# data[].attributes.body
Planning to manufacturing the third dose during 2021

# data[].attributes.body
Pfizer improved their vaccine by altering their orignial buffer to Tris, which stablize the chemicals when storge in low temperature for long period of time. FDA assessed the new product and find no new concerns about safety and effectiveness.

# data[].attributes.headline
The latest updates for Pfizer’s clinical trials

# data[].attributes.subject
The latest updates for Pfizer’s clinical trials

# data[].attributes.body
Good news for children 5 to 11 years of age:

A safe, effective vaccine is urgently needed for children younger than 12 years of age. As of November 9, 2021, a phase 1 evaluation of the BNT162b2 Covid-19 vaccine in children 5 to 11 years of age has been completed. A Covid-19 vaccination regimen consisting of two 10-μg doses of BNT162b2 administered 21 days apart was found to be safe, immunogenic, and efficacious in children 5 to 11 years of age. Phase 2 / 3 is ongoing with 2268 children randomly assigned to receive the BNT162b2 vaccine (1517 children) or placebo (751 children). [19]

# data[].attributes.headline
BNT162b2 Preclinical trial: Protection against Covid-19 in immunized rhesus macaques 

# data[].attributes.subject
BNT162b2 Preclinical trial: Protection against Covid-19 in immunized rhesus macaques 

# data[].attributes.body
To measure the clearance of SARS-CoV-2, the viral RNA levels were measured using reverse-transcriptase qPCR on samples taken from the respiratory system.

(a) The most significant result was the complete clearance of the virus from the lungs in just 3 days.

All in all, the preclinical trial proved this candidate to be an effective immunizer against COVID-19 and thus it was admitted to clinical trials

(Vogel et al, 2020)

# data[].attributes.headline
BNT162b2 Preclinical trial: Immunization of Rhesus Macaques

# data[].attributes.subject
BNT162b2 Preclinical trial: Immunization of Rhesus Macaques

# data[].attributes.body
Six non-human primates of species rhesus macaques were immunized with doses of 30 micrograms, 100 micrograms, and saline control and infected with SARS-CoV-2 55 days after immunization.

(a,b) Notably, an impressive immune response in the 100 microgram group showed three times the level of neutralizing titre compared to human serum post covid exposure. This indicates that B-cell maturation occurred to generate a large amount of IgG to combat the virus.

(c,d) Additionally, IFNγ was measured to have a strong response relative to IL-2.

(e,f) It was shown that IFNγ primarily induced a TH1 response, with a potent CD4⁺ and CD8⁺ T cell response., indicating a powerful cellular immune response.

(Vogel et al, 2020)

# data[].attributes.body
The biosimilar of the Pfizer vaccine, Spikevax from Moderna, shared the same mRNA sequence with the Pfizer vaccine but showed slightly lower effectiveness.
In contrast to Pfizer's competitors, our vaccine showed higher efficacy.

# data[].attributes.body
First agency approved usage of Pfizer. Check this out!

# data[].attributes.attachment_caption
each dose with 10 microgram RNA (1/3 of the normal version)

# data[].attributes.body
TARGET: Children from 5 to 11 years old

APPROVED in the USA: October 29, 2021. (have already been used in other countries and showed good data)

REASON: The shot size of the kid-size vaccine need to be shrunk due to the worry of inducing serious side effects and fierce immune response after administration (afraid of children not having fully developed immune system).

RESULTS: No new side effects (super rare myocarditis case after 2nd dose). Early results from Pfizer reviewed by FDA showed 90.7% effectiveness after the second dose application on children

# data[].attributes.body
Pfizer did not show high interest in vaccine development by using the mRNA technology in the past(before the pandemic), instead, they utilize mRNA to search for new cancer treatments. Most companies had not discovered the potential of mRNA technology during the progress of mRNA technology, So not a lot of resources have been put into this field during the past few decades.

# data[].attributes.attachment_caption
Extended data from figure 3 (Vogel et al, 2020)

# data[].attributes.headline
BNT162b2 Preclinical trial : Antibody response in mice

# data[].attributes.subject
BNT162b2 Preclinical trial : Antibody response in mice

# data[].attributes.body
(a) Intramuscular injections in four dosage groups of 0.2, 1, and 5 micrograms respectively as well as control of 8 BALB/c mice showed increased levels of IgG and neutralization titre relative to dosage. (b) Their affinity to (S) and the RBD specifically were measured and showed high affinity. These results indicate that the protein is translated and recognized by the immune system, which initiates the response of IgG and related factors

(c) Potent TH1 and TFH CD4 positive T cell and CD8 positive T cell responses through flow cytometry. Re-exposure of these cells ex vivo to S revealed high levels of TH1 cytokines, IL-2 and IFN gamma measured through immunoassays which showed the potency of induced cellular immunity.

(Vogel et al, 2020)

# data[].attributes.body
BNT162b2 is the name of an mRNA vaccine candidate developed in a collaboration between Pfizer and BioNTech that would eventually go on to become the officially approved vaccine.

The mRNA is delivered in a lipid nanoparticle and is N-methyl-pseudouridine nucleoside-modified RNA.

It encodes the full-length SARS-CoV-2 S protein that is locked in the perfusion conformation to increase antigen visibility. It also contains a native furin cleavage site, which allows the S2 domain to be accessible as well as the S1.

The vaccine showed to be potent at immunizing against Covid-19 and mice and clearing the disease from the lungs of non-human primates, thus it moved to clinical trials.

(Vogel et al, 2020)

# data[].attributes.headline
mRNA vaccines: Zero to Hero in a few crucial innovations

# data[].attributes.subject
mRNA vaccines: Zero to Hero in a few crucial innovations

# data[].attributes.body
Summarized is the culmination of decades of work done to overcome the challenges associated with using RNA for therapeutics:

One major issue is the delivery of the mRNA molecule. It is a much bulkier molecule than DNA due to the extra hydroxyl molecule at the 2' carbon. The mobility of the molecule, as well as target dependant delivery, is solved by engineering lipid-nanoparticles of varying sizes. Reagents are added to the nanoparticle to help in transfection across the cell membranes of a desired cell type.

mRNA is an inherently unstable molecule and is vulnerable to exonuclease degradation. To increase stability and translation, mRNA vaccines are modified with synthetic 5' caps, 5' and 3' UTRs are optimized, a 3' poly-A tail is added.

To reduce the immunogenicity of the molecule, the codon bias is accounted for in the design of the molecule. Additionally, modified nucleosides (such as N1-Methylpseudouridine) are used to reduce immunogenicity further, as well as increasing transcription

With the challenges surmounted, the benefits of an mRNA vaccine can stand out:

Compared to other vaccines, mRNA is easier to develop rapidly due to the availability of genetic information online. The day that the genome of SARS-CoV-2 was uploaded, researchers started synthesizing the RNA in their lab. This is vital when you are trying to contain a global pandemic.

mRNA would be a great vaccine platform for fast-mutating viruses because mRNA can be modified easily, specifically counteract the fast-mutating genome of SARS-CoV-2 and the emergence of new variants.

Due to this flexibility, you can code for anything you want. This allows you to test multiple candidates at once, such as different proteins or different parts of a protein.

mRNA molecules were shown to elicit a mutch more potent neutralizing antibody response when compared to DNA immunization methods.

It does not have to be localized to the nucleus to be expressed and does not carry a risk of insertional mutagenesis.

It can be expressed transiently when non-replicative or can be made self-replicative for a longer effect which allows flexibility in dosage.

(Pardi et al, 2018)

# data[].attributes.headline
Neutralizing the disease: the impact of convalescent plasma donation on Covid-19 patient outcomes

# data[].attributes.subject
Neutralizing the disease: the impact of convalescent plasma donation on Covid-19 patient outcomes

# data[].attributes.body
Prior to vaccines, our main concern was to prevent infection and treat severe cases of Covid-19 effectively to keep hospitals below capacity. Treatment centers for Covid-19 were using a variety of medications to treat the disease. One notable treatment is the use of convalescent plasma; plasma that was donated by people who were sick with SARS-CoV-2 and made a recovery. This is because their plasma contains antibodies that were made by their body to prevent infection and clear the virus.

A large-scale analysis by Joyner et al. found that there was a strong correlation between the %IgG concentration and predicting outcomes of the disease. They found that in a sample containing 52.3% ICU patients, those that were given low IgG plasma had a seven-day mortality rate of 13.7% while patients receiving high IgG plasma had a seven-day mortality rate of 8.9%. This leads them to the conclusion that IgG is vital for the clearance of the virus, as well as reducing its virulence in the host.

Additionally, a one-day difference in administering the convalescent plasma to the patients had made a huge difference. Those that received the treatment three days after being diagnosed with COVID-19 had a mortality rate of seven-day 8.7%, but those that received it four days after diagnosis had a seven-day mortality rate of 11.9%

This study shows the importance of the immune response; even in advanced cases of COVID-19,  increasing the IgG levels alone can lower mortality by significant margins. This also highlights the importance of early intervention for patient outcomes, and the limitations of treatment for Covid-19. At this time, we could improve patient outcomes, but we could not prevent infection.

Luckily for us, the efforts to create a vaccine were not only heavily expedited and incentivized, the process of developing a vaccine may have been revolutionized altogether due to the decades-long effort to bring mRNA vaccines to the forefront of clinical research.

(Joyner et al, 2020)

# data[].attributes.headline
How the body defends itself against SARS-CoV-2 at the molecular level

# data[].attributes.subject
How the body defends itself against SARS-CoV-2 at the molecular level

# data[].attributes.body
To combat a viral infection the human body has a variety of tools. One factor that plays an important role in reducing the severity of some viruses is the neutralization titre of an individual; the amount of IgG antibodies in their blood.

In the case of SARS-CoV, vaccine candidates showed that immunizing individuals resulted in a greater increase of neutralizing antibodies, rather than a T-cell mediated response. This makes sense immunologically - if the S protein is bound to an antibody, the virus cannot infect cells because it needs the RBD to bind to ACE-2. Due to its similarity to (S) in SARS-CoV, researchers had good reason to suspect that the same may be true for SARS-CoV-2.
(Yuxian et al, 2004)

# data[].attributes.body
The S protein is made up of two subunits: S1 is primarily responsible for binding to a receptor using the receptor-binding domain (RBD) and S2 is involved in membrane fusion. (1)

The S protein exists in two conformations. The prefusion conformation and the postfusion conformation. The prefusion conformation is the most common state, as it increases the accessibility of the RBD so that it may potentially bind to its target site. This is also true for epitopes that are on the surface of S1. The postfusion conformation is formed upon target-specific receptor binding, which results in the cleavage and the loss of the S1 subunit, and membrane fusion initiates. (2)

Despite the lower sequence identity overall, the 2019-nCoV RBD is more similar to SARS-CoV than the SARS-like bat coronaviruses (1). This was further verified by cryo-EM imaging of the prefusion S protein which revealed key residues in the S1 subunit (2).

In SARS-CoV, The S protein RBD binds to the human angiotensin-converting enzyme 2 (ACE2) receptor and is the main pathogenicity and virulence factor. (3)

The S protein, and the RBD in particular, were considered for a vaccine due to their ability to induce a potent neutralizing antibody (IgG) response. (3)

Due to these similarities, as well as the symptoms of the disease, 2019-nCoV is renamed SARS-CoV-2

1:(Roujin et al, 2020) 2:(Wrapp et al, 2020) 3: (Yuxian et al, 2004)

# data[].attributes.headline
The Road to a Vaccine: Disease identification and Drug Development

# data[].attributes.subject
The Road to a Vaccine: Disease identification and Drug Development

# data[].attributes.body
Cases of viral pneumonia were first identified in Wuhan, China. An RNA virus causing this disease was identified as a novel coronavirus strain in 2019. Thus, the disease was originally dubbed 2019-nCoV

# data[].attributes.attachment_caption
Figure 2a and 2b from Roujian et al, 2020

# data[].attributes.body
The sequence of 2019-nCoV was analyzed with Blastn, which was categorized into different genes.  The results are tabulated in (A). The highest sequence identity was found to be with SARS-like bat coronavirus strains, mostly ranging from 87% to 99% in different genes. One exception was the S gene, which was only 75%. Likewise, the encoded S protein was only 80% similar.

2019-nCoV was found to have a sequence identity of 79% to SARS-CoV and 50% to MERS-CoV (not pictured), which were SARS coronaviruses that caused outbreaks in 2002 and 2012 respectively.

(Roujin et al, 2020)

# data[].attributes.headline
Will the Pfizer vaccine be LESS effective? We do not know yet.

# data[].attributes.subject
Will the Pfizer vaccine be LESS effective? We do not know yet.

# data[].attributes.attachment_link.title
New Covid strain named Omicron, is 'variant of concern'

# data[].attributes.body
Next-Generation sequencing was utilized to sequence the genome of 2019-nCoV particles, sampled from nine patients viral pneumonia patients who were close to the site of the initial outbreak. Eight of the genomes were fully sequenced and had a ~98% sequence identity, the consensus of which could be used to perform sequence identity analysis. The full genome of the virus became available online.

(Roujin et al, 2020)

# data[].attributes.body
Objectives: Designed as a 1:1 vaccine candidate to placebo study to obtain safety, immune response, and efficacy data needed for regulatory review. Participants would receive two 30μg doses of the BNT162b2 candidate. The trial design allowed for interim analyses and unblinded reviews. [16]

Primary Endpoints: The number of participants with symptomatic COVID-19 who have not been infected by SARS-CoV-2 prior to immunization, as well as the number of participants with symptomatic COVID-19 regardless of whether participants have previously been infected by SARS-CoV-2. [16]

Secondary Endpoint:  The number of participants with severe COVID-19 in those groups [16]

Results: All primary efficacy endpoints with 95% efficacy. 170 confirmed cases of COVID-19. 162 cases were seen in the placebo group. 8 cases in the vaccine group. [16]

# data[].attributes.body
Objectives: Safety, immunogenicity, tolerability and optimal dose level of two vaccine candidates in healthy adults. Identify the preferred vaccine candidate. [16]

Endpoints: Assessment of local reactions, systemic events and adverse events. Levels of SARS-CoV-2 neutralizing titers, S1-binding IgG and RBD-binding IgG [16]

Results: At 7 days after a second dose, 30μg BNT162b2 elicited SARS-CoV-2–neutralizing geometric mean titers (GMTs) and robust antigen specific CD8+ and Th1-type CD4+ T-cell responses.in younger adults (18-55 years of age) and in older adults (65-85 years of age), demonstrating strong immunogenicity in both age groups. Across all populations, BNT162b2 administration was well tolerated with mild to moderate fever in fewer than 20% of the participants. [16]

# data[].attributes.body
British Medical Journal identifies serious flaws in Pfizer trial [17]:
Protocol deviation included:

Negligence of patient monitoring following shot

Lack of timely follow-up of patients with adverse effects

Vaccines not being stored at correct temperature

Mislabeling of laboratory specimens

Participant recruitment:

Pfizer wanted to ensure they recruited a diverse and representative patient population [16]. This meant selecting the right sites and managing patient recruitment [16]. However, people weren’t signing up in target areas as fast as the companies expected. Pfizer deployed mathematical models to predict COVID-19 hotspots using infection rate and location data, but they weren’t doing a good job at predicting virus hotspots more than a few weeks out.

Operational considerations:

Ultra-cold storage: Pfizer had to ensure the site was set up to manage temperatures -80 degrees Celsius to -60 degrees Celsius and have monitors on site to ensure that all of the trial protocols were followed. [16]

Ensuring safety in a pandemic: Pfizer had to ensure patient and staff safety, which they did through the use of PPE and other measures. [16]

# data[].attributes.headline
A novel trial design was Pfizer's biggest strength

# data[].attributes.subject
A novel trial design was Pfizer's biggest strength

# data[].attributes.body
Remote monitoring: Pfizer used a decentralised trial design on approximately 90% of the trial monitoring making resource assignment much more agile [16]. Pfizer reviewed reactogenicity e-diary data (daily review is optimal) during the active diary period which was next-day to one-week following the second vaccine.

Simultaneous evaluation of various mRNA candidates: Pfizer assessed up to four mRNA candidates simultaneously in Phase 1 and 2 to improve efficiency of evaluation in a greater number of volunteers [16].

Rolling data submission: FDA received key portions of the application months in advance compared with when they would in a typical timeline. This gave the FDA the opportunity to begin reviewing and resolving issues sooner, shortening the overall review time.

What does this mean for the future of clinical trials? Hybrid clinical trials make research and development less costly as well improve efficiency and the time needed to set-up. This is clearly shown as clinical trial sites were running in weeks, as opposed to months, as there are usually preparations involving locating staff in specific locations for trial monitoring. Furthermore, e-consenting for the trial not only increased the safety of its staff and health care providers, but also improved efficiency. [18]

# data[].attributes.body
What? A randomized, placebo-controlled, observer-blind, dose-finding, vaccine candidate-selection efficacy study to assess experimental vaccines that could help treat or prevent COVID-19. [16]

Who? 43, 548 healthy male and female participants aged 12-85 [16]

Where? 155 global study locations spanning six countries (US, Germany, Brazil, Turkey, Argentina and South Africa) [16]

When? A 7-month effort, with Phase 1 beginning in May 2020 and Phase 3 reaching its primary analysis in November 2020 [16]

# data[].attributes.attachment_caption
Key Events in the development of Pfizer/BioNTech's COVID-19 Vaccine. Source: Nature.com (9).

# data[].attributes.headline
Pfizer/BioNTech Vaccine Timeline - How was it developed so quickly?

# data[].attributes.subject
Pfizer/BioNTech Vaccine Timeline - How was it developed so quickly?

# data[].attributes.body
Previously, the fastest vaccine development, from viral sampling to approval, was four years, for mumps in the 1960s (9). It seemed highly optimistic and impossible to create a vaccine even by the summer of 2021. How did the Pfizer/BioNTech vaccine become the first fully-tested immunization to be approved for emergency use?

Social and political urgency requires massive funding and intense research, leading to expedited manufacturing, clinical trials, and other processes (9)

Scientists have been conducting research on related coronaviruses even before January of 2020 (9)

Safety concerns were not encountered by the companies (9)

In the trial's final stages, the silver lining was that COVID-19 was prevalent, providing sufficient evidence that the vaccine is effective (9)

# data[].attributes.attachment_caption
Number of COVID-19 vaccine doses administered in the United States as of November 17, 2021, by vaccine manufacturer. Source: Statista (8).

# data[].attributes.body
Manufacturer: Pfizer Inc. and BioNTech (5)
Name: BNT162b2 (5)
Brand Name: Comirnaty (5)
Type of Vaccine: mRNA (5)
How is it administered? Shot in the muscle of the upper arm (5)

Close to 260,000,000 COMIRNATY vaccine doses have been administered in the U.S. as of November 17th 2021 (8).

# data[].attributes.body
Legal Lawsuits
Pfizer holds the record for the largest fine paid for a healthcare fraud lawsuit, ordered to pay $2.3 billion in fines, penalties, and settlements for illegal marketing claims (3).

Other cases include aggressive marketing (i.e. illegal claims), defective heart valves, wrongful firing of employees, intellectual property claims, and others (3).

Supply Issues
Pfizer failed to meet delivery quotas or the initial doses of the COVID-19 vaccine at the end of 2020. PFE.N shares fell after the company could only ship half of the vaccines it originally planned for 2020 due to supply-chain obstacles requiring significant scale-up (6).

Patent Cliffs
Pfizer’s blockbuster Lyrica, a drug for fibromyalgia, has churned out billions and climbed to the top of the company's pharma sales charts since FDA approval in 2004. The FDA approved copycats from 10 drugmakers in July of 2019, officially putting Pfizer's top product - and its $3.6 billion in U.S. sales last year - on notice (7).

# data[].attributes.attachment_caption
Pfizer shares (PFE.N) hit a record high of $50.42 on August 17th. 2021. Source: Reuters.com (4).

# data[].attributes.body
Pfizer’s work in developing and mass-producing a vaccine for the COVID-19 virus is unparalleled. Analysts have noted that this is the fastest a vaccine has ever been approved, rolled out, and mass-administered to the public. This is also the fastest response to a pandemic in recent history (3).

The vaccine is the first:

Fully FDA-approved COVID-19 vaccine (5)

To receive FDA Emergency Use Authorization (5)

# data[].attributes.body
Let the numbers speak for themselves:

49th largest public company on Forbes Global 2000 (3)

2nd largest pharmaceutical company by revenue in 2020 (3)

$50 billion of sales annually (3)

$194 billion in 2021 market capitalization (3)

Generating $14 billion from the vaccine alone, Pfizer shares hit a record high of $50.42 in August 2021 for the first time in more than 20 years (4).

# data[].attributes.attachment_caption
Pfizer R&D Spending ($B). Source: Pfizer Inc (2).

# data[].attributes.body
Research and Development
Pfizer's R&D spending grew 13% from 2017 to 2019, spending $7.66 billion and $8.65 billion respectively. The pharmaceutical giant incurred $3.86 billion in R&D expenses during the first half of 2020 in light of its potential COVID-19 vaccine (2).

Brand Recognition
The company manufactures and markets prominent products such as Advil, Viagara, Xanax, EpiPen (3).

One of Pfizer's best-sellers, Prevnar 13, a pneumococcal conjugate vaccine, brought in $5.9 billion in revenue in 2020. Another top-seller, Ibrance, a breast cancer treatment, had $5.4 billion in 2020 revenue (1).

# data[].attributes.body
About The Company
The fine chemicals business originally established in 1849 by Charles Pfizer and Charles Erhart has now evolved into an American multinational research-based biopharmaceutical corporation (1).

Pfizer develops and manufactures medicines and vaccines for a wide range of medical fields, such as immunology, cardiology, endocrinology, and oncology (1).

# data[].attributes.body
Samantha Chan - Introduction, The Vaccine: Background Information

Helena Jovic - Clinical Trials

Veniamin Razin -  Drug development and disease identification, Molecular explanation, mRNA vaccine innovations, BNT162b2 Preclinical trial.

Runze Wang - Analysis & Future Outlook

# data[].attributes.body
1. “Pfizer Inc. 2020 Form 10-K Annual Report.” Pfizer Inc., 2021.

2. Tabios, Angelee. “R&D Report Card: Pfizer Spending Reaches 3-Year High in 2019.” S&P Market Intelligence, 29 Oct. 2020, https://www.spglobal.com/marketintelligence/en/news-insights/latest-news-headlines/r-d-report-card-pfizer-spending-reaches-3-year-high-in-2019-60765584.

3. “Pfizer SWOT Analysis 2021: HOW COVID-19 Vaccine Affects Its Performance.” PESTLE Analysis, 16 Mar. 2021, https://pestleanalysis.com/pfizer-swot-analysis/.

4. Krauskopf, Lewis, and Carew Sinéad. “Pfizer Shares Hit Record High with COVID-19 Vaccine Stocks on a Tear.” Reuters, 10 Aug. 2021, https://www.reuters.com/business/pfizer-shares-hit-record-high-with-covid-19-vaccine-stocks-tear-2021-08-10/.

5. “Comirnaty and Pfizer-BioNTech COVID-19 Vaccine.” U.S. Food and Drug Administration, 19 Nov. 2021, https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/comirnaty-and-pfizer-biontech-covid-19-vaccine.

6. Paris, Costas. “Supply-Chain Obstacles Led to Last Month’s Cut to Pfizer’s Covid-19 Vaccine-Rollout Target.” The Wall Street Journal, 3 Dec. 2020, https://www.wsj.com/articles/pfizer-slashed-its-covid-19-vaccine-rollout-target-after-facing-supply-chain-obstacles-11607027787.

7. Sagonowsky, Eric. “Lyrica Generics Roll: Pfizer Blockbuster Finally Hits Patent Cliff.” Fierce Pharma, 22 July 2019, https://www.fiercepharma.com/pharma/lyrica-generics-roll-pfizer-finally-hits-patent-cliff-for-nerve-pain-and-fibromyalgia.

8. Mikulic, Matej. “Covid-19 Vaccinations Administered Number by Manufacturer U.S. 2021.” Statista, 18 Nov. 2021, https://www.statista.com/statistics/1198516/covid-19-vaccinations-administered-us-by-company/.

9. Ball, Philip. “The Lightning-Fast Quest for COVID Vaccines — and What It Means for Other Diseases.” Nature, 18 Dec. 2020, https://www.nature.com/articles/d41586-020-03626-1.

10. Roujian, Lu et al. 2020. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. The Lancet, 395(10224):565-574 https://doi.org/10.1016/S0140-6736(20)30251-8.

11. Wrapp et al. 2020. Cryo-EM structure of the 2019-nCoV spike in the perfusion conformation.  Science, 367(6483): 1260-1263 DOI: 10.1126/science.abb2507

12. Yuxian, He et al. 2004. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine, Biochem. Biophys. Res. Commun, 324(2): 773-781 https://doi.org/10.1016/j.bbrc.2004.09.106.

13. Joyner, M. J. et al. 2020. Effect of Convalescent Plasma on Mortality among Hospitalized Patients with COVID-19: Initial Three-Month Experience. medRxiv. https://doi.org/10.1101/2020.08.12.20169359

14. Pardi, N. et al. mRNA vaccines — a new era in vaccinology. Nat Rev Drug Discov 17, 261–279 (2018). https://doi.org/10.1038/nrd.2017.243

15. Vogel, Annette B. et al. 2020. A prefusion SARS-CoV-2 spike RNA vaccine is highly immunogenic and prevents lung infection in non-human primates. bioRxiv. doi: https://doi.org/10.1101/2020.09.08.280818

16. Gruber, William C. (2020/12/10). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. New England Journal of Medicine, 383, 2603-2615. doi: 10.1056/NEJMoa2034577[2]

17. Thacker P D. Covid-19: Researcher blows the whistle on data integrity issues in Pfizer’s vaccine trial. British Medical Journal, 2021; 375 :n2635 doi:10.1136/bmj.n2635

18. Marra C, Gordon WJ, Stern AD. Use of connected digital products in clinical research following the COVID-19 pandemic: a comprehensive analysis of clinical trials. BMJ Open. 2021;11(6):e047341. 22 Jun. 2021. doi:10.1136/bmjopen-2020-047341

19. Gruber, William C. (2021/11/09). Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age. New England Journal of Medicine,  doi: 10.1056/NEJMoa2116298