, Sadoff J, et al. Immunogenicity of the Ad26.COV2.S Vaccine for COVID-19. JAMA 2021; 325:1535.

163. Barouch DH, Stephenson KE, Sadoff J, et al. Durable Humoral and Cellular Immune Responses 8 Months after Ad26.COV2.S Vaccination. N Engl J Med 2021; 385:951.

164. Collier AY, Yu J, McMahan K, et al. Differential Kinetics of Immune Responses Elicited by Covid-19 Vaccines. N Engl J Med 2021.

165. Barouch DH, Kik SV, Weverling GJ, et al. International seroepidemiology of adenovirus serotypes 5, 26, 35, and 48 in pediatric and adult populations. Vaccine 2011; 29:5203.

166. Sadoff J, Gray G, Vandebosch A, et al. Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19. N Engl J Med 2021; 384:2187.

167. Falsey AR, Sobieszczyk ME, Hirsch I, et al. Phase 3 Safety and Efficacy of AZD1222 (ChAdOx1 nCoV-19) Covid-19 Vaccine. N Engl J Med 2021.

168. https://www.jnj.com/johnson-johnson-announces-real-world-evidence-and-phase-3-data-confirming-strong-and-long-lasting-protection-of-single-shot-covid-19-vaccine-in-the-u-s (Accessed on September 22, 2021).

169. Shay DK, Gee J, Su JR, et al. Safety Monitoring of the Janssen (Johnson & Johnson) COVID-19 Vaccine - United States, March-April 2021. MMWR Morb Mortal Wkly Rep 2021; 70:680.

170. Hause AM, Gee J, Johnson T, et al. Anxiety-Related Adverse Event Clusters After Janssen COVID-19 Vaccination - Five U.S. Mass Vaccination Sites, April 2021. MMWR Morb Mortal Wkly Rep 2021; 70:685.

171. Takuva S, Takalani A, Garrett N, et al. Thromboembolic Events in the South African Ad26.COV2.S Vaccine Study. N Engl J Med 2021; 385:570.

172. World Health Organization. Interim recommendations for use of the AZD1222 (ChAdOx1-S (recombinant)) vaccine against COVID-19 developed by Oxford University and AstraZeneca. https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-AZD1222-2021.1 (Accessed on February 11, 2021).

173. Folegatti PM, Ewer KJ, Aley PK, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 2020; 396:467.

174. Flaxman A, Marchevsky NG, Jenkin D, et al. Reactogenicity and immunogenicity after a late second dose or a third dose of ChAdOx1 nCoV-19 in the UK: a substudy of two randomised controlled trials (COV001 and COV002). Lancet 2021.

175. Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet 2021; 396:1979.

176. Wall EC, Wu M, Harvey R, et al. AZD1222-induced neutralising antibody activity against SARS-CoV-2 Delta VOC. Lancet 2021; 398:207.

177. Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet 2021; 397:99.

178. Voysey M, Costa Clemens SA, Madhi SA, et al. Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials. Lancet 2021; 397:881.

179. AstraZeneca. AZD1222 US Phase III primary analysis confirms safety and efficacy. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2021/azd1222-us-phase-iii-primary-analysis-confirms-safety-and-efficacy.html (Accessed on March 28, 2021).

180. Lopez Bernal J, Andrews N, Gower C, et al. Effectiveness of the Pfizer-BioNTech and Oxford-AstraZeneca vaccines on covid-19 related symptoms, hospital admissions, and mortality in older adults in England: test negative case-control study. BMJ 2021; 373:n1088.

181. Zhu FC, Guan XH, Li YH, et al. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2020; 396:479.

182. Buchbinder SP, McElrath MJ, Dieffenbach C, Corey L. Use of adenovirus type-5 vectored vaccines: a cautionary tale. Lancet 2020; 396:e68.

183. Baraniuk C. What do we know about China's covid-19 vaccines? BMJ 2021; 373:n912.

184. Sputnik Vaccine. The Gamaleya Center statement on increasing the interval between the first and second Sputnik V vaccine shots. https://sputnikvaccine.com/newsroom/pressreleases/the-gamaleya-center-statement-on-increasing-the-interval-between-first-and-second-sputnik-v-vaccine-/ (Accessed on May 06, 2021).

185. Logunov DY, Dolzhikova IV, Zubkova OV, et al. Safety and immunogenicity of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine in two formulations: two open, non-randomised phase 1/2 studies from Russia. Lancet 2020; 396:887.

186. Xia S, Duan K, Zhang Y, et al. Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA 2020; 324:951.

187. Xia S, Zhang Y, Wang Y, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBIBP-CorV: a randomised, double-blind, placebo-controlled, phase 1/2 trial. Lancet Infect Dis 2021; 21:39.

188. Wang GL, Wang ZY, Duan LJ, et al. Susceptibility of Circulating SARS-CoV-2 Variants to Neutralization. N Engl J Med 2021; 384:2354.

189. Al Kaabi N, Zhang Y, Xia S, et al. Effect of 2 Inactivated SARS-CoV-2 Vaccines on Symptomatic COVID-19 Infection in Adults: A Randomized Clinical Trial. JAMA 2021; 326:35.

190. Zhang Y, Zeng G, Pan H, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis 2021; 21:181.

191. US Food and Drug Administration. Emergency use authorization for vaccines to prevent COVID-19: Guidance for industry. February 2021. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-vaccines-prevent-covid-19.

192. Tanriover MD, Doğanay HL, Akova M, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet 2021; 398:213.

193. Jara A, Undurraga EA, González C, et al. Effectiveness of an Inactivated SARS-CoV-2 Vaccine in Chile. N Engl J Med 2021; 385:875.

194. Ranzani OT, Hitchings MDT, Dorion M, et al. Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study. BMJ 2021; 374:n2015.

195. Ella R, Vadrevu KM, Jogdand H, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine, BBV152: a double-blind, randomised, phase 1 trial. Lancet Infect Dis 2021; 21:637.

196. Yadav PD, Sapkal GN, Abraham P, et al. Neutralization of variant under investigation B.1.617 with sera of BBV152 vaccinees. Clin Infect Dis 2021.

197. Bharat Biotech. Bharat Biotech Announces Phase 3 Results of COVAXIN: India's First COVID-19 Vaccine Demonstrates Interim Clinical Efficacy of 81%. https://www.bharatbiotech.com/images/press/covaxin-phase3-efficacy-results.pdf (Accessed on May 06, 2021).

198. Mallapaty S. India's DNA COVID vaccine is a world first - more are coming. Nature 2021; 597:161.

199. Novavax. Novavax COVID-19 Vaccine Demonstrates 90% Overall Efficacy and 100% Protection Against Moderate and Severe Disease in PREVENT-19 Phase 3 Trial. https://ir.novavax.com/2021-06-14-Novavax-COVID-19-Vaccine-Demonstrates-90-Overall-Efficacy-and-100-Protection-Against-Moderate-and-Severe-Disease-in-PREVENT-19-Phase-3-Trial (Accessed on June 25, 2021).

200. Heath PT, Galiza EP, Baxter DN, et al. Safety and Efficacy of NVX-CoV2373 Covid-19 Vaccine. N Engl J Med 2021; 385:1172.

201. CDC COVID-19 Vaccine Breakthrough Case Investigations Team. COVID-19 Vaccine Breakthrough Infections Reported to CDC - United States, January 1-April 30, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:792.

202. Teran RA, Walblay KA, Shane EL, et al. Postvaccination SARS-CoV-2 Infections Among Skilled Nursing Facility Residents and Staff Members - Chicago, Illinois, December 2020-March 2021. MMWR Morb Mortal Wkly Rep 2021; 70:632.

203. Olsen RJ, Christensen PA, Long SW, et al. Trajectory of Growth of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Variants in Houston, Texas, January through May 2021, Based on 12,476 Genome Sequences. Am J Pathol 2021; 191:1754.

204. Hagan LM, McCormick DW, Lee C, et al. Outbreak of SARS-CoV-2 B.1.617.2 (Delta) Variant Infections Among Incarcerated Persons in a Federal Prison - Texas, July-August 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1349.

205. Bergwerk M, Gonen T, Lustig Y, et al. Covid-19 Breakthrough Infections in Vaccinated Health Care Workers. N Engl J Med 2021; 385:1474.

206. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect Dis 2021.

207. Singanayagam A, Hakki S, Dunning K, et al. Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study. Lancet Infect Dis 2021.

208. Pouwels KB, Pritchard E, Matthews PC, et al. Impact of Delta on viral burden and vaccine effectiveness against new SARS-CoV-2 infections in the UK. UNPUBLISHED. https://www.medrxiv.org/content/10.1101/2021.08.18.21262237v1.full.pdf (Accessed on September 03, 2021).

209. Chia PY, Ong SWX, Chiew CJ, et al. Virological and serological kinetics of SARS-CoV-2 Delta variant vaccine-breakthrough infections: a multi-center cohort study. UNPUBLISHED. https://www.medrxiv.org/content/10.1101/2021.07.28.21261295v1 (Accessed on September 03, 2021).

210. Griffin JB, Haddix M, Danza P, et al. SARS-CoV-2 Infections and Hospitalizations Among Persons Aged ≥16 Years, by Vaccination Status - Los Angeles County, California, May 1-July 25, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1170.

211. Levine-Tiefenbrun M, Yelin I, Katz R, et al. Initial report of decreased SARS-CoV-2 viral load after inoculation with the BNT162b2 vaccine. Nat Med 2021; 27:790.

212. Harris RJ, Hall JA, Zaidi A, et al. Effect of Vaccination on Household Transmission of SARS-CoV-2 in England. N Engl J Med 2021; 385:759.

213. Shah ASV, Gribben C, Bishop J, et al. Effect of Vaccination on Transmission of SARS-CoV-2. N Engl J Med 2021; 385:1718.

214. Nasreen S, He S, Chung H, et al. Effectiveness of COVID-19 vaccines against variants of concern. UNPUBLISHED. https://www.medrxiv.org/content/10.1101/2021.06.28.21259420v1 (Accessed on July 23, 2021).

215. Sheikh A, McMenamin J, Taylor B, et al. SARS-CoV-2 Delta VOC in Scotland: demographics, risk of hospital admission, and vaccine effectiveness. Lancet 2021; 397:2461.

216. Keehner J, Horton LE, Binkin NJ, et al. Resurgence of SARS-CoV-2 Infection in a Highly Vaccinated Health System Workforce. N Engl J Med 2021; 385:1330.

217. Fowlkes A, Gaglani M, Groover K, et al. Effectiveness of COVID-19 Vaccines in Preventing SARS-CoV-2 Infection Among Frontline Workers Before and During B.1.617.2 (Delta) Variant Predominance - Eight U.S. Locations, December 2020-August 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1167.

218. https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/1005085/Vaccine_surveillance_report_-_week_29.pdf (Accessed on July 23, 2021).

219. Rosenberg ES, Holtgrave DR, Dorabawila V, et al. New COVID-19 Cases and Hospitalizations Among Adults, by Vaccination Status - New York, May 3-July 25, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1150.

220. Scobie HM, Johnson AG, Suthar AB, et al. Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status - 13 U.S. Jurisdictions, April 4-July 17, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1284.

221. Bajema KL, Dahl RM, Prill MM, et al. Effectiveness of COVID-19 mRNA Vaccines Against COVID-19-Associated Hospitalization - Five Veterans Affairs Medical Centers, United States, February 1-August 6, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1294.

222. Sheikh A, Robertson C, Taylor B. BNT162b2 and ChAdOx1 nCoV-19 Vaccine Effectiveness against Death from the Delta Variant. N Engl J Med 2021.

223. Abu-Raddad LJ, Chemaitelly H, Butt AA, National Study Group for COVID-19 Vaccination. Effectiveness of the BNT162b2 Covid-19 Vaccine against the B.1.1.7 and B.1.351 Variants. N Engl J Med 2021; 385:187.

224. Madhi SA, Baillie V, Cutland CL, et al. Efficacy of the ChAdOx1 nCoV-19 Covid-19 Vaccine against the B.1.351 Variant. N Engl J Med 2021; 384:1885.

225. Cavanaugh AM, Fortier S, Lewis P, et al. COVID-19 Outbreak Associated with a SARS-CoV-2 R.1 Lineage Variant in a Skilled Nursing Facility After Vaccination Program - Kentucky, March 2021. MMWR Morb Mortal Wkly Rep 2021; 70:639.

226. Hacisuleyman E, Hale C, Saito Y, et al. Vaccine Breakthrough Infections with SARS-CoV-2 Variants. N Engl J Med 2021; 384:2212.

227. Joint Statement from HHS Public Health and Medical Experts on COVID-19 Booster Shots. https://www.cdc.gov/media/releases/2021/s0818-covid-19-booster-shots.html (Accessed on August 20, 2021).

228. Nanduri S, Pilishvili T, Derado G, et al. Effectiveness of Pfizer-BioNTech and Moderna Vaccines in Preventing SARS-CoV-2 Infection Among Nursing Home Residents Before and During Widespread Circulation of the SARS-CoV-2 B.1.617.2 (Delta) Variant - National Healthcare Safety Network, March 1-August 1, 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1163.

229. Chemaitelly H, Tang P, Hasan MR, et al. Waning of BNT162b2 Vaccine Protection against SARS-CoV-2 Infection in Qatar. N Engl J Med 2021.

230. Tartof SY, Slezak JM, Fischer H, et al. Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study. Lancet 2021; 398:1407.

231. Tenforde MW, Self WH, Naioti EA, et al. Sustained Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Associated Hospitalizations Among Adults - United States, March-July 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1156.

232. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-09-22/04-COVID-Link-Gelles-508.pdf (Accessed on September 22, 2021).

233. Goldberg Y, Mandel M, Bar-On YM, et al. Waning Immunity after the BNT162b2 Vaccine in Israel. N Engl J Med 2021.

234. Bar-On YM, Goldberg Y, Mandel M, et al. Protection of BNT162b2 Vaccine Booster against Covid-19 in Israel. N Engl J Med 2021; 385:1393.

235. Barda N, Dagan N, Cohen C, et al.. Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for preventing severe outcomes in Israel: an observational study. Lancet 2021.

236. Moderna Announces Positive Initial Booster Data Against SARS-CoV-2 Variants of Concern https://investors.modernatx.com/news-releases/news-release-details/moderna-announces-positive-initial-booster-data-against-sars-cov/ (Accessed on May 06, 2021).

237. Falsey AR, Frenck RW Jr, Walsh EE, et al. SARS-CoV-2 Neutralization with BNT162b2 Vaccine Dose 3. N Engl J Med 2021; 385:1627.

238. FDA Briefing Document. Application for licensure of a booster dose for COMIRNATY (COVID-19 Vaccine, mRNA). Vaccines and Related Biological Products Advisory Committee Meeting, September 17, 2021. https://www.fda.gov/media/152176/download (Accessed on September 22, 2021).

239. Safety and Immunogenicity of a 50 µg Booster Dose of mRNA-1273 (Moderna COVID-19 Vaccine). Presented at the Vaccines and Related Biological Products Advisory Committee October 14-15, 2021 Meeting Presentation. https://www.fda.gov/media/153089/download (Accessed on October 21, 2021).

240. FDA Review of Effectiveness and Safety of Janssen COVID-19 Vaccine (Ad26.COV2.S) Booster Dose . Presented at the Vaccines and Related Biological Products Advisory Committee October 14-15, 2021 Meeting Presentation Meeting https://www.fda.gov/media/153130/download (Accessed on October 21, 2021).

241. Updated GTH statement on vaccination with the AstraZeneca COVID-19 vaccine, as of March 22, 2021. https://gth-online.org/wp-content/uploads/2021/03/GTH_Stellungnahme_AstraZeneca_engl._3_22_2021.pdf (Accessed on March 28, 2021).

242. Pai M, Grill A, Ivers A, et al. Vaccine-Induced Prothrombotic Immune Thrombocytopenia (VIPIT) Following AstraZeneca COVID-19 Vaccination. https://covid19-sciencetable.ca/sciencebrief/vaccine-induced-prothrombotic-immune-thrombocytopenia-vipit-following-astrazeneca-covid-19-vaccination/ (Accessed on March 31, 2021).

243. Schultz NH, Sørvoll IH, Michelsen AE, et al. Thrombosis and Thrombocytopenia after ChAdOx1 nCoV-19 Vaccination. N Engl J Med 2021; 384:2124.

244. Greinacher A, Thiele T, Warkentin TE, et al. Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med 2021; 384:2092.

245. Muir KL, Kallam A, Koepsell SA, Gundabolu K. Thrombotic Thrombocytopenia after Ad26.COV2.S Vaccination. N Engl J Med 2021; 384:1964.

246. See I, Su JR, Lale A, et al. US Case Reports of Cerebral Venous Sinus Thrombosis With Thrombocytopenia After Ad26.COV2.S Vaccination, March 2 to April 21, 2021. JAMA 2021; 325:2448.

247. Pavord S, Scully M, Hunt BJ, et al. Clinical Features of Vaccine-Induced Immune Thrombocytopenia and Thrombosis. N Engl J Med 2021; 385:1680.

248. Rosenblum HG, Hadler SC, Moulia D, et al. Use of COVID-19 Vaccines After Reports of Adverse Events Among Adult Recipients of Janssen (Johnson & Johnson) and mRNA COVID-19 Vaccines (Pfizer-BioNTech and Moderna): Update from the Advisory Committee on Immunization Practices - United States, July 2021. MMWR Morb Mortal Wkly Rep 2021; 70:1094.

249. MacNeil JR, Su JR, Broder KR, et al. Updated Recommendations from the Advisory Committee on Immunization Practices for Use of the Janssen (Johnson & Johnson) COVID-19 Vaccine After Reports of Thrombosis with Thrombocytopenia Syndrome Among Vaccine Recipients - United States, April 2021. MMWR Morb Mortal Wkly Rep 2021; 70:651.

250. European Medicines Agency. COVID-19 Vaccine Janssen: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. https://www.ema.europa.eu/en/news/covid-19-vaccine-janssen-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood (Accessed on May 10, 2021).

251. European Medicines Agency. AstraZeneca's COVID-19 vaccine: EMA finds possible link to very rare cases of unusual blood clots with low blood platelets. https://www.ema.europa.eu/en/news/astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-blood-clots-low-blood (Accessed on April 07, 2021).

252. European Medicines Agency. https://www.ema.europa.eu/en/news/covid-19-vaccine-astrazeneca-benefits-still-outweigh-risks-despite-possible-link-rare-blood-clots (Accessed on March 18, 2021).

253. Pottegård A, Lund LC, Karlstad Ø, et al. Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study. BMJ 2021; 373:n1114.

254. https://www.ema.europa.eu/en/news/meeting-highlights-pharmacovigilance-risk-assessment-committee-prac-3-6-may-2021 (Accessed on May 26, 2021).

255. Gargano JW, Wallace M, Hadler SC, et al. Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021. MMWR Morb Mortal Wkly Rep 2021; 70:977.

256. Mevorach D, Anis E, Cedar N, et al. Myocarditis after BNT162b2 mRNA Vaccine against Covid-19 in Israel. N Engl J Med 2021.

257. Witberg G, Barda N, Hoss S, et al. Myocarditis after Covid-19 Vaccination in a Large Health Care Organization. N Engl J Med 2021.

258. Verma AK, Lavine KJ, Lin CY. Myocarditis after Covid-19 mRNA Vaccination. N Engl J Med 2021; 385:1332.

259. Marshall M, Ferguson ID, Lewis P, et al. Symptomatic Acute Myocarditis in 7 Adolescents After Pfizer-BioNTech COVID-19 Vaccination. Pediatrics 2021; 148.

260. Montgomery J, Ryan M, Engler R, et al. Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military. JAMA Cardiol 2021; 6:1202.

261. Diaz GA, Parsons GT, Gering SK, et al. Myocarditis and Pericarditis After Vaccination for COVID-19. JAMA 2021; 326:1210.

262. fda.gov/news-events/press-announcements/coronavirus-covid-19-update-july-13-2021 (Accessed on July 15, 2021).

263. ema.europa.eu/en/documents/covid-19-vaccine-safety-update/covid-19-vaccine-safety-update-covid-19-vaccine-janssen-14-july-2021_en.pdf (Accessed on July 15, 2021).

264. Abu-Rumeileh S, Abdelhak A, Foschi M, et al. Guillain-Barré syndrome spectrum associated with COVID-19: an up-to-date systematic review of 73 cases. J Neurol 2021; 268:1133.

265. McDonnell EP, Altomare NJ, Parekh YH, et al. COVID-19 as a Trigger of Recurrent Guillain-Barré Syndrome. Pathogens 2020; 9.

266. Woo EJ, Mba-Jonas A, Dimova RB, et al. Association of Receipt of the Ad26.COV2.S COVID-19 Vaccine With Presumptive Guillain-Barré Syndrome, February-July 2021. JAMA 2021; 326:1606.

267. Allen CM, Ramsamy S, Tarr AW, et al. Guillain-Barré Syndrome Variant Occurring after SARS-CoV-2 Vaccination. Ann Neurol 2021; 90:315.

268. Maramattom BV, Krishnan P, Paul R, et al. Guillain-Barré Syndrome following ChAdOx1-S/nCoV-19 Vaccine. Ann Neurol 2021; 90:312.

269. US Food and Drug Administration. Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry. https://www.fda.gov/media/139638/download (Accessed on October 20, 2020).

270. WHO Target Product Profiles for COVID-19 Vaccines. April 2020. https://www.who.int/publications/m/item/who-target-product-profiles-for-covid-19-vaccines (Accessed on November 06, 2020).

271. Goodman JL, Grabenstein JD, Braun MM. Answering Key Questions About COVID-19 Vaccines. JAMA 2020; 324:2027.

272. US Food and Drug Administration. Emergency Use Authorization for Vaccines to Prevent COVID-19: Guidance for Industry. October 2020. https://www.fda.gov/media/142749/download (Accessed on November 05, 2020).

273. National Academies of Sciences, Engineering, and Medicine. 2020. Framework for Equitable Allocation of COVID-19 Vaccine. Washington, DC: The National Academies Press. https://www.nap.edu/catalog/25917/framework-for-equitable-allocation-of-covid-19-vaccine (Accessed on November 12, 2020).

274. Centers for Disease Control and Prevention. How CDC Is Making COVID-19 Vaccine Recommendations. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/recommendations-process.html (Accessed on November 12, 2020).

275. WHO Strategic Advisory Group of Experts (SAGE) on Immunization. COVID-19 vaccines: Key documents. https://www.who.int/immunization/sage/covid-19_documents/en/ (Accessed on November 12, 2020).

276. United States Department of Health and Human Services. From the Factory to the Frontlines: The Operation Warp Speed Strategy for Distributing a COVID-19 Vaccine. https://www.hhs.gov/sites/default/files/strategy-for-distributing-covid-19-vaccine.pdf (Accessed on November 18, 2020).

277. Centers for Disease Control and Prevention. Frequently Asked Questions about COVID-19 Vaccination. https://www.cdc.gov/coronavirus/2019-ncov/vaccines/faq.html (Accessed on November 18, 2020).

278. World Health Organization. Ten threats to global health in 2019. https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019 (Accessed on November 12, 2020).

279. https://www.vitaltalk.org/wp-content/uploads/Communication-skills-for-the-COVID-vaccine_v1.2-1.pdf (Accessed on January 21, 2021).

280. Centers for Disease Control and Prevention. Talking to Recipients about COVID-19 Vaccines. https://www.cdc.gov/vaccines/covid-19/hcp/index.html (Accessed on January 21, 2021).

281. Lazarus JV, Ratzan SC, Palayew A, et al. A global survey of potential acceptance of a COVID-19 vaccine. Nat Med 2021; 27:225.

282. Nguyen KH, Srivastav A, Razzaghi H, et al. COVID-19 Vaccination Intent, Perceptions, and Reasons for Not Vaccinating Among Groups Prioritized for Early Vaccination - United States, September and December 2020. MMWR Morb Mortal Wkly Rep 2021; 70:217.

283. Daly M, Jones A, Robinson E. Public Trust and Willingness to Vaccinate Against COVID-19 in the US From October 14, 2020, to March 29, 2021. JAMA 2021; 325:2397.

284. Szilagyi PG, Thomas K, Shah MD, et al. National Trends in the US Public's Likelihood of Getting a COVID-19 Vaccine-April 1 to December 8, 2020. JAMA 2020.

285. Gadoth A, Halbrook M, Martin-Blais R, et al. Cross-sectional Assessment of COVID-19 Vaccine Acceptance Among Health Care Workers in Los Angeles. Ann Intern Med 2021; 174:882.

286. Shaw J, Stewart T, Anderson KB, et al. Assessment of U.S. health care personnel (HCP) attitudes towards COVID-19 vaccination in a large university health care system. Clin Infect Dis 2021.

287. Fisher KA, Bloomstone SJ, Walder J, et al. Attitudes Toward a Potential SARS-CoV-2 Vaccine : A Survey of U.S. Adults. Ann Intern Med 2020; 173:964.

288. Centers for Disease Control and Prevention. Vaccine Safety Datalink (VSD). https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/vsd/index.html (Accessed on November 05, 2020).

289. McCarthy NL, Gee J, Weintraub E, et al. Monitoring vaccine safety using the Vaccine Safety Datalink: utilizing immunization registries for pandemic influenza. Vaccine 2011; 29:4891.

290. Yih WK, Lee GM, Lieu TA, et al. Surveillance for adverse events following receipt of pandemic 2009 H1N1 vaccine in the Post-Licensure Rapid Immunization Safety Monitoring (PRISM) System, 2009-2010. Am J Epidemiol 2012; 175:1120.

291. Lee GM, Romero JR, Bell BP. Postapproval Vaccine Safety Surveillance for COVID-19 Vaccines in the US. JAMA 2020; 324:1937.

292. Centers for Disease Control and Prevention. Enhanced safety monitoring for COVID-19 vaccines in early phase vaccination. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2020-09/COVID-03-Shimabukuro.pdf (Accessed on November 18, 2020).

293. Fine PEM, Mulholland K, Scott JA, Edmunds WJ. Community Protection. In: Plotkin's Vaccines, 7th, Plotkin SA, Orenstein WA, Offit PA, Edwards KM (Eds), Elsevier, 2018. p.1512.

294. Levine EM, Davey AS, Houstan AM. Legal Issues. In: Plotkin's Vaccines, 7th, Plotkin SA, Orenstein WA, Offit PA, Edwards KM (Eds), Elsevier, 2018. p.1601.

295. Health Resources and Services Administration. Countermeasures Injury Compensation Program. https://www.hrsa.gov/cicp (Accessed on November 20, 2020).

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COVID-19: Vaccines to prevent SARS-CoV-2 infection - UpToDate

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Vaccines to prevent SARS-CoV-2 infection are considered the most promising approach for curbing the pandemic and are being vigorously pursued. By the end of 2020, several vaccines had become available for use in different parts of the world, over 40 candidate vaccines were in human trials, and over 150 were in preclinical trials.

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Sí, ya se están utilizando varias vacunas. El primer programa de vacunación colectiva se puso en marcha a principios de diciembre de 2020 y el número de dosis vacunales administradas se actualiza aquí a diario. Se han administrado al menos 13 vacunas distintas (a través de cuatro plataformas).

El 31 de diciembre de 2020, la OMS dio luz verde a la inclusión en la Lista para uso en emergencias (EUL, por sus siglas en inglés) de la vacuna Comirnaty de Pfizer/BioNTech. El 15 de febrero incluyó también en esa lista la vacuna Covishield del SII y la vacuna AZD1222 AstraZeneca (desarrolladas por AstraZeneca/Oxford y fabricadas por el Serum Institute de la India y SK Bio, respectivamente). Posteriormente, el 12 de marzo, aceptó la inclusión de la vacuna Janssen/Ad26.COV2.S desarrollada por Johnson & Johnson. El 30 de abril se añadió a la lista la vacuna mRNA-1273 de Moderna, y el 7 de mayo, la vacuna de Sinopharm. Que fabrica el Beijing Bio-Institute of Biological Products Co Ltd, una filial del China National Biotec Group (CNBG). Por último, el 1 de junio se autorizó el uso de emergencia de la vacuna CoronaVac de Sinovac.

Para más información, véase el siguiente enlace.

Durante el mes de junio, la OMS tiene previsto incluir otras vacunas en el protocolo de uso en emergencias.

La OMS informa con regularidad de los progresos realizados durante la evaluación del cumplimiento de la normativa legal de cada una de las vacunas. El documento se puede consultar en este enlace- en inglés.

Una vez que se demuestra que una vacuna es eficaz e inocua, debe recibir la autorización de los organismos nacionales de reglamentación, fabricarse de acuerdo con las normas más exigentes y distribuirse. La OMS está trabajando con asociados de todo el mundo para ayudar a coordinar las principales etapas de este proceso, de manera que, entre otras cosas, se facilite el acceso equitativo a vacunas contra la COVID-19 inocuas y eficaces para los miles de millones de personas que las necesitarán. Para más información sobre el desarrollo de vacunas contra la COVID-19, consúltese este enlace.

Están empezando a introducirse en los países las primeras vacunas contra la COVID-19. Antes de que estas puedan administrarse:

Es preciso demostrar que son seguras y eficaces mediante ensayos clínicos de gran envergadura, dentro de la fase III del desarrollo. Estos ensayos clínicos ya se han realizado para algunas vacunas, y se están desarrollando otras vacunas candidatas- en inglés.

Antes de que la OMS estudie una posible precalificación se deben efectuar una serie de exámenes independientes sobre eficacia y seguridad, en particular un examen del cumplimiento de la normativa legal y la autorización pertinente en el país de fabricación. Parte de este proceso incumbe también al Comité Consultivo Mundial sobre Seguridad de las Vacunas.

Además de la revisión de los datos con fines reglamentarios, las pruebas también deben revisarse a fin de formular recomendaciones normativas sobre el uso de las vacunas.

El Grupo de Expertos de Asesoramiento Estratégico sobre inmunización (SAGE), un comité de expertos externo- en inglés convocado por la OMS, analiza los resultados de los ensayos clínicos de cada vacuna, los datos probatorios sobre la enfermedad, los grupos de edad afectados, los factores de riesgo de enfermedad y otra información conexa. A continuación, recomienda si debe utilizarse la vacuna y de qué manera.

Los funcionarios de cada país deciden si procede aprobar las vacunas para su uso en el país y, sobre la base de las recomendaciones de la OMS, elaboran políticas relativas a la manera en que deben ser utilizadas.

Las vacunas se deben fabricar en grandes cantidades, lo que supondrá un reto importante y sin precedentes, dado que simultáneamente se seguirán fabricando todas las demás vacunas en uso, importantes para salvar vidas.

Por último, todas las vacunas aprobadas deberán distribuirse a través de un proceso logístico complejo, con pautas rigurosas para la gestión de existencias y el control de temperatura.

La OMS trabaja con asociados de todo el mundo con el fin de acelerar cada una de las fases de este proceso y, al mismo tiempo, vela por el cumplimiento de las máximas normas de seguridad. Para más información, pulse aquí.

El efecto de las vacunas contra la COVID-19 en la pandemia dependerá de varios factores. Algunos de esos factores son: la eficacia de las vacunas; la rapidez con que se autoricen, fabriquen y distribuyan las vacunas;el posible desarrollo de otras variantes y la manera en que se vacune a las personas.

La mayoría de los científicos prevén que, como en el caso de la mayor parte de las vacunas, las que se desarrollen contra la COVID-19 no tendrán una eficacia del 100%. La OMS trabaja para asegurar que toda vacuna aprobada tenga la máxima eficacia posible, de modo que consiga el mayor efecto en la pandemia.

Científicos de todo el mundo están desarrollando muchas posibles vacunas contra la COVID-19. Todas están diseñadas para enseñar al sistema inmunitario del organismo a reconocer y bloquear de manera segura el virus causante de la COVID-19.

Se están desarrollando diversos tipos de posibles vacunas contra la COVID-19, entre ellas:

Vacunas con virus inactivados o atenuados: utilizan un virus previamente inactivado o atenuado, de modo que no provoca la enfermedad, pero aún así genera una respuesta inmunitaria.

Vacunas basadas en proteínas: utilizan fragmentos inocuos de proteínas o estructuras proteínicas que imitan el virus causante de la COVID-19, con el fin de generar una respuesta inmunitaria.

Vacunas con vectores víricos: utilizan un virus genéticamente modificado que no causa la enfermedad, pero da lugar a proteínas coronavíricas que inducen una respuesta inmunitaria.

Vacunas con ARN y ADN: un enfoque pionero que utiliza ARN o ADN genéticamente modificados para generar una proteína que por sí sola desencadena una respuesta inmunitaria.

Para más información sobre todas las vacunas contra la COVID-19 en desarrollo, véase esta publicación de la OMS, que se actualiza periódicamente.

Las vacunas contra la COVID-19 son seguras para la mayoría de las personas mayores de 18 años,incluidas aquellas con afecciones preexistentes de cualquier tipo, incluidos los trastornos autoinmunitarios. Entre estas afecciones se incluyen la hipertensión, la diabetes, el asma, las enfermedades pulmonares, hepáticas y renales, y las infecciones crónicas estables y controladas.

En caso de que en su zona haya escasez de vacunas, comente su situación con su proveedor de atención de la salud si:

Tiene un sistema inmunitario debilitado

Está embarazada o amamantando

Tiene antecedentes de alergias graves, en concreto a alguna vacuna (o a cualquiera de los ingredientes de la vacuna)

Su estado de salud es muy frágil

La vacuna protege de enfermar gravemente y de morir a causa de la COVID-19. Durante los primeros 14 días después de la vacunación, el grado de protección adquirido no es significativo; después, aumenta gradualmente. Si la pauta de vacunación es de una sola dosis, la inmunidad suele adquirirse dos semanas después. En el caso de las pautas de dos dosis, es preciso administrar ambas para lograr el mayor grado de inmunidad posible.

Si bien las vacunas contra la COVID-19 protegen de enfermar gravemente y de fallecer por esta enfermedad, no sabemos hasta qué punto evitan la infección por el virus y su transmisión a otras personas. Los datos procedentes de países muestran que las vacunas actuales protegen de la enfermedad grave y la hospitalización. Sin embargo, ninguna vacuna protege en la práctica al 100%, por lo que, lamentablemente, se pueden dar infecciones en personas vacunadas.

Los datos actuales muestran que las vacunas ofrecen cierta protección contra la infección y la transmisión, pero menos que contra la enfermedad grave y la muerte. También seguimos acumulando datos sobre las variantes preocupantes y sobre la protección que confieren las vacunas contra estas cepas con respecto al virus no mutado. Por estas razones, mientras haya una parte de la población sin vacunar, es importante mantener las demás medidas de prevención, sobre todo en los lugares con amplia circulación del SARS-CoV-2. Para seguir protegiéndonos a nosotros mismos y a los demás, paralelamente a las actividades encaminadas a reducir la transmisión del virus e incrementar la cobertura vacunal, es importante continuar manteniéndonos a 1 m de distancia de los demás, toser y estornudar en la flexura del codo, lavarnos las manos con frecuencia y llevar mascarilla, sobre todo en los lugares cerrados, concurridos o poco ventilados. También es necesario seguir siempre las indicaciones de las autoridades locales, pues se basan en la situación y el riesgo al que se está expuesto en cada lugar.

Por lo general, las vacunas se prueban primero en adultos, y solo más tarde, cuando se ha demostrado que son seguras para los adultos, se evalúan en niños, ya que estos todavía están creciendo y se están desarrollando. Además, se ha visto que la COVID-19 es más grave y peligrosa entre las poblaciones de mayor edad. Ahora que se ha determinado que las vacunas son seguras para los adultos, se están estudiando en niños.

El Grupo de Expertos en Asesoramiento Estratégico (SAGE) de la OMS ha llegado a la conclusión de que la vacuna de Pfizer/BioNTech es apropiada para personas de 12 años en adelante. Esta vacuna se puede ofrecer a los niños de 12 a 15 años que corren un mayor riesgo de contraer una forma grave de COVID-19, junto con otros grupos prioritarios en la vacunación. Se están realizando pruebas de vacunas en niños, y la OMS actualizará sus recomendaciones cuando la evidencia o la situación epidemiológica justifiquen una modificación de la política.

Si bien el suministro de vacunas es limitado, la prioridad actual es vacunar a aquellas personas que corren un mayor riesgo de contraer una forma grave de la enfermedad y que, en muchos lugares del mundo, todavía no han sido vacunadas, a saber, las personas mayores, las que padecen afecciones crónicas y los trabajadores de la salud.

La mayoría de los niños presentan un riesgo bajo de contraer una forma grave de la enfermedad, y lo que se pretende al vacunarlos es sobre todo reducir la transmisión, lo que también se puede lograr mediante las siguientes medidas de salud pública: mantener la distancia de seguridad interpersonal, lavarse las manos con frecuencia, estornudar y toser en la parte interna del codo, llevar una mascarilla si ello es apropiado para la edad y evitar los espacios muy concurridos y mal ventilados.

Es preciso realizar más estudios para conocer la eficacia de las vacunas actuales contra las variantes del virus causante de la COVID-19. Cada vez hay más pruebas que indican que la mayoría de las vacunas confieren suficiente inmunidad para combatir eficazmente la mayoría de las variantes del SARS-CoV-2, sobre todo como prevención de los síntomas graves, la hospitalización y la muerte. En cambio, sabemos que estas vacunas protegen menos contra los síntomas leves y las infecciones asintomáticas que contra las formas más graves de la enfermedad.

Probablemente, la razón por la que las vacunas conservan una protección sustancial contra la enfermedad guarda relación con la amplia respuesta inmunitaria que inducen, lo que significa que es poco probable que se den cambios o mutaciones en el virus que hagan que las vacunas sean totalmente ineficaces. Si las vacunas fueran menos eficaces contra una o más variantes, probablemente se podría modificar su composición para que protegieran contra ellas. Sin embargo, ello requeriría un examen más exhaustivo que tomaría más tiempo y que se debería basar en nuevos datos. En la actualidad, se continúa recogiendo y analizando información sobre las nuevas variantes del virus que causa la COVID-19. El SAGE revisa periódicamente estos datos y la OMS actualizará sus orientaciones cuando disponga de más información sobre el impacto de variantes específicas en vacunas concretas.

Mientras se espera a disponer de más información, tenemos que continuar haciendo lo posible por frenar la propagación del virus a fin de evitar que aparezcan mutaciones que puedan reducir la eficacia de las vacunas disponibles. Es decir: mantenerse a una distancia de al menos 1 metro de los demás, toser o estornudar en la flexura del codo, lavarse las manos con frecuencia, usar mascarilla, evitar las habitaciones abarrotadas y mal ventiladas, y abrir una ventana.

Todavía estamos investigando la duración de la inmunidad contra la COVID-19 que aparece tras la infección natural por el virus que la causa. Estamos empezando a obtener pruebas que indican que pasar esta enfermedad puede conferir una inmunidad potente. Sin embargo, debido a que el tipo de inmunidad que confiere la infección es distinto en función de la persona, es más difícil predecirla que cuando se administra la vacuna. Los científicos continúan investigando para comprender mejor este fenómeno.

Lo que sabemos seguro es que la COVID-19 es potencialmente mortal y puede tener consecuencias duraderas, y que las vacunas autorizadas contra esta enfermedad han salvado la vida a miles de millones de personas sin causarles efectos indeseados. Es mucho más seguro vacunarse contra la COVID-19 que contraer la enfermedad. Vacúnese en cuanto le llegue el turno y siga habiendo lo posible por protegerse a sí mismo y a los demás.

A medida que se dispone de más información sobre la COVID-19 y la inmunidad frente a ella, la OMS actualiza sus orientaciones y recomendaciones.

No hay pruebas de que la seguridad o la eficacia de las vacunas contra la COVID-19 se vean afectadas por cualquier cosa que coma o beba antes o después de vacunarse, incluido el alcohol. Sin embargo, el consumo de alcohol puede incrementar los efectos secundarios normales de leves a moderados que puede experimentar después de la vacunación, como dolor de cabeza y cansancio. Por ello, es aconsejable evitar el consumo de alcohol hasta que hayan pasado los efectos secundarios tras la vacunación. Obtenga más información sobre los efectos secundarios de las vacunas contra la COVID-19.

Aunque las vacunas contra la COVID-19 son muy eficaces para prevenir la enfermedad grave y la muerte, sigue existiendo la posibilidad de que se infecte después de haberse vacunado. Siga protegiéndose a sí mismo y a los demás manteniendo el distanciamiento físico, usando una mascarilla bien ajustada sobre la nariz y la boca, limpiándose las manos con frecuencia, quedándose en casa si se siente mal, cubriéndose al toser o estornudar y manteniendo los espacios interiores bien ventilados. El consumo de alcohol puede hacer que no esté tan atento a la hora de practicar estos comportamientos y, por tanto, puede ponerle a usted y a los demás en peligro.

Tenga en cuenta que el consumo de alcohol puede aumentar el riesgo de padecer otros problemas de salud.

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Enfermedad por el coronavirus (COVID-19): Vacunas

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Sí, ya se están utilizando varias vacunas. El primer programa de vacunación colectiva se puso en marcha a principios de diciembre de 2020 y el número de dosis vacunales administradas se actualiza aquí a diario. Se han administrado al menos 13 vacunas distintas (a través de cuatro plataformas).

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Encuesta en el Mercado Arenales Ica sobre el COVID-19

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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

ANXIETY DISORDERS

Remote cognitive behavioral therapy for panic disorders (April 2021)

While cognitive behavioral therapy is a first line treatment for panic disorder, limited availability, long wait times to get appointments, and cost have reduced its accessibility, particularly during the COVID-19 pandemic. In a meta-analysis of 21 randomized and nonrandomized studies including over 1600 individuals with panic disorder, various forms of remotely delivered CBT (internet delivered, videoconferencing, and bibliotherapy) showed large effect sizes on panic symptoms over 24 months, similar to those with face to face CBT [ 1]. The efficacy of remotely delivered CBT has important implications for its broader availability and may ultimately lessen barriers to treatment for panic disorder. (See "Psychotherapy for panic disorder with or without agoraphobia in adults", section on 'Remote CBT and internet-delivered exposure therapy'.)

BIPOLAR DISORDER

Prenatal antipsychotics and psychopathology in the offspring (September 2021)

Maternal use of antipsychotics during pregnancy does not appear to increase the risk of psychopathology in offspring. A retrospective study of electronic medical records identified over 400,000 mother-child pairs in which 706 had gestational exposure to antipsychotics [ 2]. After adjusting for potential confounding factors, the risks of attention-deficit hyperactivity disorder and autism spectrum disorder in the exposed and nonexposed children were comparable. These results are reassuring for pregnant patients with bipolar disorder who require antipsychotics. (See "Teratogenicity, pregnancy complications, and postnatal risks of antipsychotics, benzodiazepines, lithium, and electroconvulsive therapy", section on 'Developmental effects'.)

Lamotrigine in bipolar disorder (May 2021)

Lamotrigine is often used for bipolar major depression, but may be associated with an increased risk of arrhythmias in patients with pre-existing cardiac disease. Following reports of chest pain and cardiac arrest in patients treated with lamotrigine, the US Food and Drug Administration conducted in vitro studies of the drug at therapeutically relevant serum concentrations [ 3]. The results prompted the agency to issue a warning that lamotrigine can slow ventricular conduction and increase the risk of serious arrhythmias in patients with clinically important structural or functional cardiac disease, multiple risk factors for coronary artery disease, or using other sodium channel blockers. Although the benefits of lamotrigine in patients with bipolar disorder and underlying heart disease may outweigh the risks, we suggest that clinicians attempt to avoid using the drug in these patients. (See "Bipolar major depression in adults: Choosing treatment", section on 'Third-line medications'.)

NEUROCOGNITIVE DISORDERS

Clinical use of pimavanserin in patients with neurodegenerative dementias (September 2021)

Pimavanserin is a newer antipsychotic agent that has been approved in the United States (US) since 2016 for treatment of psychosis in patients with Parkinson disease (PD). Two new reports expand information on both efficacy and potential risks in patients with neurodegenerative diseases:

●In a randomized discontinuation trial of pimavanserin in 351 patients with dementia-related psychosis, among those who responded initially to treatment, relapses were approximately half as common in patients assigned to continued pimavanserin compared with placebo [ 4].

●In a retrospective cohort study of >20,000 older adults with PD living in long-term care facilities in the US, pimavanserin use, compared with nonuse, was associated with an increased adjusted risk of 30-day hospitalization and mortality at multiple time points [ 5]. Residual confounding is possible, although other studies have raised similar safety concerns for antipsychotic agents as a class.

Like other antipsychotic agents, pimavanserin should be used selectively in patients with dementia and/or PD after discussing potential risks and benefits of treatment, alternative therapies for psychosis ( algorithm 1 and algorithm 2), and risks related to ongoing symptoms. (See "Management of nonmotor symptoms in Parkinson disease", section on 'Refractory psychotic symptoms' and "Management of neuropsychiatric symptoms of dementia", section on 'Antipsychotic drugs'.)

DEPRESSIVE DISORDERS

Electroconvulsive therapy and risk of serious medical events (September 2021)

Electroconvulsive therapy (ECT) is underutilized due to stigma and concerns about medical complications. However, in a retrospective cohort study of over 10,000 patients hospitalized for depression, the rate of serious medical events was low and trended lower among those exposed to ECT compared with a propensity score-matched unexposed group (0.25 versus 0.33 events per person-year) [ 6]. Serious medical events were defined as a composite of hospitalization for nonpsychiatric reasons and non-suicide mortality within 30 days of the exposure date or corresponding index date. Clinicians can use these findings and previous data to reassure candidates for ECT that it is one of the safest procedures performed under general anesthesia. (See "Overview of electroconvulsive therapy (ECT) for adults", section on 'Adverse general medical effects'.)

Electroconvulsive therapy and suicide (September 2021)

Electroconvulsive therapy (ECT) is often beneficial for patients with severe, treatment-resistant depression and may reduce the risk of suicide. In a Swedish national registry study comparing >5500 patients hospitalized for depression who received ECT with a similar number who did not, fewer patients in the ECT group died of suicide during the 12 months following hospital admission (1.1 versus 1.6 percent, after adjusting for potential confounding factors) [ 7]. We suggest offering ECT to patients with treatment-resistant depression and suicidal behavior. (See "Unipolar major depression in adults: Indications for and efficacy of electroconvulsive therapy (ECT)", section on 'Suicidality'.)

Unipolar major depression and digital psychotherapy (June 2021)

Digital formats may increase access to psychotherapy for depression, but evidence of effectiveness is limited. Two randomized trials conducted separately in Peru and Brazil compared digitally-based behavioral activation with usual care in patients with depression plus hypertension and/or diabetes [ 8]. The digital intervention was administered over six weeks by a smartphone app and nurse assistants who facilitated treatment through telephone calls, whereas the control group received treatment at the discretion of local clinicians. At three-months follow-up, more patients in the intervention group experienced a ≥50 percent reduction in the primary outcome (depressive symptoms, quality of life, and functioning); however, at six-months follow-up, the outcome was comparable for the two groups. We generally recommend avoiding digital interventions as a primary component of psychiatric care. (See "Unipolar depression in adult primary care patients and general medical illness: Evidence for the efficacy of initial treatments", section on 'Digital interventions'.)

Psilocybin plus psychotherapy for unipolar major depression (May 2021)

Psilocybin (a psychedelic compound) plus psychotherapy is an investigational regimen for treatment of refractory depression. A six week phase 2 trial in 59 patients with unipolar major depression receiving psychological support compared psilocybin (two 25 mg doses three weeks apart) with escitalopram plus psilocybin (two 1 mg doses three weeks apart) [ 9]. Both groups had a similar change in QIDS-SR-16 depression score from baseline, although remission (defined as QIDS-SR-16 score ≤5) occurred in twice as many patients receiving psilocybin alone. There were no serious adverse effects in either group; the most common adverse effects in both groups were headache and nausea. These results warrant further study of psilocybin in larger trials of longer duration and compared with other standard antidepressants. (See "Unipolar depression in adults: Management of highly resistant (refractory) depression", section on 'Drug therapies'.)

MEDICAL CONSEQUENCES OF PSYCHIATRIC DISORDERS

Preexisting psychiatric disorders and COVID-19-related outcomes (September 2021)

Patients with preexisting psychiatric disorders who develop SARS-CoV-2 infection may be at increased risk for severe COVID-19. In a meta-analysis of observational studies including nearly 1.5 million COVID-19 patients, preexisting psychiatric disorders (>40,000 patients) were associated with increased risks of COVID-19-related hospitalization and death, which remained after adjustment for confounding factors [ 10]. Patients with psychotic or mood disorders were at highest risk. These findings underscore the importance of SARS-CoV-2 vaccination in this vulnerable population, which may be less informed or have reduced access to care. (See "COVID-19: Psychiatric illness", section on 'Patients with pre-existing psychiatric illness'.)

SUBSTANCE USE DISORDERS

Aggressive buprenorphine dosing in individuals with opioid use disorder (August 2021)

Aggressively treating opioid use disorder (OUD) at a first encounter is a potential way to mitigate delays in access to care, although the efficacy and safety of this approach are uncertain. In a retrospective review of 579 individuals with OUD who were seen in the emergency department, aggressive initial dosing of buprenorphine (12 to 32 mg, given as monoproduct without naltrexone) was well tolerated with a low incidence of nausea or vomiting and without toxicity (ie, sedation or respiratory depression) [ 11]. Fewer than 1 percent had precipitated withdrawal. The extended opioid blockade provided by the high dose may lessen withdrawal sufficiently to facilitate acceptance of buprenorphine by the patient and thus improve transition to outpatient treatment. (See "Pharmacotherapy for opioid use disorder".)

TRAUMA - AND STRESSOR-RELATED DISORDERS

MDMA for severe PTSD (August 2021)

Severe PTSD can be difficult to treat, and response to pharmacologic treatment varies; MDMA, the recreational drug also known as ecstasy, may be effective. In a trial including 90 individuals with severe PTSD, MDMA combined with manualized psychotherapy led to both a greater improvement in PTSD symptoms and a greater decline in functional impairment than manualized psychotherapy with placebo [ 12]. Additionally, more individuals in the treatment group no longer met diagnostic criteria for PTSD than those in the placebo group (67 versus 32 percent). MDMA was not associated with adverse effects such as addiction, suicidality, or prolonged QTc interval. Despite potential benefits, the legal status of MDMA prevents clinical use outside of trials. (See "Pharmacotherapy for posttraumatic stress disorder in adults", section on '3,4 methylenedioxymethamphetamine (MDMA)'.)

OTHER PSYCHIATRY

Suicide in nurses and physicians (September 2021)

Older studies reported increased risks of suicide among physicians. However, in a retrospective study of United States suicide data from 2017 to 2018 in over 600 nurses, 200 physicians, and 40,000 individuals in the general population, the incidence of suicide among nurses was significantly higher than that in the general population (relative risk [RR] 1.18), whereas physicians had a similar incidence (RR 1.01), after adjusting for sex differences [ 13]. Nurses also had a nonstatistically significant increased incidence of suicide compared with physicians. The elevated suicide risk in nurses may be due to job demands, avoiding use of psychiatric care due to stigma, or access to medications as a means of suicide. Thus, efforts to enhance well-being in physicians should be accompanied by similar initiatives for nurses. (See "Suicidal ideation and behavior in adults".)

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The following represent additions to UpToDate from the past six months that were considered by the editors and authors to be of particular interest. The most recent What's New entries are at the top of each subsection.

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Síntomas psicóticos por primera vez en un paciente después de la infección por COVID-19: informe de caso A.

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Síntomas psicóticos por primera vez en un paciente después de la infección por COVID-19: informe de caso A.

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Los, Kacper; Kulikowska, Joanna; Waszkiewicz, Napoleon.

Affiliation

Los K; Department of Psychiatry, Medical University of Bialystok, Bialystok, Poland.

Kulikowska J; Department of Neurology, Medical University of Bialystok, Bialystok, Poland.

Waszkiewicz N; Department of Psychiatry, Medical University of Bialystok, Bialystok, Poland.

Article in English | MEDLINE | ID: mdl-34721104

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First-Time Psychotic Symptoms in a Patient After COVID-19 Infection-A Case Report. | Front Psychiatry;12: 726059, 2021. | MEDLINE

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First-Time Psychotic Symptoms in a Patient After COVID-19 Infection-A Case Report.

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Encuesta en el Mercado Arenales Ica sobre el COVID-19          INDIVIDUALES 

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Encuesta en el Mercado Arenales Ica sobre el COVID-19          INDIVIDUALES 

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Covid-19: distancia y mascarillas no bastan en espacios mal ventilados    

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Covid-19: distancia y mascarillas no bastan en espacios mal ventilados    

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Esta guía reúne las medidas sanitarias y los consejos prácticos a seguir para protegerte a ti y a las personas de tu entorno de la covid-19. Prevenir los contagios es el mejor sistema para evitar la propagación del virus y preservar el bien más preciado: la salud.La lucha contra el coronavirus es una responsabilidad compartida.

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ICA: POBLACIÓN NO ACATA MEDIDAS DE SEGURIDAD

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¿Cómo funciona la vacuna contra el Covid-19?

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_Abarca Mendoza Franco Samuel
_Buleje Mendoza Ronald Alex
_ Cervantes Medina Piero Armando

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Data Science for COVID-19, Volume 2: Societal and Medical Perspectives presents the most current and leading-edge research into the applications of a variety of data science techniques for the detection, mitigation, treatment and elimination of the COVID-19 virus. At this point, Cognitive Data Science is the most powerful tool for researchers to fight COVID-19. Thanks to instant data-analysis and predictive techniques, including Artificial Intelligence, Machine Learning, Deep Learning, Data Mining, and computational modeling for processing large amounts of data, recognizing patterns, modeling new techniques, and improving both research and treatment outcomes is now possible.

Provides a leading-edge survey of Data Science techniques and methods for research, mitigation and the treatment of the COVID-19 virus

Integrates various Data Science techniques to provide a resource for COVID-19 researchers and clinicians around the world, including the wide variety of impacts the virus is having on societies and medical practice

Presents insights into innovative, data-oriented modeling and predictive techniques from COVID-19 researchers around the world, including geoprocessing and tracking, lab data analysis, and theoretical views on a variety of technical applications

Includes real-world feedback and user experiences from physicians and medical staff from around the world for medical treatment perspectives, public safety policies and impacts, sociological and psychological perspectives, the effects of COVID-19 in agriculture, economies, and education, and insights on future pandemics

Academics (scientists, researchers, MSc. PhD. students) from the fields of Computer Science and Engineering, Biomedical Engineering, Biology, Chemistry, Electronics and Communication Engineering, and Information Technology. The audience also includes interested professionals-experts from both public and private industries of medical, computer, data science, information technologies. Data Science, Medical, Biomedical, Artificial Intelligence, Machine Learning, Deep Learning, and even Data (i.e. Image, Signal) Processing oriented courses given at especially Health, Biology, Biomedical Engineering or similar programs of universities, institutions

Cover image

Title page

Table of Contents

Copyright

Contributors

Foreword

Preface

1. Essentials of the COVID-19 coronavirus

1. Introduction

2. Materials and methods

3. Revealed essential features of COVID-19 coronavirus

Abbreviations

2. Docking study of transmembrane serine protease type 2 inhibitors for the treatment of COVID-19

1. Introduction

2. Materials and methods

3. Results

4. Discussion

5. Conclusions

3. Gut-lung cross talk in COVID-19 pathology and fatality rate

1. Introduction

2. Adult human gut microbiota

3. Respiratory tract microbiota

4. Gut-lung cross talk during viral COVID-19

5. Suggested COVID-19 intervention strategies through the use of probiotics and prebiotics

6. The role of probiotic in ventilator-associated pneumonia

4. Data sharing and privacy issues arising with COVID-19 data and applications

1. Introduction

2. The process of accelerating COVID-19 research

3. Medical data and sharing

4. COVID-19 applications and privacy

5. Discussion and suggestions for further research

5. COVID-19 outlook in the United States of America: a data-driven thematic approach

1. Introduction

2. Sociotechnical theory

3. Methodology

4. Results

5. Discussions

6. Conclusion

6. Artificial intelligence and COVID-19: fighting pandemics

1. Introduction

2. Phases for fighting pandemics

3. Present artificial intelligence efforts for fighting COVID-19

4. Ethical use of artificial intelligence while fighting COVID-19

5. Ongoing lessons from COVID-19

6. Concluding remarks

7. Data science: a survey on the statistical analysis of the latest outbreak of the 2019 pandemic novel coronavirus disease (COVID-19) using ANOVA

1. Introduction

2. Background

3. Overview of dataset

4. Statistical analysis

5. Outbreak of COVID-19, as of March 31, 2020

6. Outbreak of COVID-19, as of April 25, 2020

7. Comparison of COVID-19 in March and April

8. Conclusion

8. Application of big data in COVID-19 epidemic

1. Introduction

2. The growth of data in healthcare

3. Big data privacy and ethical challenges in COVID-19

4. Big data analytics in COVID-19 epidemic

5. Conclusion

9. Artificial intelligence-based solutions for COVID-19

1. Introduction

2. Technologic solutions to help combat the COVID-19 outbreak

3. Limitations and future scope

10. Telemedicine applications for pandemic diseases, with a focus on COVID-19

1. Introduction

2. Telemedicine applications during epidemic/pandemic

3. Telemedicine applications for COVID-19

4. Discussion

5. Conclusions and future work

11. Impact of COVID-19 and lockdown policies on farming, food security, and agribusiness in West Africa

1. Introduction

2. Methods

3. Results

4. Discussion

5. Conclusion and recommendations

12. Study and impact analysis of COVID-19 pandemic clinical data on infection spreading

1. Introduction

2. Related work

3. Clinical data analysis

4. Case study

5. Proposed model for the prediction of COVID-19

6. Conclusion and future scope

13. Toward analyzing the impact of healthcare treatments in industry 4.0 environment-a self-care case study during COVID-19 outbreak

1. Introduction

2. Case study: experimental simulation, results, and analysis

3. Conclusion

14. Big data processing and analysis on the impact of COVID-19 on public transport delay

1. Introduction

2. Data preparation

3. Methodology

4. Case study

5. Conclusion and future work

15. The role of societal research and centers in analyzing society in pandemic times

1. Introduction

2. Materials and methods

3. Findings

4. Discussion

5. Conclusions and suggestions/future work

16. Modeling and predicting the spread of COVID-19: a continental analysis

1. Introduction

2. A continental review of modeling and prediction studies

3. Discussion

4. Conclusion

17. Applications of Building Information Modeling for COVID-19 spread assessment due to the organization of building artifacts

1. Introduction

2. Summarizing the applications of Building Information Modeling for CSAOBA

3. An add-in tool for building-level communal spread due to seating arrangements within a room

4. Case study

5. Discussion

6. Conclusion

18. COVID-19 diagnosis-myths and protocols

1. Introduction

2. Diagnostic methods

3. Conclusion

19. "Quarantined within a quarantine": COVID-19 and GIS Dynamic Scenario Modeling in Tasmania, Australia

1. Introduction

2. Managing pandemics with data science and technology

3. Australia and COVID-19

4. Data science context

5. Tasmania COVID-19 spread: systems dynamic modeling

6. North West Tasmania emergency response and recovery dynamic scenario modeling

7. Conclusions and future work

20. Essentials of COVID-19 and treatment approaches

1. Introduction

2. History and epidemiology

3. Structure of SARS-CoV-2

4. Pathogenesis

5. Treatment approaches

6. Various approaches to design vaccine

7. Conclusions

21. Coronavirus epidemic and its social/mental dimensions: the Turkey case

1. Introduction

2. Looting culture and perspectives with phenomenology

3. Unethical criminal and the "produced anxiety"®

4. Self-ostracism® and the coronavirus hallucination

5. Political structure of the coronavirus and the cultural racism

6. Conclusion: Foucault, "big locking down," and "the world is a great madhouse"

22. Coronavirus: a scientometric study of worldwide research publications

1. Introduction

2. Methodology

3. Analysis and results

4. Results and Findings

5. Conclusion

23. The effects of COVID-19 pandemic on Western Balkan financial markets

1. Introduction

2. Literature review

3. What is coronavirus

4. The effects of globalization

5. Materials and methods

6. Discussion

7. Conclusion

Appendix

24. Prioritization of health emergency research and disaster preparedness: a systematic assessment of the coronavirus disease 2019 pandemic

1. Introduction

2. Data analytics

3. Evaluation of collaboration network in health emergency research

4. Analytic platforms

5. Results

6. Discussion

7. Conclusion

Appendix A. Supplementary data

25. A review on epidemiology, genomic characteristics, spread, and treatments of COVID-19

1. Introduction

2. Origin of coronavirus

3. Epidemiology of coronavirus

4. Transmission

5. Genome structure

6. Phylogenetic analysis

7. Statistical analysis on COVID-19

8. Clinical features of COVID-19

9. Treatment with drugs

10. Progress on vaccines

11. Conclusions

26. Control of antibiotic resistance and superinfections as a strategy to manage COVID-19 deaths

1. Introduction

2. Effect of superinfections on immune response and the severity of COVID-19 infection

3. Antibiotic resistance as a challenge in the COVID-19 pandemic

4. Alternative treatment strategies to overcome antibiotic resistance as a contributor to COVID-19 deaths

5. Mouthwashes as an early preventive strategy

27. Assessment of global research trends in the application of data science and deep and machine learning to the COVID-19 pandemic

1. Introduction

2. Data and methodology

3. Results and discussion

4. Conclusion

28. Identification of lead inhibitors of TMPRSS2 isoform 1 of SARS-CoV-2 target using neural network, random forest, and molecular docking

1. Introduction

2. Materials and methods

3. Result and discussion

29. The linkage between the epidemic of COVID-19 and oil prices: case of Saudi Arabia, January 22 to April 17

1. Introduction

2. Materials and methods

3. Coronavirus: pandemic scaring the world

4. Empirical results

5. Conclusion and recommendation

30. Role of big geospatial data in the COVID-19 crisis

1. Introduction

2. Materials and methods

3. Background

4. GeoAI: geospatial artificial intelligence and health geographics

5. Big geospatial data and infectious disease pattern

6. Case studies of China and Taiwan

7. Results and discussions

8. Conclusion

31. COVID-19: will it be a game changer in higher education in India?

1. Introduction

2. Proposed basic learning model

3. COVID-19: challenges in Indian education

4. Proposed simulation

5. Analysis of results

6. Conclusion

32. Are the northern and southern regions equally affected by the COVID-19 pandemic? An empirical evidence from Nigeria

1. Introduction

2. Materials and methods

3. Results and discussion

4. Conclusion and recommendation

33. COVID-19 lethality reduction using artificial intelligence solutions derived from telecommunications systems

1. Introduction

2. Literary review

3. European Telecommunications Standards Institute architecture

4. Data required to reduce COVID lethality

5. Adaptation of the European Telecommunications Standards Institute architecture to the needs of public services

6. Conclusion

34. The significance of daily incidence and mortality cases due to COVID-19 in some African countries

1. Introduction

2. Literature review

3. Materials and methods

4. Results and discussion

5. Conclusion

35. Data interpretation leading to image processing: a hybrid perspective to a global pandemic, COVID-19

1. Introduction

2. Literature review

3. Data analysis

4. Case study: COVID-19

5. Image processing analysis

6. Results and discussion

7. Conclusion and future work

Appendix A: Country-wise coronavirus details

36. COVID-19: in the direction of monitoring the pandemic in India

1. Introduction

2. Origin and mode of transmission of COVID-19

3. Clinical characteristics of COVID-19

4. Current scenario of COVID-19 in India

5. Precautions taken in India for controlling COVID-19 spread

6. Problems faced in controlling COVID-19 spread

7. Significance and outcomes of the adopted measures

8. Future measures

9. Conclusion

37. Potential antiviral therapies for coronavirus disease 2019 (COVID-19)

1. Introduction

2. Genome organization

3. Epidemiology and clinical features

4. Potential antiviral therapies under consideration

5. Conclusion and future work

Index

No. of pages: 812

Language: English

Copyright: © Academic Press 2021

Published: October 22, 2021

Imprint: Academic Press

Paperback ISBN: 9780323907699

eBook ISBN: 9780323907705

Utku Kose

Dr. Utku Kose is an Associate Professor at Süleyman Demirel University, Turkey. He received his PhD from Selcuk University, Turkey in the field of computer engineering. He has more than 100 publications to his credit, including articles, authored and edited books, proceedings, and reports. He is also a series editor of the 'Biomedical and Robotics Healthcare Series' (CRC Press). His research interests include artificial intelligence, machine ethics, artificial intelligence safety, optimization, chaos theory, distance education, e-learning, computer education, and computer science.

Affiliations and Expertise

Associate Professor, Department of Computer Engineering, Süleyman Demirel University, Isparta, Turkey

Deepak Gupta

Dr. Deepak Gupta is an eminent academician; plays versatile roles and responsibilities juggling between lectures, research, publications, consultancy, community service, PhD and post-doctorate supervision. With 12 years of rich expertise in teaching and two years in industry; he focuses on rational and practical learning. He has contributed important literature in the fields of Human-Computer Interaction, Intelligent Data Analysis, Nature-Inspired Computing, Machine Learning and Soft Computing. He is an Assistant Professor at Maharaja Agrasen Institute of Technology, Delhi, India. He has completed his Post-Doc from Inatel, Brazil, and Ph.D. from Dr. APJ Abdul Kalam Technical University. He has served as Editor-in-Chief, Guest Editor, and Associate Editor in SCI and various other reputed journals (Elsevier, Springer, Wiley & MDPI). He is currently a Post-Doc researcher at University of Valladolid, Spain. He has authored/edited a number of books, including Advanced Computational Techniques for Virtual Reality in Healthcare and Handbook of Computer Networks and Cyber Security: Principles and Paradigms from Springer, He has published 101 scientific research publications in reputed International Journals and Conferences including 49 SCI Indexed Journals of IEEE, Elsevier, Springer, Wiley and many more. He has also published one patent. He is Editor-in-Chief of Computers and Quantum Computing and Applications journal, Associate Editor of Expert Systems (Wiley), Intelligent Decision Technologies (IOS Press), Journal of Computational and Theoretical Nenoscience, and Honorary Editor of ICSES Transactions on Image Processing and Pattern Recognition. He is also a series editor of Intelligent Biomedical Data Analysis, De Gruyter (Germany).

Affiliations and Expertise

Assistant Professor, Maharaja Agrasen Institute of Technology, Guru Gobind Singh Indraprastha University, Delhi, India

Victor de Albuquerque

Victor Hugo C. de Albuquerque [M'17, SM'19] is a collaborator Professor and senior researcher at the Graduate Program on Teleinformatics Engineering at the Federal University of Ceará, Brazil, and at the Graduate Program on Telecommunication Engineering, Federal Institute of Education, Science and Technology of Ceará, Fortaleza/CE, Brazil. He has a Ph.D in Mechanical Engineering from the Federal University of Paraíba (UFPB, 2010), an MSc in Teleinformatics Engineering from the Federal University of Ceará (UFC, 2007), and he graduated in Mechatronics Engineering at the Federal Center of Technological Education of Ceará (CEFETCE, 2006). He is a specialist, mainly, in Image Data Science, IoT, Machine/Deep Learning, Pattern Recognition, Robotic.

Affiliations and Expertise

Professor and Senior Researcher, Federal University of Ceara, Fortaleza, Graduate Program on Teleinformatics Engineering,Fortaleza/CE, Brazil

Ashish Khanna

Dr. Ashish Khanna has 16 years of expertise in teaching, entrepreneurship, and research and development. He received his PhD from the National Institute of Technology, Kurukshetra, India, and completed a post-doc degree at the National Institute of Telecommunications (Inatel), Brazil. He has published around 40 SCI-indexed papers in IEEE Transactions, and in other reputed journals by Springer, Elsevier, and Wiley, with a cumulative impact factor of above 100. He has published around 90 research articles in top SCI/ Scopus journals, conferences, and book chapters. He is co-author or editor of numerous books, including 'Advanced Computational Techniques for Virtual Reality in Healthcare' (Springer), 'Intelligent Data Analysis: From Data Gathering to Data Comprehension' (Wiley), and 'Hybrid Computational Intelligence: Challenges and Applications' (Elsevier). His research interests include distributed systems, MANET, FANET, VANET, Internet of Things, and machine learning. He is one of the founders of Bhavya Publications and the Universal Innovator Lab, which is actively involved in research, innovation, conferences, start-up funding events, and workshops. He is currently working at the Department of Computer Science and Engineering, Maharaja Agrasen Institute of Technology, New Delhi, India, and is also a Visiting Professor at the University of Valladolid, Spain.

Affiliations and Expertise

Sr. Assistant Professor, Department of Computer Science and Engineering, Maharaja Agrasen Institute of Technology (MAIT), New Delhi, India

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Data Science for COVID-19, Volume 2: Societal and Medical Perspectives presents the most current and leading-edge research into the applications of a variety of data science techniques for the detection, mitigation, treatment and elimination of the COVID-19 virus. At this point, Cognitive Data Science is the most powerful tool for researchers to fight COVID-19.

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Original articles

COVID-19 Diagnosis with Deep Learning

Diagnóstico de COVID-19 con Deep Learning

Ph.D. in Geomatics Engineering, Yildiz Technical University, Turkey. Affiliation: Assistant Professor, Department of Geomatics Engineering, Gumushane University, Gumushane, Turkey. E-mail: hatice.catal@yahoo.com.tr

The coronavirus disease 2019 (COVID-19) is fatal and spreading rapidly. Early detection and diagnosis of the COVID-19 infection will prevent rapid spread. This study aims to automatically detect COVID-19 through a chest computed tomography (CT) dataset. The standard models for automatic COVID-19 detection using raw chest CT images are presented. This study uses convolutional neural network (CNN), Zeiler and Fergus network (ZFNet), and dense convolutional network-121 (DenseNet121) architectures of deep convolutional neural network models. The proposed models are presented to provide accurate diagnosis for binary classification. The datasets were obtained from a public database. This retrospective study included 757 chest CT images (360 confirmed COVID-19 and 397 non-COVID-19 chest CT images). The algorithms were coded using the Python programming language. The performance metrics used were accuracy, precision, recall, F1-score, and ROC-AUC. Comparative analyses are presented between the three models by considering hyper-parameter factors to find the best model. We obtained the best performance, with an accuracy of 94,7%, a recall of 90%, a precision of 100%, and an F1-score of 94,7% from the CNN model. As a result, the CNN algorithm is more accurate and precise than the ZFNet and DenseNet121 models. This study can present a second point of view to medical staff.

Keywords: COVID-19; deep learning; convolutional neural network; Zeiler and Fergus network; dense convolutional network-121

La enfermedad del coronavirus 2019 (COVID-19) es fatal y se está propagando rápidamente. La detección y el diagnóstico tempranos de la infección por COVID-19 evitarán la propagación rápida. Este estudio tiene como objetivo detectar COVID-19 automáticamente a partir del conjunto de datos de tomografía computarizada de tórax (TC). Se presentan los modelos estándar para la detección automática de COVID-19 utilizando imágenes de TC de tórax sin procesar. El estudio consta de arquitecturas de red neuronal convolucional (CNN), red Zeiler y Fergus (ZFNet) y red convolucional densa-121 (DenseNet121) de modelos de redes neuronales convolucionales profundas. Los modelos propuestos se presentan para proporcionar diagnósticos precisos para clasificación binaria. Los conjuntos de datos se obtuvieron de una base de datos pública. Este estudio retrospectivo incluyó 757 imágenes de TC de tórax (360 imágenes de TC de tórax COVID-19 confirmadas y 397 imágenes no COVID-19). Los algoritmos se codificaron utilizando el lenguaje de programación Python. Los parámetros de desempeño que se utilizaron fueron exactitud, precisión, recuperación, puntaje-F1 y ROC-AUC. Se presentan análisis comparativos entre los tres modelos considerando factores de hiperparámetros para encontrar el mejor modelo. Obtuvimos el mejor rendimiento, con exactitud del 94,7%, recuperación del 90%, precisión del 100% y puntuación-F1 del 94,7% del modelo de CNN. Como resultado, el algoritmo de CNN es más exacto y preciso que los modelos ZFNet y DenseNet121. Este estudio puede presentar un segundo punto de vista al personal médico.

Palabras clave: COVID-19; deep learning; red neuronal convolucional; red Zeiler y Fergus; red convolucional densa-121

Introduction

Machine-learning (ML) techniques have been used in medical imaging and infectious disease diagnosis (Lundervold and Lundervold, 2019; ; ). The coronavirus disease 2019 (COVID-19), which started to spread from Wuhan (China), as of the end of December 2019 (; ), has affected the whole world. According to the updated data, there have been more than 134 957 021 confirmed cases and 2 918 752 confirmed deaths because of COVID-19 in 223 countries as of 11 April 2021 (). Coronaviruses (CoVs) are related to zoonotic viruses that can cause disease in mammal or bird species (Tezer and Bedir Demirdag, 2020). Various medical approaches are available to diagnose and detect COVID-19 in patients, such as the transcription-polymerase chain reaction (RT-PCR) test kits () and chest computed tomography (CT) images. Chest CT scans have played a vital role in diagnosis during this pandemic (; ; ; ). Early detection, diagnosis, isolation, and treatment are critical to preventing further spread of the disease (). In some cases, real-time polymerase chain reactions can give incorrect or inadequate information (). It is critical to develop cost-effective and accurate detection methods that all countries can benefit from. Deep learning (DL) is a part of machine learning (). Recently, this technique has shown effective performance in the field of medical image processing. DL-based research has been presented for the detection of COVID-19. This includes artificial neural networks (ANN), convolutional neural networks (CNN), recurrent neural networks (RNN, a hybrid classifier architecture) (); ResNet50, Incep-tionV3, and InceptionResNetV2 (); nCOVnet (); DarkCovidNet (); VGG-19 (Ioannis and Bessiana, 2020); COVID-NET (Wang and Wong, 2020); and Xception and ResNeXt () models using X-ray images. At the same time, studies that detect COVID-19 using CT images have been presented in the literature. AlexNet, VGG-16, VGG-19, SqueezeNet, GoogLeNet (), ResNet-50 as a specific model (), DenseNet (), and DenseNet201 () algorithms have used CT images for COVID-19 detection and diagnosis. Although there are studies on the subject, there is still insufficient literature. Deep learning algorithms can help develop a new useful diagnosis and management system for COVID-19 cases. In this study, we have proposed three models for an automatic prediction of COVID-19 using DL-based using chest CT images. The proposed models have an end-to-end architecture that uses feature extraction methods and raw chest-CT images for analysis. These models are a customized CNN, ZFNet, and DenseNet121. We reached this accuracy by means of a large-size dataset and multi-layer models. Along with the customized CNN model, we proposed a small-size nonstandard dataset.

Radiologists have to be pioneers in medical imaging and interpretation during the COVID-19 pandemic, but the medical staff are currently under heavy workloads. Therefore, DL-based approaches can help contribute to the medical system and offer a secondary perspective.

This study is organized as follows: in section 2 (Materials and methods), we give a short overview of the literature in deep learning and the proposed models; we describe how we obtained the dataset, and we present architecture charts and plots. Then, we provide a statistical analysis. In section 3 (Results), we show the results of the experiment. After that, we discuss and interpret the obtained results and conclusions.

Materials and methods

In this section, we define the dataset used in the study for DL. The second part is followed by the proposed CNN, ZFNet, and DenseNet121. It compares the performance of these three models. We built DL-based platforms for automatic detection and prediction of COVID-19 ( Figure 1).

Deep learning is a subclass of machine learning and is the most popular approach in artificial intelligence applications (). DL is a method that imitates the human brain in the use of information and aims for new approaches in complex data solutions. The most important feature that distinguishes deep learning from traditional neural networks is that it has more than one hidden layer (Sejnowski and Tesauro, 1989). Generally, the architecture of convolutional neural networks consists of input, convolution, pooling, convolution, pooling, fully connected, fully connected, and output prediction ().

The data were downloaded and used from the GitHub public database. The COVID-CT-Dataset has 360 CT images containing clinical findings of COVID-19 from 216 patients and 397 non-COVID-19 CT images (Github/UCSD-). No human and no animal rights were violated. The research was performed according to the principles of the Declaration of Helsinki. We used the Keras deep learning library with the TensorFlow backend to implement deep learning models ( Figure 3). This study was done on a personal laptop equipped with an Intel 15 processor, 6 GB of RAM, and a GTX 940MX NVidia GPU with 2GB of VRAM. Table 1 shows the DL methods used and statistics of the dataset for chest CT images.

A chest CT dataset was used ( Figure 2), which was obtained with different techniques and did not have standard features. Therefore, all images were pre-processed.

Problem solving with the help of deep learning is equivalent to optimally designing a multi-layered network structure. The raw CT dataset and 100 epochs were used as the input layer in our study ( Figures 4 to 6). BatchNormalization caused the model to learn better during training, and it also positively affected the stability of the network.

CNNs have been used in imaging-based classification in various medical areas (Lakhani and Sundaram, 2017; ). They have been significantly practiced in medical image processing to develop health research (). CNNs are a kind of artificial neural network with multiple layers contributing to high accuracy and cost reduction in its large datasets (). The customized CNN's architecture contains 3 layers instead of 2 in the 2-3-4 layers ( Figure 4). Therefore, we increased the model's performance in terms of accuracy.
Performance measures
This study used the receiver operating characteristic (ROC) curve to evaluate classifier output quality. ROC curve analysis is generally used in medical studies for evaluating the diagnostic accuracy of a continuous class (). The confusion matrix is based on four parameters, identified as True Positive (TP), False Positive (FP), False Negative (FN), and True Negative (TN), as shown in Table 2. Accuracy, precision, recall, F1-score, and ROC-AUC metrics were used for performance measurement ().

Source: Author

Experimental results

We used CNN, ZFNet, and DenseNet121 DL algorithms to detect COVID-19 for training, validation, and testing purposes. Visual performance plots are given in Figures 7 to 9, and the evaluation results of the methods are shown in Table 3.

Source: Author

Source: Author

Source: Author

Source: Author

We obtained the best performance with the customized CNN model, with an accuracy of 94,7%, a recall of 90%, a precision of 100%, and an Fl-score of 94,7%. The lowest performance values were obtained by DenseNet121 with an accuracy of 84,2%, a recall of 76,5%, a precision of 85%, and an Fl-score of 81,2%. The confusion matrix for the detection of COVID-19 obtained from the study is given in Figure 7. Accuracy, precision, recall, Fl-score, and ROC-AUC were used for performance evaluation ( Table 3).

The loss function layer is used to calculate the expected results predicted by the vital features () ( Figure 8).

According to the results of the ROC curve ( Figure 9), we obtained the best result from the CNN model with 95%, the second best result from the ZFNet model with 86,8%, and the lowest result with the DenseNet121 model (83,5%).

Conclusions

In this study, we focused on the detection and prediction of COVID-19 using chest CT imaging. As a result, the CNN algorithm gave more satisfactory and higher accuracy than ZFNet and DenseNet121. The additional layers we applied for the CNN model increased the study's performance (while the standard CNN ROC-AUC value was 94%, it increased to 95% with the customized method). We presented a different perspective to the standard CNN approach. According to the results, the customized CNN model can be used to automatically predict the COVID-19 disease.

A major limitation of this study is the use of a limited number of COVID-19 chest CT images; it can offer radiologists and medical staff a second perspective. COVID-19 diagnosis performed using DL-based algorithms can help medical staff with reporting and interpreting. In future work, studies with more datasets and different machine learning methods will be presented.

Acknowledgments

We would like to thank Veysel Turk and Serhat Kaya for their technical contribution.

References

GitHub/UCSD-AI4H. (2020, April 20). COVID CT. https://github.com/UCSD-AI4H/COVID-CT [ Links ]

Ioannis, D. A. and Bessiana, B. (2020). COVID-79: Automatic Detection from X-Ray Images Utilizing Transfer Learning with Convolutional Neural Networks. https://arxiv.org/ftp/arxiv/papers/2003/2003.11617.pdf [ Links ]

Narin, A., Kaya, C., and Pamuk, Z. (2020). Automatic Detection of Coronavirus Disease (COVID- 79) Using X-Ray Images and Deep Convolutional Neural Networks. https://arxiv.org/ftp/arxiv/papers/2003/2003.10849.pdf [ Links ]

Wang, L. and Wong, A. (2020). COVID-Net: A Tailored Deep Convolutional Neural Network Design for Detection of COVID-79 Cases from Chest Radiography Images. https://arxiv.org/pdf/2003.09871.pdf [ Links ]

World Health Organization (WHO) (2021, April 11). World Health Organization. https://www.who.int/emergencies/diseases/novel-coronavirus-2019 [ Links ]

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Original articles COVID-19 Diagnosis with Deep Learning Diagnóstico de COVID-19 con Deep Learning Ph.D. in Geomatics Engineering, Yildiz Technical University, Turkey. Affiliation: Assistant Professor, Department of Geomatics Engineering, Gumushane University, Gumushane, Turkey. E-mail: hatice.catal@yahoo.com.tr The coronavirus disease 2019 (COVID-19) is fatal and spreading rapidly. Early detection and diagnosis of the COVID-19 infection will prevent rapid spread.

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review

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Biosafety measures to prevent COVID-19 in healthcare professionals: an integrative review

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ABSTRACT Objective: to identify the main biosafety measures for preventing COVID-19 in...

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CANAL ENFERMERO - Consejo General Enfermería

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Mascarillas: cómo poner y retirar paso a paso

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This topic will discuss the management of COVID-19 in hospitalized adults. Our approach to hospital management evolves rapidly as clinical data emerge. Clinicians should consult their own local protocols for management, which may differ from our approach. Interim guidance has been issued by the World Health Organization and, in the United States, by the Centers for Disease Control and Prevention [ 2,3] and the National Institutes of Health COVID-19 Treatment Guidelines Panel [ 4]. Links to these and other related society guidelines are found elsewhere. (See 'Society guideline links' below.)

The management of patients with COVID-19 in the home and outpatient setting is discussed in detail elsewhere. (See "COVID-19: Outpatient evaluation and management of acute illness in adults".) (Related Pathway(s): and .)

Respiratory and critical care of patients with COVID-19 are also discussed separately. (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)" and "COVID-19: Management of the intubated adult".)

This approach to evaluation reflects our institution's practice, which was established with interdisciplinary input. Although we check several laboratory tests to evaluate patients with documented or suspected COVID-19, the prognostic value of many of them remains uncertain, and other institutions may not include all these tests.

At least initially, we check the following laboratory studies daily:

●Complete blood count (CBC) with differential, with a focus on the total lymphocyte count trend

●Complete metabolic panel

●Creatine kinase (CK)

●C-reactive protein (CRP)

Initially, we check the following studies every other day (or daily if elevated or in the intensive care unit):

●Prothrombin time (PT)/partial thromboplastin time (PTT)/fibrinogen

We check the following studies at baseline and repeat them if abnormal or with clinical worsening:

●Lactate dehydrogenase, repeated daily if elevated

●Troponin, repeated every two to three days if elevated

●Electrocardiogram (ECG), with at least one repeat test after starting any QTc-prolonging agent (see "COVID-19: Arrhythmias and conduction system disease", section on 'Monitoring for QT prolongation')

We also check hepatitis B virus serologies, hepatitis C virus antibody, and HIV antigen/antibody testing if these have not been previously performed. Chronic viral hepatitis could affect interpretation of transaminase elevations and exacerbate hepatotoxicity of certain therapies; underlying HIV infection may change the assessment of the patient's risk for deterioration and would warrant initiation of antiretroviral therapy.

We check a portable chest radiograph in hospitalized patients with COVID-19; for most patients, this is sufficient for initial evaluation of pulmonary complications and extent of lung involvement. Although chest computed tomography (CT) was frequently used in China for evaluation of patients with COVID-19, we reserve chest CT for circumstances that might change clinical management, in part to minimize infection control issues related to transport. This is consistent with recommendations from the American College of Radiology [ 5]. Although certain characteristic chest CT findings may be seen in COVID-19, they cannot reliably distinguish COVID-19 from other causes of viral pneumonia. (See "COVID-19: Clinical features", section on 'Imaging findings'.)

We do not routinely obtain echocardiograms on patients with COVID-19; developments that might warrant an echocardiogram include increasing troponin levels with hemodynamic compromise or other cardiovascular findings suggestive of cardiomyopathy. Acute myocardial injury has been a described complication of COVID-19. (See "COVID-19: Evaluation and management of cardiac disease in adults", section on 'Targeted cardiac evaluation'.)

Secondary bacterial infection has not been a frequently reported feature of COVID-19; if this is suspected (eg, based on chest imaging or sudden deterioration), we check two sets of blood cultures and sputum Gram stain and culture. Procalcitonin can be checked to assess the risk of secondary bacterial infection; however, since elevated procalcitonin levels have been reported as COVID-19 progresses, they may be less specific for bacterial infection later in the disease course [ 6-9].

GENERAL MANAGEMENT ISSUES

Empiric treatment for bacterial pneumonia in select patients - For patients with documented COVID-19, we do not routinely administer empiric therapy for bacterial pneumonia. Data are limited, but bacterial superinfection does not appear to be a prominent feature of COVID-19.

However, since the clinical features of COVID-19 may be difficult to distinguish from bacterial pneumonia, empiric treatment for community-acquired pneumonia is reasonable when the diagnosis is uncertain. Empiric treatment for bacterial pneumonia may also be reasonable in patients with documented COVID-19 if there is clinical suspicion for it (eg, new fever after defervescence with new consolidation on chest imaging). If empiric antibiotic therapy is initiated, we attempt to make a microbial diagnosis (eg, through sputum Gram stain and culture, urinary antigen testing) and reevaluate the need to continue antibiotic therapy daily. In such settings, a low procalcitonin may be helpful to suggest against a bacterial pneumonia; however, elevated procalcitonin has been described in COVID-19, particularly late in the course of illness, and does not necessarily indicate bacterial infection [ 6-9]. (See "Procalcitonin use in lower respiratory tract infections", section on 'Guiding antibiotic therapy'.)

Prevention of and evaluation for venous thromboembolism - We favor pharmacologic prophylaxis of venous thromboembolism for all hospitalized patients with COVID-19, consistent with recommendations from several expert societies [ 12-14]. Dosing and selection of pharmacologic agents to prevent venous thromboembolism in hospitalized patients with COVID-19 are discussed in detail elsewhere ( algorithm 1). (See "COVID-19: Hypercoagulability", section on 'Inpatient VTE prophylaxis'.)

Several studies suggest a high rate of thromboembolic complications among hospitalized patients with COVID-19, particularly those who are critically ill. The thromboembolic risk with COVID-19 as well as the evaluation for and management of these complications are discussed in detail elsewhere. (See "COVID-19: Hypercoagulability", section on 'VTE' and "COVID-19: Hypercoagulability", section on 'Full-dose anticoagulation'.)

Initial concerns about potential negative effects of NSAIDs in patients with COVID-19 [ 15,16] have not been supported by most observational data, which have failed to identify worse COVID-19 outcomes with NSAID use compared with acetaminophen or no antipyretic use [ 17-21]. As an example, in a study of patients who were hospitalized for COVID-19 in the United Kingdom, rates of in-hospital mortality, invasive ventilation, and oxygen requirement were not different among the 4205 patients who had used systemic NSAIDs the two weeks prior to hospitalization compared with propensity score-matched controls [ 21].

The European Medicines Agency (EMA), WHO, and the United States NIH COVID-19 Treatment Guidelines Panel do not recommend that NSAIDs be avoided when clinically indicated [ 4,22,23].

Avoiding nebulized medications - Inhaled medications should be administered by metered dose inhaler, whenever possible, rather than through a nebulizer, to avoid the risk of aerosolization of SARS-CoV-2 through nebulization.

If a nebulizer must be used, appropriate infection control precautions should be taken. These are discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Aerosol-generating procedures/treatments' and "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)", section on 'Nebulized medications'.)

Managing chronic medications

We do not initiate statins or aspirin in patients with COVID-19 who do not have pre-existing indications for them. More data are needed to determine whether statins or aspirins have direct benefits for COVID-19.

Retrospective studies have suggested that statin use is associated with a lower rate of intensive care unit admission or death in patients with COVID-19 [ 29-33]. Statins are known inhibitors of the MYD88 pathway, which results in marked inflammation, and have been reported to stabilize MYD88 levels in the setting of external stress in vitro and in animal studies [ 34]. Dysregulation of MYD88 has been noted and associated with poor outcomes in SARS-CoV and MERS-CoV infections, but this has not been described with SARS-CoV-2.

Similarly, observational data suggest that baseline aspirin use is associated with lower mortality among patients with COVID-19 [ 35].

Immunomodulatory agents - Use of immunosuppressing agents has been associated with increased risk for severe disease with other respiratory viruses, and the decision to discontinue prednisone, biologics, or other immunosuppressivedrugs in the setting of COVID-19 must be determined on a case-by-case basis.

These issues are discussed in detail elsewhere:

●(See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected patients during the pandemic, and issues related to COVID-19 vaccination in cancer patients" and "COVID-19: Risks for infection, clinical presentation, testing, and approach to infected patients with cancer", section on 'Management of cancer therapy'.)

●(See "COVID-19: Issues related to solid organ transplantation", section on 'Adjusting immunosuppression'.)

●(See "COVID-19: Care of adult patients with systemic rheumatic disease", section on 'Medication management with documented or presumptive COVID-19'.)

●(See "COVID-19: Issues related to gastrointestinal disease in adults", section on 'Adjusting IBD medications'.)

●(See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Continuation of immunosuppressive therapies'.)

COVID-19-SPECIFIC THERAPY

Approach - The optimal approach to treatment of COVID-19 is evolving. Trial data suggest a mortality benefit with dexamethasone as well as with adjunctive tocilizumab or baricitinib and a possible clinical benefit with remdesivir. Based on the pathogenesis of COVID-19, approaches that target the virus itself (eg, antivirals, passive immunity, interferons) are more likely to work early in the course of infection, whereas approaches that modulate the immune response may have more impact later in the disease course ( figure 1).

Defining disease severity - Mild disease is characterized by fever, malaise, cough, upper respiratory symptoms, and/or less common features of COVID-19, in the absence of dyspnea. Most of these patients do not need hospitalization.

If patients develop dyspnea, that raises concern that they have at least moderate severity disease, and these patients often warrant hospitalization. Patients can have infiltrates on chest imaging and still be considered to have moderate disease, but the presence of any of the following features indicates severe disease:

●Hypoxemia (oxygen saturation ≤94 percent on room air)

●Need for oxygenation or ventilatory support

Given oxygen saturation targets in patients with hypoxemia, most individuals with severe disease warrant some form of oxygen supplementation. Assessment of oxygen saturation in individuals with dark skin pigmentation warrants special attention, as pulse oximetry may overestimate the oxygen saturation in such patients. This is discussed in detail elsewhere, as are recommended thresholds for oxygen supplementation. (See "COVID-19: Respiratory care of the nonintubated hypoxemic adult (supplemental oxygen, noninvasive ventilation, and intubation)", section on 'Oxygenation targets'.)

This definition of severe disease is consistent with the definition used by the US Food and Drug Administration [ 37]. Some studies have used other features in addition to hypoxemia to characterize severe disease, such as tachypnea, respiratory distress, and >50 percent involvement of the lung parenchyma on chest imaging [ 38].

●For those with risk factors for severe disease who were hospitalized for COVID-19, we suggest remdesivir. Trial data suggest that remdesivir may improve time to recovery in such patients, although the magnitude of effect is uncertain [ 39-41]. If supplies are limited, we prioritize remdesivir for patients on low-flow oxygen supplementation at baseline, as discussed below. We suggest not using dexamethasone, which may be associated with worse outcomes in such patients [ 42]. Administration and dosing of remdesivir and evidence informing its use are discussed elsewhere. (See 'Remdesivir' below.)

●For those with risk factors for severe disease who were hospitalized for a non-COVID-19 reason and have incidental SARS-CoV-2 infection, we do not use remdesivir. Although monoclonal antibody therapy is not routinely used for hospitalized patients, in these situations, we evaluate whether they would be eligible for receiving it according to emergency use authorizations (EUAs), as with certain high-risk outpatients ( table 3). Monoclonal antibody therapy for nonsevere COVID-19 is discussed in detail elsewhere. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Monoclonal antibodies'.)

●For patients who have no oxygen requirement and who have no risk factors for progression to severe disease, we suggest supportive care only.

These patients warrant monitoring for clinical worsening. If they develop an oxygen requirement related to COVID-19, we treat them as described below. (See 'Patients with oxygen requirement/severe disease' below.)

We also encourage enrollment in clinical trials for treatment of nonsevere disease, if available. A registry of international clinical trials can be found at covid-trials.org.

In the United States, an EUA has been granted for convalescent plasma. However, we do not use convalescent plasma outside of clinical trials for patients with nonsevere disease given the lack of benefit in published trials thus far. (See 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)' below.)

Patients with oxygen requirement/severe disease - We prioritize COVID-19-specific therapy for hospitalized patients who have severe disease and require oxygen supplementation due to COVID-19. The approach depends on the oxygen or ventilatory requirement:

We also suggest remdesivir in these patients but prioritize it for patients on low-flow supplemental oxygen. The clinical benefit of remdesivir is unclear in patients who need higher levels of noninvasive support.

● Patients who require mechanical ventilation or extracorporeal membrane oxygenation (ECMO) - For such patients, we recommend low-dose dexamethasone; for those who are within 24 to 48 hours of admission to an ICU and within 96 hours of hospitalization, we also suggest adjunctive tocilizumab. Trial data suggest that dexamethasone and the addition of tocilizumab each improve mortality in this population when used early in hospitalization. We do not routinely use baricitinib, as more data are needed in this population, but it is a reasonable alternative to tocilizumab if the latter is not available. We suggest not routinely using remdesivir in this population. Although it is reasonable to add remdesivir in individuals who have only been intubated for a short time (eg, 24 to 48 hours), the clinical benefit of this is uncertain.

For all these patients, if dexamethasone is not available, other glucocorticoids at equivalent doses are reasonable alternatives. (See 'Dexamethasone and other glucocorticoids' below.)

Remdesivir is approved or available for emergency use in some countries but is not universally available [ 43-45]. Furthermore, some guidelines panels suggest not using remdesivir because of a lack of clear reduction in mortality [ 46,47]. (See 'Remdesivir' below.)

In addition to these therapies, we often refer patients to clinical trials of other therapies, if they allow concurrent use. A registry of international clinical trials can be found at covid-trials.org.

We do not routinely use convalescent plasma outside clinical trials because a clear clinical benefit has not been demonstrated. The potential role of monoclonal antibodies for hospitalized patients is restricted to a small subset of individuals, as discussed above and elsewhere. (See 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)' below.)

We generally suggest against off-label use of other agents. Although repurposed use of agents available for other medical indications has been described, for most of these agents there are insufficient data to know whether they have any role in treatment of COVID-19; thus, we recommend that such agents only be used in the setting of a clinical trial.

Specific treatments

Dexamethasone and other glucocorticoids

● Use of dexamethasone - We recommend dexamethasone for severely ill patients with COVID-19 who are on supplemental oxygen or ventilatory support. We use dexamethasone at a dose of 6 mg daily for 10 days or until discharge, whichever is shorter. If dexamethasone is not available, it is reasonable to use other glucocorticoids at equivalent doses (eg, total daily doses of hydrocortisone 150 mg, methylprednisolone 32 mg, or prednisone 40 mg), although data supporting use of these alternatives are more limited than those for dexamethasone. In contrast, we recommend that dexamethasone (or other glucocorticoids) not be used for either prevention or treatment of mild to moderate COVID-19 (patients not on oxygen). These recommendations are largely consistent with those of other expert and governmental groups [ 4,36,46,48,49]. (See 'Patients with oxygen requirement/severe disease' above.)

Glucocorticoids may also have a role in the management of refractory shock in critically ill patients with COVID-19. These issues are discussed elsewhere. (See "COVID-19: Management of the intubated adult", section on 'Use of glucocorticoids for non-COVID-19 reasons'.)

● Monitoring for adverse effects - Patients receiving glucocorticoids should be monitored for adverse effects. In severely ill patients, these include hyperglycemia and an increased risk of infections (including bacterial, fungal, and Strongyloides infections); the rates of these infections in patients with COVID-19 are uncertain. Nevertheless, pre-emptive treatment of Strongyloides prior to glucocorticoid administration is reasonable for patients from endemic areas (ie, tropical and subtropical regions). This is discussed elsewhere (see "Strongyloidiasis", section on 'Preventive treatment'). Major side effects of glucocorticoids are also discussed in detail elsewhere. (See "Major side effects of systemic glucocorticoids".)

The majority of the efficacy data on glucocorticoids in these meta-analyses comes from a large open-label trial in the United Kingdom in which 2104 and 4321 patients with confirmed or suspected COVID-19 were randomly assigned to receive dexamethasone (given at 6 mg orally or intravenously daily for up to 10 days) or usual care, respectively [ 42]. Reductions in 28-day mortality with dexamethasone in the overall trial population and in prespecified subgroups were as follows:

*Overall - 17 percent relative reduction (22.9 versus 25.7 percent, rate ratio [RR] 0.83, 95% CI 0.75-0.93).

*Patients on invasive mechanical ventilation or ECMO at baseline - 36 percent relative reduction (29.3 versus 41.4 percent, RR 0.64, 95% CI 0.51-0.81). Age-adjusted analysis suggested a 12.3 percent absolute mortality reduction.

*Patients on noninvasive oxygen therapy (including noninvasive ventilation) at baseline - 18 percent relative reduction (23.3 versus 26.2 percent, RR 0.82, 95% CI 0.72-0.94). Age-adjusted analysis suggested a 4.1 percent absolute mortality reduction.

In contrast, a benefit was not seen among patients who did not require either oxygen or ventilatory support; there was a nonstatistically significant trend towards higher mortality (17.8 versus 14 percent, RR 1.19, 95% CI 0.91-1.55). Results were similar when analysis was restricted to the patients with laboratory-confirmed COVID-19 (89 percent of the total population).

The optimal dose of dexamethasone is uncertain. In a randomized trial from Europe and India that included nearly 1000 adults with COVID-19 who needed at least 10 L of supplemental oxygen or ventilatory support, 12 mg daily of dexamethasone resulted in trends toward more days alive without life support at 28 days (22 versus 20.5 days; adjusted mean difference 1.3 days, 95% CI 0-2.6) and lower 28-day mortality (27 versus 32 percent, adjusted RR 0.86, 95% CI 0.68-1.08) compared with 6 mg daily, but these differences were not statistically significant [ 54]. Unless additional trial data indicate that a higher dose is superior, we continue to use the same 6 mg dose studied in the large trial from the United Kingdom.

Data on the efficacy of other glucocorticoids are limited to small trials, several of which were stopped early because of the findings of the trial above [ 55-57]. Individual trials of hydrocortisone in critically ill patients failed to demonstrate a clear benefit [ 55,56]; in a meta-analysis that included three trials evaluating hydrocortisone, there was a nonstatistically significant trend toward reduced 28-day mortality compared with usual care or placebo (OR 0.69, 95% CI 0.43-1.12) [ 50]. Trials evaluating methylprednisone have not demonstrated a clear benefit. In a randomized trial from Brazil that included 393 patients with suspected or confirmed severe COVID-19 (77 percent of whom were on oxygen or ventilatory support), there was no difference in 28-day mortality rates with methylprednisolone compared with placebo (37 versus 38 percent) [ 58]. It is uncertain whether the apparent difference in results compared with the larger dexamethasone trial is related to the glucocorticoid formulation and dose, other differences between the trial populations, or issues related to statistical power.

● Use of baricitinib - We suggest baricitinib as an option for patients requiring high-flow oxygen or noninvasive ventilation and for select patients who are on low-flow oxygen but are progressing toward needing higher levels of respiratory support despite initiation of dexamethasone. We generally reserve baricitinib for those who are within 96 hours of hospitalization or within 24 to 48 hours of initiation of ICU-level care, similar to the study population in the large trials. We do not use baricitinib in patients who have also received an IL-6 pathway inhibitor, as these agents have not been studied together and the safety of coadministration is uncertain. As with tocilizumab, we only use baricitinib with caution in immunocompromised patients. This approach is largely consistent with recommendations from the NIH COVID-19 Treatment Guidelines Panel [ 4]. In the United States, an emergency use authorization (EUA) was issued for baricitinib in combination with remdesivir in patients with COVID-19 who require oxygen or ventilatory support [ 59]; however, data also support use of baricitinib independent of remdesivir use. Tofacitinib, another JAK inhibitor, may be an alternative if baricitinib is not available. (See 'Patients with oxygen requirement/severe disease' above.)

Baricitinib is given at 4 mg orally once daily for up to 14 days. The dose is reduced in patients with renal insufficiency, and its use is not recommended if the estimated glomerular filtration rate (eGFR) is <15 mL/min per 1.7 ³ m ².

● Efficacy - Emerging data suggest that baricitinib may provide a mortality benefit for select patients with severe disease, even if they are already on dexamethasone. In a multinational placebo-controlled, randomized trial of 1525 hospitalized adults with COVID-19 who were not receiving invasive mechanical ventilation but had at least one elevated inflammatory marker (median CRP was 65 mg/L), adding baricitinib to standard of care reduced 28-day mortality (8.1 versus 13.1 percent with placebo; hazard radio [HR] 0.57, 95% CI 0.41-0.78); the reduction in mortality was maintained at 60 days [ 60]. Most participants (79 percent) were also receiving glucocorticoids, mainly dexamethasone, and 20 percent received remdesivir. Among the subgroup of patients who were on high-flow oxygen or noninvasive ventilation at baseline, the mortality with baricitinib was 17.5 percent versus 29.4 percent with placebo (HR 0.52, 95% CI 0.33-0.80); mortality rates with baricitinib were also lower than with placebo for individuals who were not on oxygen or on low-flow oxygen at baseline, but these differences were not statistically significant. A smaller trial that has been reported in abstract form only suggested that baricitinib also reduced mortality compared with placebo among 101 patients on mechanical ventilation or ECMO at enrollment (39 versus 58 percent, HR 0.54, 95% CI 0.31-0.96), but additional details from this trial are necessary to critically assess the findings [ 61].

Tofacitinib may also have clinical benefit, although data are more limited. In a randomized trial of 289 patients hospitalized with COVID-19, most of whom were receiving glucocorticoids, tofacitinib (10 mg twice daily for up to 14 days) reduced the combined outcome of death and respiratory failure at 28 days compared with placebo (18 versus 29 percent, relative risk 0.63, 95% CI 0.41-0.97) [ 65]. There was also a trend toward lower all-cause mortality (2.8 versus 5.5 percent, HR 0.49, 95% CI 0.15-1.63), but this was not statistically significant.

IL-6 pathway inhibitors (eg, tocilizumab) - Markedly elevated inflammatory markers (eg, D-dimer, ferritin) and elevated pro-inflammatory cytokines (including interleukin [IL]-6) are associated with critical and fatal COVID-19, and blocking the inflammatory pathway may prevent disease progression [ 66]. Several agents that target the IL-6 pathway have been evaluated in randomized trials for treatment of COVID-19; these include the IL-6 receptor blockers tocilizumab and sarilumab and the direct IL-6 inhibitor siltuximab.

We only use tocilizumab in patients who are also taking dexamethasone (or another glucocorticoid) and generally limit it to a single dose. We do not use tocilizumab in patients who are receiving baricitinib, as these agents have not been studied together and the safety of coadministration is uncertain. Tocilizumab should be avoided in individuals with hypersensitivity to tocilizumab, uncontrolled serious infections other than COVID-19, absolute neutrophil count (ANC) <1000 cells/microL, platelet counts <50,000, alanine aminotransferase (ALT) >10 times the upper limit of normal (ULN), and elevated risk for gastrointestinal perforation. Tocilizumab should be used with caution in immunocompromised individuals as very few were included in randomized trials. Data regarding sarilumab are less robust than those for tocilizumab.

Recommendations from expert and governmental guideline groups vary slightly. The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends adding tocilizumab to dexamethasone in recently hospitalized patients who are on high-flow oxygen or greater support and have either been admitted to the ICU within the prior 24 hours or have significantly increased inflammatory markers of inflammation; some panel members also suggested adding tocilizumab to patients on conventional oxygen supplementation if they had rapidly increasing oxygen needs and a CRP level ≥75 mg/L [ 4]. The Infectious Diseases Society of America (IDSA) suggests adding tocilizumab to standard of care (ie, glucocorticoids) for hospitalized adults who have progressive severe or critical COVID-19 and have elevated markers of systemic inflammation [ 36]. The National Health Service in the United Kingdom recommends consideration of tocilizumab as an adjunct to dexamethasone in patients with severe COVID-19 [ 67]. These include patients who have hypoxemia (oxygen saturation repeatedly <92 percent on room air) or are on supplementary oxygen and have a CRP ≥75 mg/L as well as those who started on respiratory support (high-flow oxygen, noninvasive ventilation, or invasive mechanical ventilation) in the prior 24 hours. For the latter group, sarilumab is recommended as an alternative if tocilizumab supplies are limited.

*In an open-label trial in the United Kingdom that included 4116 patients with suspected or confirmed COVID-19, hypoxemia (oxygen saturation <92 percent on room air or oxygenation supplementation of any kind), and a CRP level ≥75 mg/L, adding one to two doses of weight-based tocilizumab to usual care reduced the 28-day mortality rate compared with usual care alone (31 versus 35 percent, relative risk 0.85, 95% CI 0.76-0.94) [ 70]. Among those who were not on mechanical ventilation at baseline, tocilizumab similarly reduced the combined endpoint of progression to mechanical ventilation or death. There did not appear to be a statistically significant difference in mortality risk reduction by level of baseline respiratory support. Most of the trial participants (82 percent) were also using glucocorticoids, mainly dexamethasone, and subgroup analysis suggested that they were more likely to benefit from tocilizumab than were individuals who did not receive glucocorticoids.

*Preliminary results of another open-label international randomized trial that included 803 patients with severe COVID-19 who were admitted to the intensive care unit and required initiation of either respiratory or cardiovascular support suggested a mortality benefit of IL-6 pathway inhibitors [ 71]. Tocilizumab (n = 353) and sarilumab (n = 48) each reduced in-hospital mortality compared with standard of care (28 and 22 versus 36 percent; adjusted odds ratio for hospital survival 1.64, 95% credible interval [CrI] 1.14-2.35 for tocilizumab and 2.01, 95% CrI 1.18-4.71 for sarilumab). All patients were enrolled within 24 hours of admission to the intensive care unit, >80 percent received concomitant glucocorticoids, and 33 percent received remdesivir.

The reasons for the different findings among trials are uncertain. The trials that suggested a benefit with tocilizumab reported somewhat higher overall mortality rates compared with other trials, potentially reflecting more severely ill populations. This possibility is supported by a post-hoc analysis of a trial that did not originally show a benefit, in which tocilizumab was associated with a reduction in death and mechanical ventilation only among those with a CRP level >150 mg/L [ 79]. Trials that suggested a benefit also reported a high rate of concomitant glucocorticoid use, which most other trials did not; whether this is a relevant factor is uncertain. Finally, some of the trials that failed to show a benefit reported non-statistically significant trends towards a benefit, and these trials may have been underpowered to identify an effect.

In the United States, the Food and Drug Administration (FDA) approved remdesivir for hospitalized children ≥12 years and adults with COVID-19, regardless of disease severity [ 83]. The suggested adult dose is 200 mg intravenously on day 1 followed by 100 mg daily for 5 days total (with extension to 10 days if there is no clinical improvement and in patients on mechanical ventilation or ECMO). If a patient is otherwise ready for discharge prior to completion of the course, remdesivir can be discontinued. The pharmacokinetics of remdesivir in the setting of renal impairment are uncertain, and it is prepared in a cyclodextrin vehicle that accumulates in renal impairment and may be toxic; thus, remdesivir is not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/min per 1.73 m ² unless the potential benefit outweighs the potential risk. Given the short duration of therapy and the low concentration of the cyclodextrin vehicle, the risks in patients with renal impairment may be relatively low [ 84], and case series have reported safe use of remdesivir in patients with acute kidney injury and chronic kidney disease [ 85]. Liver enzymes should be checked before and during remdesivir administration; alanine aminotransferase elevations >10 times the upper limit of normal should prompt consideration of remdesivir discontinuation.

● Efficacy - Remdesivir has been evaluated for both severe and non-severe COVID-19 in hospitalized patients:

-In an interim report of the WHO-sponsored, multinational SOLIDARITY trial of patients hospitalized with COVID-19, there was no difference in overall 28-day mortality between the 2750 patients randomly assigned to open-label remdesivir and the 2708 patients assigned to standard care (RR 0.95, 95% CI 0.81-1.11) [ 40]. In an accompanying meta-analysis that included data from SOLIDARITY and the trials discussed below, there appeared to be a trend toward lower mortality with remdesivir among those who were not on mechanical ventilation at baseline, but this did not reach statistical significance (RR 0.8, 95% CI 0.63-1.01). There was no mortality benefit among those on ventilation at baseline (RR 1.16, 95% CI 0.85-1.60).

-ACTT-1, a multinational, randomized, placebo-controlled trial of remdesivir (given for up to 10 days or until death or discharge) included 1062 patients with confirmed COVID-19 and evidence of lung involvement; 85 percent had severe disease and 27 percent were receiving invasive mechanical ventilation or ECMO at baseline [ 39]. Remdesivir resulted in a faster time to recovery, defined as discharge from the hospital or continued hospitalization without need for supplemental oxygen or ongoing medical care (median 10 versus 15 days with placebo; rate ratio for recovery 1.29, 95% CI 1.12-1.49). Remdesivir reduced time to recovery whether patients were randomized within or after 10 days of symptom onset. However, in subgroup analysis, the reduced time to recovery was only statistically significant among patients who were on low-flow oxygen at baseline. Among the subset of patients on mechanical ventilation or ECMO at baseline, the time to recovery was similar with remdesivir and placebo (rate ratio for recovery 0.98, 95% CI 0.70-1.36), although it is possible that follow-up was too short to detect a difference.

Overall, there was a trend towards lower 29-day mortality that was not statistically significant (11.4 versus 15.2 percent with placebo, hazard ratio [HR] 0.73, 95% CI 0.52-1.03). Among the subset of patients who were on oxygen supplementation but did not require high-flow oxygen or ventilatory support (either noninvasive or invasive), there was a statistically significant mortality benefit at that time point (4.0 versus 12.7 percent, HR 0.30, 95% CI 0.14-0.64).

In ACTT-1, the large trial described above, remdesivir (given for up to 10 days) did not appear to reduce time to recovery among the 119 patients with mild-moderate disease (ie, no hypoxemia or tachypnea; five versus six days, recovery rate ratio 1.29, 95% CI 0.91-1.83), although the number of patients in that subgroup was underpowered to show a significant effect [ 39].

Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)

Use of monoclonal antibodies in outpatients with mild to moderate COVID-19 is discussed in detail elsewhere. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Monoclonal antibodies'.)

● Convalescent plasma - Convalescent plasma from individuals who have recovered from COVID-19 has been hypothesized to have clinical benefit for COVID-19, and in the United States, emergency use authorization has been granted for high-titer convalescent plasma among hospitalized patients with COVID-19 who are early in the course of disease or have impaired humoral immunity [ 97]. However, the available evidence does not support a clear role for convalescent plasma in patients with severe disease, and because of the lack of evident benefit, we suggest not using convalescent plasma for mechanically ventilated patients and not using it outside the context of clinical trials for other hospitalized patients. Observational data suggest that convalescent plasma may have a role for individuals with immunocompromising conditions or deficits in antibody production (eg, those receiving anti-CD20 therapies, those with hematologic malignancies) [ 98,99], although randomized trial data in these populations are lacking and emerging data are more robust for monoclonal antibodies, as discussed above. Convalescent plasma is also being evaluated in outpatient populations with nonsevere COVID-19 and as post-exposure prophylaxis. (See 'Patients with oxygen requirement/severe disease' above and "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Monoclonal antibodies' and "COVID-19: Convalescent plasma and hyperimmune globulin" and "COVID-19: Risks for infection, clinical presentation, testing, and approach to infected patients with cancer", section on 'Convalescent plasma'.)

Despite some observational evidence suggesting that early administration of convalescent plasma with high antibody titers was associated with lower mortality rates, randomized trials in hospitalized patients have not demonstrated a clear clinical benefit of convalescent plasma, including large trials that stopped enrollment for lack of mortality benefit [ 100-109]. (See "COVID-19: Convalescent plasma and hyperimmune globulin".)

Others - Many other agents with known or putative antiviral or immunomodulating effects have been proposed for use in patients with COVID-19 but have insufficient evidence of clinical benefit. Use of these agents for COVID-19 should be limited to clinical trials, if used at all; their efficacy has not been proven, and extensive off-label use may result in excess toxicity and critical shortages of drugs for proven indications. A registry of international clinical trials can be found at covid-trials.org, as well as on the WHO website and at clinicaltrials.gov.

● Ivermectin - In patients with COVID-19, we reserve ivermectin for prevention of Strongyloides reactivation in select individuals receiving glucocorticoids (see "Strongyloidiasis", section on 'Preventive treatment'). We do not use ivermectin for treatment of COVID-19 outside of clinical trials, as with other interventions that are not supported by high-quality data, consistent with recommendations from the WHO [ 3]. Systematic reviews and meta-analyses comparing ivermectin with placebo or standard of care have highlighted that the data on ivermectin for COVID-19 are of low quality [ 51,52,110,111]. As an example, in a meta-analysis of 16 trials evaluating ivermectin (only four included patients with severe disease), the effects on mortality, need for invasive mechanical ventilation, and duration of hospitalization were all very uncertain because of limitations in trial design and low numbers of events [ 51]. Although some meta-analyses have suggested clinical benefit (including mortality benefit) with ivermectin [ 112-114], these analyses pooled trials with active comparators (such as hydroxychloroquine), with unclear ascertainment of infection and disease severity, and with uncertain outcome assessment, all of which contribute further to low confidence in the findings; one large unpublished trial that suggested a mortality benefit and was included in these meta-analyses was subsequently removed by the preprint server [ 115]. Although ivermectin administered in a hospital setting has not been associated with excess serious adverse events in studies, gastrointestinal and neurologic side effects have been reported in individuals who obtained ivermectin at high or uncertain doses without prescription (eg, from internet or veterinary sources) [ 116]. Ivermectin had originally been proposed as a potential therapy based on in vitro activity against SARS-CoV-2; however, the drug levels used in the in vitro studies far exceed those achieved in vivo with safe drug doses [ 117].

● Hydroxychloroquine/chloroquine - We suggest not using hydroxychloroquine or chloroquine in hospitalized patients given the lack of clear benefit and potential for toxicity. Several large randomized trials failed to identify a mortality or other clinical benefit for hospitalized patients with COVID-19 [ 118-124]. In June 2020, the US FDA revoked its EUA for these agents in patients with severe COVID-19, noting that the known and potential benefits no longer outweighed the known and potential risks [ 125]. The potential toxicity of hydroxychloroquine and chloroquine, including QTc prolongation and arrhythmias, is discussed in detail elsewhere. (See "COVID-19: Arrhythmias and conduction system disease", section on 'Patients receiving therapies that prolong the QT interval' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Adverse effects' and "Methemoglobinemia", section on 'Dapsone'.)

● Favipiravir - Favipiravir is an RNA polymerase inhibitor available in some countries in Asia (including India and Russia) for treatment of nonsevere COVID-19. Data on outcomes are mixed; some trials have suggested more rapid virologic clearance and clinical improvement with favipiravir, but most were limited by potential confounders (eg, because of co-administration of immunomodulatory agents and other therapies) [ 126-128]. Trials have not identified a mortality benefit [ 126,127,129,130].

● IL-1 inhibitors - Interleukin-1 (IL-1) is a pro-inflammatory cytokine that has been associated with severe COVID-19, and some data suggest that treatment with IL-1 inhibitors (eg, anakinra) is associated with reduced COVID-19-associated mortality, but the potential role of IL-1 inhibitors in management of COVID-19 is uncertain [ 135-137]. One randomized trial performed in Italy and Greece evaluated subcutaneous anakinra for 10 days in hospitalized patients with COVID-19 who had an elevated soluble urokinase plasminogen activator receptor (suPAR), a biomarker that has been associated with disease progression in some studies; most participants were also receiving dexamethasone [ 138]. At 28 days, anakinra increased the likelihood of clinical recovery (50.4 versus 26.5 percent; unadjusted odds of a worse clinical severity score 0.36, 95% CI 0.26-0.49) and reduced mortality compared with placebo (3.2 versus 6.9 percent, hazard ratio 0.45, 95% CI 0.21-0.98). However, the suPAR biomarker is not widely available, so these results are difficult to apply in the United States and elsewhere. Additionally, it is uncertain whether anakinra offers advantages over other immunomodulatory agents that have demonstrated efficacy (eg, IL-6 inhibitors or JAK inhibitors). Other trials of IL-1 inhibitors (including anakinra in hospitalized patients with nonsevere COVID-19 [ 139] and canakinumab in patients with severe COVID-19 [ 140]) have not identified a reduction in ventilator-free or overall survival. In a randomized trial of 116 patients hospitalized with mild to moderate COVID-19, there was no evidence of clinical benefit of anakinra plus usual care compared with usual care alone; no difference was detected in the rates of mechanical ventilation or death at 14 days (34 versus 35 percent).

● Other immunomodulatory agents - In addition to JAK inhibitors (see 'Baricitinib and JAK inhibitors' above), IL-6 pathway inhibitors (see 'IL-6 pathway inhibitors (eg, tocilizumab)' above) and IL-1 inhibitors (discussed above), immunomodulatory agents from various other classes, including other cytokine inhibitors [ 141], other kinase inhibitors [ 142-145], complement inhibitors [ 146,147], bradykinin pathway inhibitors [ 148], and hematopoietic colony-stimulating factors agonist and antagonists [ 149,150], are being evaluated. Their use has been described mainly in case series and other observational studies. Although an unpublished report of a randomized trial suggested a survival benefit of lenzilumab, an anti-granulocyte-macrophage colony stimulating factor (GM-CSF) monoclonal antibody, in patients with severe COVID-19, uncertainties in trial design and outcomes reduce confidence in these findings [ 151].

● Azithromycin (with or without hydroxychloroquine) - We do not use azithromycin, either alone or in combination with hydroxychloroquine, for treating COVID-19. Randomized trials and observational studies have not demonstrated a clinical benefit [ 122,152-157].

● Vitamin D - In patients with COVID-19, vitamin D supplementation may be appropriate to meet the recommended intake or treat deficiency. However, we do not exceed the recommended upper level of intake, and there is no clear evidence that vitamin D supplementation or high-dose vitamin D improves COVID-19 outcomes. These data are discussed elsewhere. (See "Vitamin D and extraskeletal health", section on 'COVID-19'.)

Other agents that have been proposed for COVID-19 therapy include the HCV antivirals sofosbuvir plus daclatasvir [ 163-165], the selective serotonin receptor blocker fluvoxamine [ 166], famotidine [ 167-169], and zinc [ 170]. Clinical data thus far are insufficient to support a role for these agents in hospitalized patients, and for other agents (eg, colchicine [ 171-173]), accumulating data suggest no clinical benefit in this population. As above, their use for COVID-19 should be limited to clinical trials.

Some patients may develop acute respiratory distress syndrome (ARDS) and warrant intubation with mechanical ventilation. Management of ARDS in patients with COVID-19 and other critical care issues are discussed in detail elsewhere ( table 4). (See "COVID-19: Management of the intubated adult".)

In addition to ARDS, other complications of infection include arrhythmias, acute cardiac injury, acute kidney injury, thromboembolic events, and shock. Management of these complications is discussed elsewhere.

●(See "COVID-19: Arrhythmias and conduction system disease".)

●(See "COVID-19: Evaluation and management of cardiac disease in adults".)

●(See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Acute kidney injury'.)

●(See "COVID-19: Hypercoagulability".)

DISCHARGE - The decision to discharge a patient with COVID-19 is generally the same as that for other conditions and depends on the need for hospital-level care and monitoring.

Continued need for infection control precautions should not prevent discharge home if the patient can appropriately self-isolate there; long-term care facilities may have specific requirements prior to accepting patients with COVID-19. Criteria for discontinuing precautions and infection control issues in long-term care facilities are discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection", section on 'Discontinuation of precautions'.)

Older age (eg, >65 years), underlying medical comorbidities, and discharge to a skilled nursing facility have been associated with an increased risk of readmission following hospitalization for COVID-19 [ 174]. Patients with COVID-19 generally warrant outpatient follow-up through telehealth or an in-person visit following discharge from the hospital. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Outpatient management following inpatient or ED discharge'.)

INSTITUTIONAL PROTOCOLS - Several academic medical institutions in the United States have developed COVID-19 management protocols that are publicly available:

● Brigham and Women's Hospital

● Massachusetts General Hospital

● Mount Sinai Health System

● University of Washington Medicine

Partners in Health has also released resources for clinicians and organizations in resource-limited settings.

SPECIAL SITUATIONS

Overall, the management of COVID-19 in patients with HIV is the same as in patients without HIV; HIV should not be a reason to exclude a patient from clinical trials or other interventions [ 175]. However, drug interactions with antiretroviral agents are important to assess before starting any new therapies.

Although certain antiretroviral agents have been hypothesized to have efficacy against SARS-CoV-2, antiretroviral regimens should not be adjusted based on concern for COVID-19. Lopinavir-ritonavir is being evaluated in trials for patients with COVID-19, although data from randomized trials do not suggest a benefit [ 158,176]. If a patient with HIV is not on a protease inhibitor-containing regimen, the regimen should not be changed to include a protease inhibitor outside the context of a clinical trial and without consultation with an expert in the management of HIV [ 177]. One observational study of patients with HIV in Spain suggested that baseline use of tenofovir disoproxil fumarate plus emtricitabine (TDF-FTC) was associated with a lower rate of COVID-19 diagnosis and a lower COVID-19-associated mortality rate compared with other nucleoside reverse transcriptase inhibitor backbones (including tenofovir alafenamide plus emtricitabine); however, potential confounders (including underlying comorbidities and institutional differences in prescribing) were not accounted for in the analysis [ 178].

INFORMATION FOR PATIENTS - UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 th to 6 th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 th to 12 th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: COVID-19 overview (The Basics)" and "Patient education: COVID-19 and pregnancy (The Basics)" and "Patient education: COVID-19 and children (The Basics)" and "Patient education: COVID-19 vaccines (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Indications for hospitalization - Many patients with known or suspected COVID-19 have mild disease that does not warrant hospital-level care; having such patients recover at home is preferred. Indications for hospitalization are discussed in detail elsewhere. (See "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Determine if in-person evaluation warranted'.)

● Continuing chronic medications - Specific concern for COVID-19 should not impact the decision to start or stop angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs). People who are on an ACE inhibitor or ARB for another indication should not stop their medication. (See "COVID-19: Issues related to acute kidney injury, glomerular disease, and hypertension", section on 'Renin angiotensin system inhibitors'.)

We continue statins in hospitalized patients with COVID-19 who are already taking them. We also continue aspirin unless there is concern for bleeding risk. (See 'Statins and aspirin' above.)

● Approach to patients with no oxygen requirement - For such patients who have clinical ( table 2) or laboratory ( table 1) risk factors for severe disease and were hospitalized for COVID-19, we suggest remdesivir ( Grade 2C). Individuals who have risk factors but were hospitalized for other reasons (ie, have incidental SARS-CoV-2 infection) may be eligible for monoclonal antibody therapy, similar to high-risk outpatients. For patients without any risk factors, care is primarily supportive. All patients warrant close monitoring for disease progression. (See 'Patients without oxygen requirement' above and "COVID-19: Outpatient evaluation and management of acute illness in adults", section on 'Monoclonal antibodies'.)

*For patients receiving low-flow supplemental oxygen, we suggest low-dose dexamethasone and remdesivir ( Grade 2C). If they have significantly elevated inflammatory markers (eg, C-reactive protein [CRP] level ≥75 mg/L), have escalating oxygen requirements despite dexamethasone, and are within 96 hours of hospitalization, we suggest adding either baricitinib or tocilizumab on a case-by-case basis ( Grade 2C). If supplies of tocilizumab or baricitinib are limited, we prioritize them for more severely ill patients on higher levels of oxygen support. For immunocompromised patients, we also evaluate whether monoclonal antibody therapy is available through an investigational new drug application.

*For patients receiving high-flow supplemental oxygen or non-invasive ventilation, we recommend low-dose dexamethasone ( Grade 1B). If they are within 24 to 48 hours of admission to an intensive care unit (ICU) or receipt of ICU-level care (and within 96 hours of hospitalization), we suggest either baricitinib or tocilizumab in addition to dexamethasone ( Grade 2B). We also suggest adding remdesivir ( Grade 2C); if supplies are limited, we prioritize remdesivir for patients who are on low-flow oxygen supplementation at baseline.

*For patients who require mechanical ventilation or extracorporeal membrane oxygenation, we recommend low-dose dexamethasone ( Grade 1B). For those who are within 24 to 48 hours of admission to an ICU (and within 96 hours of hospitalization), we suggest adding tocilizumab to dexamethasone ( Grade 2B). If tocilizumab is not available, baricitinib is a reasonable alternative. We suggest not routinely using remdesivir in this population ( Grade 2C).

*If dexamethasone is not available, other glucocorticoids at equivalent doses are reasonable alternatives.

● Limited role for other therapies - We generally do not use other agents off-label for treatment of COVID-19. In particular, we suggest not using hydroxychloroquine, chloroquine, or lopinavir-ritonavir in hospitalized patients given the lack of clear benefit and potential for toxicity ( Grade 2B). We also suggest not using ivermectin for COVID-19 therapy in hospitalized patients ( Grade 2C). We suggest not routinely using convalescent plasma for hospitalized patients ( Grade 2B). (See 'Others' above and 'Antibody-based therapies (anti-SARS-CoV-2 monoclonal antibodies and convalescent plasma)' above.)

● Infection control - Infection control is an essential component of management of patients with suspected or documented COVID-19. This is discussed in detail elsewhere. (See "COVID-19: Infection prevention for persons with SARS-CoV-2 infection".)

ACKNOWLEDGMENTS - The UpToDate editorial staff acknowledges Eric Meyerowitz, MD, Camille Kotton, MD, Michael Mansour, MD, Pritha Sen, MD, Ramy Elshaboury, PharmD, Ronak Gandhi, PharmD, and Boris Juelg, MD, for their contributions to this topic review.

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COVID-19: Management in hospitalized adults - UpToDate

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1.-vitrinas [Internet]. Bvsalud.org. [citado el 3 de diciembre de 2021]. Disponible en: https://bvsalud.org/vitrinas/es/post_vitrines/nuevo_coronavirus/
2.-Kim YR, Liu A. Social distancing, trust and post-COVID-19 recovery. Tour Manag. 2022;88(104416):104416
3.-Li S, Yan Y. DATA-driven shock impact of COVID-19 on the market financial system. Inf Process Manag. 2022;59(1):102768.
4.-De La Serna JM. Aspectos Psicológicos Del COVID-19. Litres; 2021
5.-Łoś K, Kulikowska J, Waszkiewicz N. First-time psychotic symptoms in a patient after COVID-19 infection-A case report. Front Psychiatry. 2021;12:726059.
6.-Elsevier. Data Science for COVID-19: Volume 2: Societal and Medical Perspectives. 1a ed. Kose U, Gupta D, Costa de Albuquerque VH, Khanna A, editores. San Diego, CA: Academic Press; 2021
7.-Catal Reis H. COVID-19 diagnosis with deep learning. Ing Investig. 2021;42(1):e88825.
8.-Gestión R. El 49% cree que medidas del Gobierno controlarán parcialmente el Covid-19 [Internet]. Gestión. 2020 [citado el 3 de diciembre de 2021]. Disponible en: https://gestion.pe/peru/encuesta-datum-coronavirus-peru-covid-19-el-49-cree-que-medidas-del-gobierno-controlaran-parcialmente-el-covid-19-noticia/
9.-Soriano AR. Manual para actuar frente a la covid-19. MARGE BOOKS; 2020
10.-Inmunización [Internet]. Paho.org. [citado el 3 de diciembre de 2021]. Disponible en: https://www.paho.org/es/temas/inmunizacion
11.-Enfermedad por el coronavirus (COVID-19): Vacunas [Internet]. Who.int. [citado el 3 de diciembre de 2021]. Disponible en: https://www.who.int/es/emergencies/diseases/novel-coronavirus-2019/question-and-answers-hub/q-a-detail/coronavirus-disease-(covid-19)-vaccines?adgroupsurvey={adgroupsurvey}&gclid=CjwKCAiAs92MBhAXEiwAXTi25xVKPS_-kuAzd4bvhJAPZ8N4npMBn8k03c8D1MjS9lt84QeauJl-uhoChQ4QAvD_BwE
12.-CDC. Diferentes vacunas contra el COVID-19 [Internet]. Cdc.gov. 2021 [citado el 3 de diciembre de 2021]. Disponible en: https://espanol.cdc.gov/coronavirus/2019-ncov/vaccines/different-vaccines.html
13.-Perú - COVID-19 - Vacunas administradas [Internet]. Expansion.com. [citado el 3 de diciembre de 2021]. Disponible en: https://datosmacro.expansion.com/otros/coronavirus-vacuna/peru
14.-¿Cómo funciona la vacuna contra el Covid-19? [Internet]. Youtube; 2021 [citado el 3 de diciembre de 2021]. Disponible en: https://www.youtube.com/watch?v=qyDTyout7e4

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-se concluye que la prevención es lo mejor para combatir el contagió del corona virus que a rebatado muchas vidas 

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-se concluye que la prevención es lo mejor para combatir el contagió del corona virus que a rebatado muchas vidas 

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se llega a la conclusión de que si todos cumplimos las recomendaciones que nos brinda el ministerio de salud va ver menos contagios 

# data[].attributes.subject
se llega a la conclusión de que si todos cumplimos las recomendaciones que nos brinda el ministerio de salud va ver menos contagios 

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se llega a la conclusión que las vacunas reduciendo el riesgo de las personas de infectarse por el virus que causa el COVID-19, incluida esta nuevas variante. Las vacunas siguen siendo altamente efectivas para prevenir la hospitalización y la muerte.

# data[].attributes.subject
se llega a la conclusión que las vacunas reduciendo el riesgo de las personas de infectarse por el virus que causa el COVID-19, incluida esta nuevas variante. Las vacunas siguen siendo altamente efectivas para prevenir la hospitalización y la muerte.