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Adopting the slogan 'Prevention is better than cure', this Ministry of Health poster attempts to persuade people to adopt a healthier lifestyle. It was hoped that by improving the general health of the nation, the cost of running the NHS would eventually be reduced.
Catalogue reference: INF 13/194, no. 2 (undated)

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Adopting the slogan 'Prevention is better than cure', this Ministry of Health poster attempts to persuade people to adopt a healthier lifestyle. It was hoped that by improving the general health of the nation, the cost of running the NHS would eventually be reduced. Catalogue reference: INF 13/194, no.

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Public protests as Nigeria bans use of untested HIV vaccine

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Last week, the Nigerian governent banned any further use of an untested HIV vaccine developed by controversial surgeon, Jeremiah Abalaka, until investigations on its claimed efficacy are complete. "The vaccine has killed more people than it has cured", said Nigeria's Vice-President, Alhaji Atiku Abubakar.

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Six common misconceptions about immunization

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Common misconceptions about immunization. Responsibility of Adwoa. Adapted from CDC material

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A new report by the Centre for Countering Digital Hate (CCDH) has lambasted social media companies for allowing the anti-vaccine movement to remain on their platforms. The report's authors noted that social media accounts held by so-called anti-vaxxers have increased their following by at least 7·8 million people since 2019. "The decision to continue hosting known misinformation content and actors left online anti-vaxxers ready to pounce on the opportunity presented by coronavirus", stated the report. The CCDH warned that the growing anti-vaccine movement could undermine the roll-out of any future vaccine against COVID-19.

The report noted that 31 million people follow anti-vaccine groups on Facebook, with 17 million people subscribing to similar accounts on YouTube. The CCDH calculated that the anti-vaccine movement could realise US$1 billion in annual revenues for social media firms. As much as $989 million could accrue to Facebook and Instagram alone, largely from advertising targeting the 38·7 million followers of anti-vaccine accounts. Huge sums indeed, but it is worth noting that, in 2019, Facebook generated revenue of $70·7 billion.

A survey commissioned by the CCDH and released alongside their report found that around one in six British people were unlikely to agree to being vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a similar proportion had yet to make up their mind. The survey, which polled 1663 people, found that individuals who relied on social media for information on the pandemic were more hesitant about the potential vaccine. WHO has warned of an infodemic of false information about COVID-19 spreading online. Around a third of respondents to a six-country survey by the Reuters Institute for the Study of Journalism reported that they had seen "a lot or a great deal of false or misleading" information about COVID-19 on social media during the previous week.

"Attention grabbing headlines with sensationalist content can attract even the savviest internet users and studies have shown they tend to generate more user engagement", warned the Organisation for Economic Cooperation and Development, in July, 2020. "As a result, content personalisation algorithms can repeatedly expose people to the same or similar content and ads even on the basis of disinformation."

The CCDH report divided the online anti-vaccine movement into four (sometimes overlapping) groups. First, campaigners work full-time to foment distrust in vaccines, but they only reach 12% of the total audience that follows the anti-vaccine movement. Second, entrepreneurs reach around half of the anti-vaccine following, exposing them to advertisements for products purporting to have health benefits. The CCDH report accuses Facebook of being a "shopfront for anti-vaxx products", directing customers to online marketplaces where these products can be purchased. Imran Ahmed, founder and chief executive officer of CCDH, advocates prosecuting vendors who make false claims about their products. "Going after a few high-profile hucksters who are exploiting and encouraging anti-vaccine sentiment to make money would be a powerful disincentive to anyone else considering choosing the same path", he said. Conspiracy theorists constitute the third category. Finally, there are the communities, which have a relatively small following and are mainly to be found on Facebook.

In 2019, several social media firms pledged to act against the anti-vaccine movement. Facebook announced that it would not recommend content that contained misinformation on vaccines. YouTube removed advertisements from anti-vaccine videos, meaning the account holders would not make money, and Twitter ensured that the National Health Service or Department of Health and Human Services would appear as the first result for anyone searching for vaccine-related topics in the UK and USA, respectively.

In August, 2020, Facebook deleted a video posted by the US President, Donald J Trump, in which he suggested that children were "almost immune" to SARS-CoV-2, on the grounds that it contained "harmful COVID misinformation". Twitter suspended Trump's campaign account, which posted the same video. "The platforms genuinely want to tackle this problem", explained Heidi Larson, director of the Vaccine Confidence Project at the London School of Hygiene and Tropical Medicine. "Facebook have hired a lot of people to work on this and they are genuinely motivated to find answers. You often find that the staff in the social media firms are putting pressure on management to get things right-people want to feel good about where they work." Facebook uses fact-checkers to identify and label false information about COVID-19. Twitter has similar policies. Alongside Facebook, it has also offered free advertising space to WHO and national health authorities.

The CCDH is unconvinced. Their latest report, entitled Failure to Act, describes how out of 912 posts containing misinformation about COVID-19, fewer than one in 20 were dealt with by social media companies. Ahmed argues for a far sterner response: removing the anti-vaccine movement from the platforms. "The first step is to de-platform", he said. "Shutting down spaces and de-platforming individuals is the single most effective tool for dealing with these sorts of malign actors." Ahmed cites studies from counterterrorism, in which de-platforming was found to cause networks to fragment. "It is the one thing that absolutely works. It cripples the networks and it is the best way to stop the anti-vaxx infection from spreading", he stated.

Vish Viswanath, Professor of Health Communication in the Department of Social and Behavioral Sciences at the Harvard T H Chan School of Public Health, disagrees. "De-platforming makes me nervous", he said. "This is an issue of freedom of speech. Unless you have a situation where there is blatant misinformation that is directly causing harm, you have to ask 'where do you draw the line?' You might have actors whose anti-vaxx activities are not taking place on their social media channel, are they also to be removed?" Shutting down conspiracy theorists and campaigners risks making them into martyrs and could even lend credence to their arguments that they are speaking truth to power. "You cannot just take away the stage, and assume these people are going to go away", adds Larson. "We are talking about very deep-rooted beliefs; they will simply find another stage."

The CCDH-commissioned survey found strong public support for sanctions such as financial penalties and advertising boycotts against social media companies that declined to remove "material designed to spread fake news or misinformation on vaccines". Ahmed points out that 98% of Facebook's revenues come from advertising. "If advertisers are scared off by the content on a site, then there is a strong incentive for the platforms to remove it; we have seen plenty of examples of advertisers refusing to be associated with particular material", he explained.

Instead of de-platforming, Viswanath advises that vaccine advocates should be putting their energy into rebutting anti-vaccine arguments. "Groups such as the CCDH deserve a great deal of credit for calling attention to this issue, and adopting such a combative attitude", he said. "For much too long, the pro-vaccine groups have been reactive and reticent; they have assumed that science can speak for itself. That has not worked. We need to throw light on these malign actors, refute their arguments very aggressively and proactively."

Viswanath believes that the platforms are still not acting quickly enough. "They are making some tentative steps, but it is insufficient. It is not adequate to simply flag inappropriate posts; people will still read them and we know that even if a falsehood is labelled as such, people will still remember it, and some people will believe it", he said. "Our response has to draw on the science of how people develop these beliefs and then we can take up strategies to call the anti-vaxxers on their misinformation, rather than completely eliminate their voices." Ahmed counters that there is limited evidence on the efficacy of rebuttal. "The best way to stop someone from becoming an anti-vaxxer is to stop them from becoming infected in the first place", he stated. "I want to reduce the R ₀, rather than treat the disease."

Public attitudes towards vaccination can be split into three categories. First, there are people who have been persuaded of the merits of vaccination. In the UK and USA, this group constitutes somewhere between 70% and 90% of the population. Second, there are dogmatic anti-vaxxers. "These are people on the fringes", explains Viswanath. "They are not going to change their views." Between the two groups lies a third comprising people who are undecided. "These people have legitimate questions", said Viswanath. "They want to do the right thing, but they have doubts. This is where we need to be focusing our attention."

The anti-vaccine movement look as if they have already figured this out. A paper published in Nature earlier this year mapped online views on vaccination. The authors concluded that "although smaller in overall size, anti-vaccination clusters manage to become highly entangled with undecided clusters in the main online network, whereas pro-vaccination clusters are more peripheral". They warned that in a decade the anti-vaccination movement could overwhelm pro-vaccination voices online. If that came to pass, the consequences would stretch far beyond COVID-19.

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The online anti-vaccine movement in the age of COVID-19

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A new report by the Centre for Countering Digital Hate (CCDH) has lambasted social media companies for allowing the anti-vaccine movement to remain on their platforms. The report's authors noted that social media accounts held by so-called anti-vaxxers have increased their following by at least 7·8 million people since 2019.

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Summary

Since the invention of the smallpox vaccine, vaccines have greatly reduced the prevalence of diseases everywhere in the world. This research article explains which vaccines are available and where they are, what their impact on global health is, and how the world can make more progress against early death and disease with the help of vaccines.

All our charts on Vaccination

Not every child who should be vaccinated is vaccinated

This chart shows the global vaccination coverage of one-year-olds with some of the most important vaccines recommended by the WHO. For many essential vaccines coverage is now much higher than 80%. However, the rates of vaccination are still not sufficient.

If you click the play button you see that the coverage for most vaccines has increased substantially over time.

The vaccine against diphtheria, tetanus and pertussis, is often used as the key metric for global vaccination coverage because it is a good indicator for access to routine immunization services. In 2018, coverage of the third dose of DTP was 86%. This means that out of 135 million under-one-year-olds more than 19 million did not receive full immunization. The coverage of the first dose of DTP was 90% indicating that 13.5 million children were not vaccinated in 2018.

In 2018, only 35% of children globally received the rotavirus vaccine, which protects children from diarrheal diseases - one of the leading causes of child mortality. Similarly, pneumococcal vaccine that protects children from pneumonia - the leading cause of child mortality - only reached 47% of one-year-olds.¹

Related chart - the number of children vaccinated. This chart shows how many one-year-olds were vaccinated globally.

Why do not all children in the world receive vaccinations?

This chart shows that it is in poor countries where vaccination coverage is low. The vaccine coverage against diphtheria, pertussis (whooping cough), and tetanus is a good marker of the strength of a country's immunization programs since several administrations are required. All rich countries have vaccination coverage rates of more than 90%. It is in low- and middle-income countries where coverage is low - in some countries below 50%.

But the chart also shows that some poor countries - like Burundi, Rwanda, and Bangladesh - achieve high coverage rates. Similarly, countries in which a large share of the population is living in extreme poverty often - but not always - have lower immunization rates, as this chart shows.

We know that vaccines save lives. But how many lives vaccines have they saved?

The World Health Organisation (WHO) suggests that vaccination prevents 2-3 million deaths each year.² However, while we are certain that vaccines have saved millions of lives, calculating a precise number is impossible. Also the quoted number from the WHO is in important ways a very low estimate.

The counterfactual world, in which vaccines would have never been developed, would be so different that an estimate of the impact of vaccines is impossible. One example that makes this clear is to consider the impact of the smallpox vaccine: Smallpox was once an extremely common and deadly infectious disease, but it has been eradicated globally back in 1977 thanks to the vaccination against the disease. It is impossible to know exactly how many people would die of smallpox today if scientists had not developed the vaccine. Reasonable estimates are in the range of around 5 million lives per year, which implies that between 1980 and 2018 around 150 to 200 million lives have been saved.³ This makes clear why it is so difficult to estimate the number of lives saved every year and why the WHO estimate is rather low.

The basic mechanism by which vaccines work is simple: Vaccines create immunity in an individual by introducing a weakened or killed form of the pathogen that make us ill - such as bacteria or viruses - or its toxins or one of its surface proteins. The vaccine induces acquired immunity so that when your body encounters the real disease-causing agent it is ready to mount a defense.

There is a collective social benefit in a high vaccination coverage. For most diseases, the greater the proportion of people who are immunized, the better protected is everyone in the population as the disease transmission can be reduced or stopped. Herd immunity is a community protection that is created when a high percentage of the population is vaccinated, such that it less likely that the infectious disease spreads.⁴

Herd immunity provides a protective barrier, especially also for those who cannot be vaccinated. These include vulnerable groups such as babies too young to be vaccinated or immune-compromised children who are the first potential victims of low vaccination rates.

When a person is immune to a disease they can act as a barrier to slow down or prevent the transmission of disease to other people. When the number of people in a population that are immune against a disease is reached, such that a disease no longer persists in the population, this is called the herd immunity threshold (HIT). The table shows the HIT for several diseases. Measles and pertussis are highly contagious airborne diseases and a larger share of people need to be vaccinated to stop the transmission. Because of this these diseases have the highest HIT rates that need to be reached. For example, two doses of measles vaccination offers 99% protection, while in the absence of immunization, the lifetime risk of infection is nearly 100%.⁵

Herd Immunity Thresholds of vaccine-preventable diseases⁶

Disease

Transmission

Basic reproduction number

Herd Immunity Threshold

Progress made with vaccination

In total there are now at least 28 human diseases against which we have effective vaccines.⁷ The breakthrough that allowed us to get there was made in the late 18th century, the smallpox vaccine was the very first vaccine.

Vaccination has a long history. An early form of vaccination was referred to as 'variolation' or more broadly as 'inoculation'. Practised for a long time in Asia, this was an ancient technique of deliberate smallpox infection in which dried smallpox scabs were blown up the nose to infect the person with a form of the disease which was often milder. By the 1700s variolation had spread to Africa, India and the Ottoman Empire, followed by the UK and America, where the method of infection more frequently used was a puncture to the skin.

Variolation did work, but there were large risks. Those variolated could contract the more severe form of smallpox and die, and they could also transmit the disease to others.

In 1796 English physician Edward Jenner demonstrated another method of inoculation in which he relied on cowpox. Cowpox is a similar disease to smallpox and it had previously been observed that an infection with cowpox can protect against smallpox. Jenner conducted an experiment using matter from a cowpox lesion to inoculate his gardener's eight-year-old son James Phipps. Two months later Jenner exposed the boy to smallpox lesion matter and when Phipps did not develop smallpox he concluded that he was protected against the disease. Jenner called the procedure 'vaccination' after 'vacca' the Latin word for cow because of the origin of this first vaccination from the cowpox virus.

Following the findings of Jenner as the first scientific attempt to control disease by vaccination, the smallpox vaccine went through many iterations, with the newer vaccines produced by modern cell culture techniques (passing the virus through cell culture makes the vaccine safer). By the middle of the 20th century confidence grew that smallpox could be the first disease that humankind might be able to eradicate. In 1967 the WHO launched a global eradication of smallpox program. Mass vaccination of over 80% of a country's population ensued but people who were nomadic or lived in politically unstable regions posed particular problems. A number of innovations came in the development of foot-powered injector called the "ped-o-jet" and then the bifurcated needle, which was efficient and cost-effective to use.

In order to reach large sections of population, epidemiologist William Foege developed Eradication Escalation (E2) to contain smallpox outbreaks during October (the seasonal low point of smallpox transmission where prevention of just few cases could stop a smallpox chain transmission). Other obstacles faced included forcibly vaccinating an Indian religious leader to convince his followers to be vaccinated, negotiation of ceasefires for vaccine transport in war-torn Nigeria, vaccinating in concentric rings around an outbreak, and cash bounties to reward the reporting of smallpox cases. Finally in 1977 the last case of naturally contracted smallpox was reported in Somalia, in Ali Maow Maalin, and in 1980 the WHO announced that smallpox had been eradicated. We cover the history of smallpox, including the vaccination and eradication, in more detail in our entry on smallpox.

The chart here shows a timeline of innovation in the development of vaccines. Each bar begins in the year in which the pathogenic agent was first linked to the disease and the bar ends in the year in which a vaccination against that pathogen was licensed in the US.

For some diseases there has been a relatively short timespan between when the infectious agent was linked to the disease and when a vaccine was developed. The quickest was 10 years for measles. The agent was linked to the disease in 1953 and the vaccine was licensed in the U.S. in 1963.

Malaria is proving harder as it has been over a century since the agent was linked to the disease. Alphonse Laveran discovered in 1880 that the Plasmodium parasite is the cause for malaria.⁸

Early vaccines developed in the last several decades were insufficiently effective and until recently none of the scientific efforts led to a licensed vaccine. Recently there has been new hope for a malaria vaccine as we document in the relevant section in our entry on malaria.

Vaccine innovation has followed both scientific and political-economic developments:

Bacterial culture techniques which allowed the development of bacterial vaccines for diphtheria, tetanus, and pertussis in the early 1900s.

The first and second world wars prompted combined efforts by universities, governments, and private companies.

By the 1950s viral tissue culture techniques allowed the development of vaccines against polio, measles, mumps, rubella, and varicella (chickenpox).

New technologies in molecular biology and advanced chemistry techniques have most recently led to vaccines against hepatitis B, influenza, and pneumococcus, which causes pneumonia and meningococus, which causes meningitis and septicaemia.

The visualization here shows the reduction in cases and deaths from vaccine-preventable diseases in the United States after the introduction of each vaccine. This data was published by Roush and Murphy (2007)⁹ and the data can be viewed in a table here.

For several diseases the US has achieved a 100% reduction of cases and deaths and for many other diseases the reduction is often very substantial as well.

Reduction of cases and deaths of vaccine-preventable diseases in the United States after the introduction of the vaccine.¹⁰

The introduction of a vaccine was not the only reason for progress against these diseases, as the visualization shows. The case-fatality rates of measles was falling in high income countries such as the US prior to the introduction of the vaccine in 1960 - this is best seen by switching from the linear to the logarithmic axis. Improved living conditions, nutrition, and medical advancements meant that contracting measles was less and less likely to be fatal.

The rate of cases however was virtually unchanged until after the measles vaccine was introduced - as our visualization shows.¹¹

A visualization showing the total number of cases and deaths can be seen here.

The WHO estimates that 2 to 3 million deaths are prevented every year through immunization against diphtheria, tetanus, whooping cough, and measles. ¹²

Nonetheless, the WHO also estimates that VPDs are still responsible for 1.5 million deaths each year.

In the chart we see the global number of deaths of children younger than 5 years per year from 1990 to 2017. The number of deaths which are wholly or partially preventable by vaccines are shown in color.¹³ The chart shows that the reductions in child deaths over this 25-year period were primarily achieved by a reduction of the number of deaths from vaccine-preventable diseases: The decline in causes which are not vaccine preventable has been modest, while the number of child deaths caused by diseases for which vaccines are available declined from 5.1 million deaths in 1990 to 1.8 million deaths 27 years later.

Two vaccines are responsible for saving millions each year: 'DTP' against diphtheria, tetanus, and pertussis (whooping cough) and 'MMR' against measles, mumps, and rubella.¹⁴ Before the measles vaccine was introduced in 1963, measles caused a large number of deaths globally, estimated at 2.6 million each year . Because about 86% of the world population is immunized today, the number of people killed by measles have been cut dramatically to an estimated 95,000 deaths in 2017. Tetanus and pertussis were also previously much bigger killers, with pertussis affecting especially children younger than 5 years and tetanus striking newborns ( killing an estimated 787,000 newborns in 1988, compared with 49,000 in 2013 ).

However, the gains in global vaccination coverage have slowed down slightly in the last few years. The WHO estimates that 19.5 million infants worldwide are still at risk of VPDs because they miss out on basic vaccines. ¹⁵

In addition, all the recommended doses of a vaccine need to be received for it to be most effective. In the case of measles three vaccine doses are recommended. Even though an estimated 85% of children receive their first dose of the vaccine, this drops to 64% for the second dose. Therefore, it is not only lack of vaccination that is a problem, but it is under-vaccination that leads to deaths from VPDs.

What then are the most deadly VPDs? Which diseases continue to kill the most people?

Determining which are the most deadly VPDs requires acknowledging that some vaccinations are more effective than others. While most vaccines included in national routine schedules are highly effective, a better vaccine for tuberculosis (TB) is desperately needed. It is Sub-Saharan Africa and parts of Asia in particular that Tuberculosis: are affected by TB, as the world map shows.

The vaccine for TB - Bacillus Calmette-Guérin (BCG) - has been in use for nearly 100 years. It protects against severe forms of TB but is not effective against pulmonary TB (in the lungs) and has variable effectiveness against TB in adults. ¹⁶,¹⁷

Furthermore, resistance of antibiotics used to treat TB is increasing, meaning some people can no longer be cured by drugs. The estimated number of people in 2016 with multi-drug resistant TB was 490,000 .

The fact that there is not a fully effective vaccine and that antibiotic treatment is facing serious difficulties makes TB the most deadly VPD.

Meningococcal meningitis and hepatitis B are also deadly VPDs.

Despite the introduction of Meningococcal Meningitis: MenAfriVac in 2010, an effective vaccine against the most common type of meningitis in that region, meningococcal meningitis killed almost 130,000 people in 2016. Many cases occur in the so-called 'meningitis belt' of sub-Saharan Africa, crossing from Senegal to Ethiopia. Not all the countries in the meningitis belt have implemented mass vaccination campaigns for MenAfriVac and also do not benefit from the expensive MenACWY vaccine introduced into richer countries to protect against other types of meningococcal meningitis. ¹⁸,¹⁹

in preventing disease), meaning increased vaccination could lead to a significant reduction in deaths. Still, global coverage of the hepatitis B vaccine is lagging. In 2015, while Hepatitis B: The vaccine against hepatitis B is also very effective ( an estimated 95% effectiveness 84% coverage was reached for the third dose of the vaccine, the coverage for the birth dose was only 39%. Estimates from mathematical models have shown that if infant coverage would reach 90%, and the first dose administered at birth, 84% of global hepatitis B-related deaths could be prevented. ²⁰

Eradication is the ultimate goal of vaccination against a disease.

While the benefits might possibly be forgotten as vaccine-preventable diseases have lost their threat thanks to the introduction of the vaccines it is still true that people around the world - including those in richer countries - continue to benefit from vaccinations.

One of the greatest successes of global health is eradication of smallpox. Smallpox, which just decades ago killed several hundred thousand people every year was successfully eradicated in 1980 thanks to the global vaccination program.²¹

Public support and skepticism

Today vaccines protect millions of people around the world from infectious diseases. In this fight we are much, much further ahead than most people realize.

The first chart shows the evidence for this misperception. In this chart we plotted the survey responses that people gave when they were asked "How many of the world's 1-year old children today have been vaccinated against some disease?". The correct answer was 85.8%; this is the share of 1-year olds that received the third dose of the combination vaccine that protects against Diphtheria, Tetanus, and Pertussis (whooping cough).

But in all countries in which people were surveyed people were much too pessimistic about the global coverage. Americans think that only 35% of the world's children are vaccinated, the true coverage is 50 percentage points higher.²²

In Japan people were even more pessimistic and thought that only 18% were vaccinated. As it is often the case in questions on global development we again see that people in poorer countries have a more accurate view of the world: in Kenya and Senegal people thought that vaccines reach around two thirds of all children in the world, but even these highest estimates are 20 percentage points too low.

We hugely underestimate global vaccination coverage²³

The chart here illustrates how outdated people's answers are. Most individuals think that the global vaccination coverage today is as low as it was in the 1980s or even earlier.²⁴

The World Health Organization recommends routine vaccinations to prevent illness, death and disability from diseases including diphtheria, pertussis (whooping cough), tetanus, polio, measles, and hepatitis B.²⁵

We have created a chart that shows the absolute number of one-year-olds who have received the vaccinations.

Where the biggest gap in vaccination lies is with all children being fully vaccinated and protected as much as possible from infectious diseases. Gavi, the Vaccine Alliance, has analysis that suggests only 7% of infants in the 73 poorest countries are fully immunized (that is, receiving all doses of all recommended vaccines).

The London-based research charity The Wellcome Trust published their Wellcome Global Monitor in 2019 on attitudes to science and major health challenges. It is the world's largest study of its kind, surveying over 140,000 people from over 140 countries. As part of the Gallup World Poll, the 30-question survey ran during 2018.²⁶

The Wellcome Trust survey asked three core questions related to attitudes to vaccines: do people think that vaccines are important for children to have; do they think vaccines are safe; and do they believe vaccines are effective.

More than 9-in-10 people in the world (92%) think that vaccines are important for children to have.

How support varies across the world is shown in the map. We see high support for vaccination across almost all countries. In most countries over 80% of respondents think child vaccination is important, in many countries it is over 90% who think so.

There is a visible North-South divide in attitudes: support is highest across South Asia at 98%; 97% in South America; 94% in Northern Africa; and 92% in Southern Africa. Support is still high, but lower across North America (87%); Western Europe (83%) and Eastern Europe (80%).

Of those surveyed in Venezuela, Palestine, Ethiopia and Northern Cyprus thought vaccines were most important: 100% were in favour.²⁷

Some parents may not agree for children to be vaccinated if they think vaccines are unsafe or could potentially cause side-effects which are worse than the benefits. How prevalent are these safety concerns?

Globally, a small share of people disagree that vaccines are safe. Only 7% of respondents across the world said they "strongly disagree" or "somewhat disagree" with the statement 'Vaccines are safe'.

In many countries these concerns are very low: in Bangladesh, for example, less than 1% disagree that vaccines are safe. In neighbouring India, only 2% disagree. We see this distribution across the world in the map.

Trust in vaccines is not high everywhere. There are some clear outliers. The French were most skeptical: 1-in-3 disagreed that vaccines were safe. Many in neighbouring Switzerland and Belgium were also very skeptical: more than 20% disagreed. Other countries with high mistrust of vaccine safety were Gabon (26%); Togo (25%); Russia (24%); Austria (21%), and Iceland (21%).

In response to the statement 'Vaccines are effective', only 5% of respondents across all surveyed countries said they "strongly disagree" or "somewhat disagree". The vast majority of people do not think of vaccines as ineffective.

But, as with the other surveyed questions, this varies significantly across countries. We see this in the map. In some countries, very few respondents disagreed: less than 1% in Bangladesh and Egypt; 2% in India and Ethiopia; and 3% in China, Germany and the UK.

Liberia is most skeptical with 28% disagreeing that vaccines are effective. But skepticism was also high in France (18%); Namibia (16%); Nigeria (16%); and Peru (15%).

The finding of the Wellcome Trust of mostly very positive attitudes towards vaccines - a health intervention that saves millions of lives and eradicated one of the worst diseases humanity ever faced - is a very positive finding.

But there is a concerning finding which is hidden when we look only at agreement and disagreement to the questions in the Global Monitor.

Take Japan as one example. Only 66% of Japanese respondents thought vaccines were important for children to have - very low in comparison to other countries. But few disagreed that vaccines were safe (only 8%) and disagreed that they're effective (only 3%). If few people thought they were unsafe and ineffective, why would support for vaccines be so low?

Many Japanese respondents did not answer either way. 28% answered "neither agree nor disagree" to whether child vaccination is important; 55% to the question regarding the safety of vaccines; and one-third were undecided on their effectiveness. It's difficult here, without further questions, to fully interpret the opinions of those in this undecided category: maybe they had no opinion; or they thought vaccines could be safe or effective in some cases, but not all; or some vaccines were safe but others were not. With this data, it's impossible to fully understand their reasoning.

This stance was common across several other countries, as we see in the map.

While being undecided or divided is perhaps less concerning than denialism on the importance, safety and effectiveness of vaccination, it nonetheless suggests that many are unaware of the massive role vaccines have played in eradicating diseases, and saving lives across the world. The success story of vaccines is one we don't tell often enough.

It's also true that people in the 'neither' group may be more likely to be convinced by arguments that are put forward by those who deny the safety, effectiveness and importance of vaccination. In a related post we take a look at why denialism around vaccination exists, and what is effective in addressing it.

The crucial question to ask when considering the importance of vaccine skepticism is: does it actually have an effect on behaviour? Does it really affect the share of children who are vaccinated?

In the chart we see the comparison of vaccination rates - here as the share of children who were immunized against diphtheria, pertussis and tetanus (DTP) in 2015, the latest year available - to the share of respondents in a given country who disagreed that vaccines are safe.

You can also see this relationship for measles vaccine coverage.

Overall we see that widespread public concern for vaccine safety does not appear to be strongly correlated with vaccination rates. While one-third of the French public disagrees with their safety, 97% of children in France are vaccinated.

There are numerous other reasons, however, why vaccination rates in some countries are low: in low-to-middle income countries the availability, affordability and access to vaccines can be poor. Having low coverage rates often doesn't reflect the population's view of them. As the chart shows, in many poor countries the situation is the opposite as in France: the vast majority of the population considers vaccine safe, but only about every second child receives the DTP vaccine.

One country which stands out is Ukraine: there we see that vaccination rates are uncharacteristically low for its income level - less than 1-in-4 children receive the DTP vaccine. Skepticism of vaccine safety in Ukraine is high at 15%.

The visualization shows the relationship between the share of people who trust doctors and nurses in their country and share who disagree that vaccines are safe. Overall we see that countries with higher levels of distrust in the safety of vaccines tend to also have less trust in health professionals.

There are however some outliers: France has relatively high trust in health staff, but are most mistrusting of vaccine safety.

Health officials are worried that skepticism of vaccination will begin to translate to lower vaccination rates. One reason being attributed to higher skepticism is the spread of misinformation on social media.

Social media firms do have a responsibility for dealing with misinformation and need to consider how to react carefully. Currently, social and online media companies are being asked by politicians in the US and UK to ban or control anti-vaccination messaging. Banning or strict control could reduce the exposure to such messages but does not solve the root problem: the public are asking questions about vaccines and are looking to find answers online. A worry is that banning certain sorts of information and groups will fuel suspicion and only drive activity elsewhere.

Nonetheless, demands on social media firms to act is increasing. A request for action by Adam Schiff to the CEOs of Google and Facebook sparked a cascade of responses. In an open letter, he asked for action against vaccine misinformation and similar demands have been made since, from the UK Health Secretary Matt Hancock among others.

Countries vary in whether vaccination is compulsory, mandatory (required according to specific mandates), or voluntary. Navin and Largent (2017) provide a helpful distinction between these policies. A compulsory policy is when refusing vaccination is illegal, while mandatory vaccination when certain goods and services are limited for not vaccinating.²⁸

Which policy is followed has depended much on historical legacy, which becomes clear when one considers some of the different regulations and their history around the world:

Compulsory vaccination: Many Eastern Bloc countries introduced compulsory vaccination during the communist era. Vaccination was previously compulsory in Romania for example and after a drop in vaccination rates the country is going through the process of reintroducing compulsory vaccination. The same is true for Italy and also France, which had compulsory vaccination for three diseases but increased this number to 11 in January 2018 in response to a drop in vaccination rates.

Mandatory vaccination: Some countries, such as the United States, have mandates for vaccination where a child is required to be vaccinated to enter state school or daycare. An early case in the US paved the way for state jurisdiction to protect public health in light of personal liberty.²⁹ In Jacobson v. Massachusetts (1905) the Supreme Court ruled that states have the authority to require vaccination against smallpox during a smallpox epidemic. Since then the US has had a history of school vaccination requirements. The increased number of children in public schools as a result of the compulsory school attendance law led to an increased risk of smallpox outbreaks, through close contact in large crowded classrooms.³⁰ Similarly in Australia two policies penalize parents for not vaccinating their children. The 'No jab no play' policy removed unvaccinated children from state-sponsored childcare. The 2016 'No jab no pay' policy removes state welfare by not providing the universal 'Family Allowance' welfare payments for parents who are conscientious objectors of vaccination.

Voluntary vaccination: Some countries where vaccination is voluntary had early pushback against vaccination, as in the UK and the Netherlands. In 1853 a law was passed in England and Wales requiring universal vaccination against smallpox, but opposition from anti-vaccinationists led to laws being passed to allow for conscientious objection.³¹

Vaccination requirements for country entry: For countries in Africa and South America where yellow fever is endemic or where the mosquito vector is present a certificate of proof of vaccination is required. Only then will the country issue a visa upon entry to that country to prevent importation of this disease (particularly if travellers come from, or have visited other yellow fever endemic areas).³² In past centuries (17th to 19th), yellow fever was transported to North America and Europe, causing large outbreaks that disrupted economies and development, and in some cases decimated populations. Throughout the 18th and 19th century, yellow fever was among the most feared diseases in the ports of the Old and New World. Saudi Arabia is the only country that requires the additional vaccinations of meningococcal disease and polio for pilgrims visiting Mecca.

Whether compulsory vaccination results in improved vaccination rates is not a straightforward question to tackle because it is highly dependant on country context, historical circumstance, cultural and social norms, as well as the practicalities of implementing and enforcing such a law.

Certainly in Eastern Bloc countries when the vaccination law was compulsory, vaccination rates have been high but it is unclear whether to attribute this to the law or the behaviours and mechanisms of compliance under communist rule. Certain vaccinations have historically been compulsory such as smallpox, polio, and yellow fever. Here vaccination rates have also been high but it also encouraged organised opposition to vaccination and public discontent. This is a major concern for public health authorities that a relationship of trust, between governments and citizens is threatened (particularly for health where a rhetoric of self-responsibility, personalisation, and choice is encouraged).

There are countries with high vaccination rates without compulsory vaccination and governments do not want to disrupt public trust and self-responsibility by making vaccination compulsory, particularly if it is not seen as needed. It has been argued that high coverage has been achieved through "other approaches or efforts" and so acceptance of compulsory vaccination might be problematic in countries such as Sweden, Norway, Denmark, the Netherlands, and the UK.³³

In recent years governments have acted in response to epidemics to make vaccinations compulsory, as we have seen for 2017-18 with compulsory vaccinations in France, Italy, Germany, and Romania.

One country where we can see the effect of variation in vaccination policy is the US. In the US states decide what vaccine exemptions are permitted for children who receive education in schools or use daycare. Public schooling unfortunately means that schools are sites of epidemics for childhood diseases, which is the reason such vaccination laws are required.

In individual states exemptions are granted for medical reasons but many states also allow for philosophical, personal belief or religious exemptions. Only three states - Mississippi, West Virginia, and California - only allow for medical exemption. Californian immunization rates have increased following a new Senate Bill SB 277 in 2015 to remove non-medical exemptions to vaccination.

Vaccination coverage of children, by US state in 2016/17³⁴

Concerns about the supply of vaccines in an epidemic or pandemic have been raised. For example, the supply of yellow fever vaccine was limited for the outbreak in Angola in 2016 leading to the recommendation of a fractional dose to extend existing supplies.³⁵

Laurie Garrett argues that because the drug had become so cheap (60 cents for each vaccine 2008) few companies had an incentive to produce it and world stocks of the vaccine were nearing zero, forcing the WHO to dilute donated vaccines from countries like Brazil (which sent 18 million doses) by 5 to 1 with the hope they would still be sufficiently effective. Romania experienced a situation of parallel vaccine exports in 2016 where more vaccines were exported than was supplied to meet the country's needs. A shortage of the measles, mumps, and rubella (MMR) vaccine was partly responsible for the measles outbreak in 2016-17.³⁶

In Venezuela, a country experiencing an economic crisis, there are severe shortages of medicines, including vaccines, which has led to an estimated one million unvaccinated children and the re-emergence of diseases such as diphtheria and measles.

There are five big pharmaceutical companies³⁷ that account for 80% of vaccine production: Sanofi Pasteur, GlaxoSmithKline, Merck, Pfizer, and Novartis.³⁸

Many vaccines are only provided by one or two suppliers. For newer vaccines there are often particularly few suppliers due to the high investment needed to develop a vaccine.³⁹ As one would expect from competition, the WHO reports that when vaccines are produced by a greater number of suppliers it leads to a decline of the prices of those vaccines.⁴⁰

In the past vaccines were often viewed as less profitable products for pharmaceutical companies, which led to a lack of investment and some companies pulling out of production altogether.⁴¹

But this has changed as the revenue of the global vaccines market has increased and richer country governments and insurance companies have been willing to pay more for new vaccines.

In addition, growing economies such as India and China are investing more in vaccines as well as developing their domestic manufacturing capacity. Poorer countries now have Gavi to help governments pool resources and make advance purchase commitments.⁴²

Gavi is an international organisation created in 2000 to bring together public and private sectors, with the goal of equal access to new and underused vaccines for children in poorer countries. It subsidizes vaccines that otherwise would not be affordable for low-income countries. In addition to subsidizing vaccines themselves, Gavi offers vaccine introduction grants, which help to cover the costs of introduction of new vaccines into routine immunization schedules. The map here shows which countries are eligible for GAVI support.

Some vaccines still remain expensive. For example, the pertussis vaccine is available in two versions: whole cell (wP) containing the whole pertussis bacterium or acellular (aP) which contains a part of the pertussis bacterium. The pertussis vaccine is often combined with diphtheria and tetanus to produce either a DTwP or DTaP vaccine.⁴³

DTaP is slightly more expensive; it is sometimes called 'the painless vaccine' because it causes less of a local reaction and pain but should not be given to children over the age of seven. However, DTwP has been shown to be more efficacious at preventing the transmission and spread of disease to unvaccinated people and to those with weak immunity.

New vaccines tend to be more expensive as they are under patent protection. For example when the HepB vaccine was developed many lower income countries could not afford to pay $30 per dose.⁴⁴

Today there is often a differentiation between the prices paid by countries as shown in the small table.

Price differences for vaccines between the US and developing countries⁴⁵

Vaccine Cost per dose in a developing country Cost per dose in the US

HepB

$0.58 - 13.20

$50 - 100

BCG

$0.16 - 1.11

$100 - 200

Yellow fever

$4.30 - 21.30

$50 - 100

Chickenpox (varicella) is an example of a vaccine that some countries adopt into their routine childhood vaccination schedules, while others do not. The question that follows is why there is a difference in opinion for introducing widespread uptake of a vaccine or not. Japan was one of the first countries to adopt universal chickenpox vaccination.⁴⁶

The Centers for Disease Control and Prevention in the US ran the Varicella Active Surveillance Project (VASP) from 1995 through to 2010 to monitor the impact of the varicella vaccination program and the key finding is shown in the chart. The coverage of the vaccine in Los Angeles County rose from 37.9% in 1997 to 95.1% in 2010, and in Philadelphia from 41.2% in 1997 to 94.6% in 2010 (one-dose vaccinations for children between 19 and 35 months of age). By 2010, varicella incidence declined by 98% in Antelope Valley (California) and West Philadelphia (Pennsylvania) compared with 1995. Outbreaks and hospitalizations also decreased rapidly. From 1995 to 1998, hospitalization rates ranged from 2.2 to 3.3 per 100,000 population but by 2006-2010 this had declined to 0.2 per 100,000 in Antelope Valley and 0.5 per 100,000 in Philadelphia.

Chickenpox is an example that can also help to answer the question of whether better hygiene or vaccination are in fact responsible for the reduced rates of disease. Although both are important, a more recently adopted vaccination such as chickenpox can demonstrate the effects of vaccination in reducing the rate of disease after the importance of hygiene was discovered and became a preventative measure against disease. As hygiene standards already reached high levels, the additional benefit of the vaccine is confirmed. The impact on disease rates demonstrate it is not hygiene but vaccination that reduced the incidence of chickenpox so dramatically in the US.

Coverage, Impact, and Potential

The chart shows the number of global deaths caused by some of the most common and serious vaccine-preventable diseases.

By selecting 'change country' it is possible to see this change for any country in the world and extending the timeline will let you see the change in deaths over time.

There are more diseases for which vaccines are available now and even more are under development currently. The WHO publishes list of 26 diseases for which vaccines are available - including Japanese encephalitis, pneumococcal disease, varicella/chicken pox, HPV, Hepatitis A and rotavirus.

Diphtheria, tetanus, and pertussis are all bacterial diseases and a combination vaccine against all three diseases is commonly used.

Diphtheria primarily infects the throat and upper airways and is fatal in 5 - 10% of cases.

Tetanus is not passed person-to-person but through spores of a bacteria living in soil and animal intestinal tracts. These bacteria enter the body through wounds and release a toxin that affects the nerves, which causes muscle stiffness and spasms.

Pertussis is a highly contagious disease of the respiratory tract, commonly known as whooping cough. Children who contract pertussis tend to have coughing spells that last four to eight weeks, but the highest fatality is in young infants. Vaccinating health workers and pregnant women is the most effective strategy for preventing disease in infants too young to be vaccinated.

The chart shows the progress over time of DTP3 immunization coverage of children around the world. By clicking on any country you can see the change in that country over time.

The WHO reports in 2017 that 85% of infants worldwide (116.5 million infants) received 3 doses of diphtheria-tetanus-pertussis vaccine (DTP3). Also in 2016 130 countries had reached at least 90% coverage with the DTP3 vaccine.⁴⁷

If we look at the change over time by world region it is South Asia in particular that stands out. While 85% of one-year-olds today are immunized, that same figure was as low 6% in 1980.

Within each country there can be substantial differences in vaccination coverage. The WHO reports that in all regions children in the richest 20% of urban households are more likely to get immunized than children from the poorest 20% of households.

Some countries lag behind however. Ukraine stands out as having particularly low DTP vaccination rates in 2015 of 23%, falling from 98% in 1999. Ed Holt writing for the Lancet in 2013 attributed the decline to: "A combination of public mistrust in vaccinations, poor vaccine supply, and corruption in the health system".⁴⁸ Therefore Ukraine is suffering from a combination of factors effecting vaccination rates from public attitudes and systemic delivery problems. Furthermore, the unrest since 2014 and Russian military intervention is likely to have worsened matters. Today only Equatorial Guinea reports even lower rates at 16%. As Human Rights Watch observes, very little of the country's wealth is being directed towards the needs of citizens.

The number of under-vaccinated children in Nigeria remains high, with 3.4 million children going without the DTP3 vaccine (compared with 2.9 million in India).

Measles is a highly contagious virus-caused disease that, despite a safe and effective vaccine being available, infects thousands of people globally. Around 90,000 people die because of measles every year, the huge majority of whom (87%) are children younger than 5. Measles vaccination has resulted in an 84% drop in measles deaths between 2000-2016.⁴⁹

The world map shows the share of children vaccinated with the first dose of measles vaccine.

You can switch to the 'chart' view to see the global coverage against vaccines. The measles vaccine was developed in 1963. In 1983 - the first year for which global data is available - only every second child was vaccinated against measles. In the latest data this share has increased to 85% globally up from 72% in 2000.⁵⁰

The sub-Saharan African region achieves the lowest measles vaccination rates, along with conflict-ridden and unstable countries (e.g. Syria, Afghanistan, and Iraq). But also some of the Pacific Islands - such as Papua New Guinea and Vanuatu - are performing poorly.

Today (data from 2014) 114.3 million children are vaccinated against measles every year, which is on average 313,071 children every single day.⁵¹

As of 2018, the WHO estimate that 171 countries had included a second dose as part of routine immunization. Two doses are needed for a higher level of protection.⁵²

The map here shows the coverage of the second dose (MCV2) of the measles vaccine. The current global average is 67%. The coverage is lowest in South Africa and many countries in Sub-Saharan Africa still have not introduced the vaccine into their immunization coverage.⁵³

This scatterplot compares the vaccination coverage against measles with the coverage against DTP3.

The second visualization shows the discussed increase of the global vaccination coverage of one-year-olds and the simultaneous decline of reported cases of the disease; from close to 1,000 cases per million people globally to 28 cases per million. This represents a 33-fold reduction.

For country by country change over time see this visualization.

The first widely-used rotavirus vaccine was approved in the United States in 2006. Today, there are four oral rotavirus vaccines recommended for use by the World Health Organisation (WHO): Rotarix, RotaTeq, RotaSiil, and Rotavac.⁵⁴

Rotarix and RotaTeq are the most widely used and both have shown good efficacy against rotavirus infections in clinical trials.⁵⁵ ⁵⁶

Since the use of rotavirus vaccines have been approved, they have had a notable impact on the reduction of rotavirus-related deaths. According to a study published in 2018, the use of rotavirus vaccines prevented approximately 28,900 child deaths globally in 2016. However, as the chart shows, full vaccine use - that is a 100% coverage globally - could have prevented an additional 83,200 deaths.⁵⁷ This means that, even at the current rates of efficacy, 53% of all deaths in children under-5 from rotavirus in 2016 could have been avoided by full vaccine coverage.

In addition to saving lives, the rotavirus vaccine also reduces the burden on healthcare systems. Between 2008 and 2016 the introduction of the rotavirus vaccine has reduced the number of diarrhea-related hospital admissions on average by 40%.⁵⁸

If there is so much scope for saving more children's lives, what is the reason that these children are still dying?

There are two key barriers to achieving the full potential of the rotavirus vaccine: immunization rates, and the efficacy of the vaccine in specific regions.

According to the WHO, by the end of 2018, 101 countries were using the rotavirus vaccine. The major drivers for the introduction of the vaccine are the burden of diarrheal diseases, the availability of funding, and a favourable political climate for vaccines.⁵⁹

The vaccine is only given to children - it's recommended that the vaccination should be initiated 15 weeks after birth and finished by the 32nd week. However, the global coverage is still very low: it is estimated that just 35% of under one-year-olds were vaccinated in 2018.⁶⁰

The map shows the WHO estimates on the share of one-year olds who received the full recommended dosage of the vaccine (two immunizations for Rotarix vaccine or three immunizations for RotaTeq vaccine). For many countries where data coverage is low, it's expected that the share of infants receiving the vaccine is very low. Some countries however did see rapid increases in rates of immunization. In a period of only a few years countries including Sudan, Malawi and Gambia have increased immunisation rates from below 10% to 80-95% - click on the country to see the change over time.

Since most rotavirus cases occur in Sub-Saharan Africa where mortality from rotavirus infection is also the highest, it is essential to increase and maintain high immunisation coverage in this region. However, in addition to delivering the vaccine for those who need it, we also need to work on improving its efficacy.

Vaccine efficacy for the rotavirus vaccine is defined as the percentage reduction of the rate of diarrhea incidences in vaccinated versus unvaccinated groups of children. It is well established that the efficacy of the rotavirus vaccine is not the same across all countries - in countries with high child mortality rates the vaccine shows much lower efficacy.⁶¹

The chart is from a recent study by Clark et al., which looked at how the efficacy of live oral rotavirus vaccines changes in different countries following vaccination. The chart shows that in countries with high child mortality rates, not only is the immediate vaccine efficacy lower - 98% in low child mortality countries versus 66% in high child mortality countries - but also the vaccine efficacy decreases faster in high child mortality countries over time.⁶²

Five years after vaccination, the rotavirus vaccine reduces the chances of getting diarrhea by 90% in low child mortality countries and only by 30% in high mortality countries.

The table shows how good the rotavirus vaccine is at preventing severe diarrhea and reducing hospitalization due to diarrhea in children under-5 in different regions.⁶³

In high-income countries, rotavirus vaccination has been shown to reduce the cases of severe rotavirus diarrhea by 91% and hospitalization by 94%. In Eastern Asia and Latin America, the effectiveness rates are lower but still high - preventing 88% and 80% of severe diarrhea cases, respectively. However, effectiveness in South Asia and Sub-Saharan Africa is significantly lower, only reducing severe diarrhea in around half of the cases.

The reasons for different responses to the vaccine are not entirely clear.⁶⁴ ⁶⁵

We are still at quite an early stage of the rotavirus vaccine use. Although the vaccine has brought huge benefits already, it could go even further. Improving vaccination coverage, particularly across Sub-Saharan Africa and South Asia is key to continued reduction of childhood deaths from diarrhea. Even at moderate levels of vaccine efficacy, a significant number of additional additional child deaths could be prevented every year. The bar chart above that shows the number of preventable deaths illustrates the potential for extended vaccine coverage to save many more lives. And this is already taking into account the regional differences in the vaccine's effectiveness.

In addition to increased coverage, improving the effectiveness of the vaccine would go even further in tackling one of the leading causes of death.

Outcome

Region

Vaccine effectivness

Severe rotavirus diarrhea

Developed

91%

Eastern Asia and Southeast Asia

88%

Latin America and Caribbean

80%

Southern Asia

50%

Sub-Saharan Africa

46%

Hospitalization due to rotavirus infection

Developed

94%

Eastern Asia and Southeast Asia

94%

Latin America and Caribbean

84%

Sub-Saharan Africa

58%

But we have another highly effective intervention: a vaccine against the major pathogen responsible for pneumonia in children.

Streptococcus pneumoniae is the leading cause of pneumonia in children under 5 - it was responsible for 52% of all fatal pneumonia cases in children in 2016.⁶⁶ Pneumococcal vaccines are vaccines that target S. pneumoniae bacteria. Here we look at their effectiveness and how we can maximise the number of children they save.

Since the World Health Organisation (WHO) started recommending including pneumococcal vaccines in national immunisation programmes for children in 2007, there has been a progressive increase in the number of countries using the vaccine. You can see the uptake in the vaccine across the world using the 'play' button on the map below.

But the coverage of pneumococcal vaccines is still low in many countries. In India and Nigeria - the two countries with the greatest number of childhood deaths from pneumonia in 2017 - only 44% and 58% of one-year-olds are vaccinated, respectively.

In 2018, less than half (47%) of one-year-olds in the world received the full course of pneumococcal vaccination. This means that 55 million children who could be protected by the vaccine are still not vaccinated against it - an appallingly high number for a vaccine that not only protects from pneumonia, the leading cause of childhood death, but also a range of other diseases (as discussed below).⁶⁷

Streptococcus pneumonia, often simply referred to as pneumococcus, is a bacterium that is often found in the upper respiratory tract of healthy people. Generally, the bacterium is harmless or causes milder illnesses such as bronchitis, sinusitis, and ear infections. Pneumococcal vaccines are effective against these milder illnesses as well, but importantly also protects from what is called pneumococcal invasive disease (PID). PID occurs when the pneumococcus moves from colonizing the upper respiratory tract to colonizing sites that are normally sterile, such as blood, cerebrospinal fluid or pleural cavity (fluid-filled space surrounding the lungs).⁶⁸ Bacterial invasion leads to life-threatening diseases such as sepsis, meningitis and severe pneumonia.

There are two types of pneumococcal vaccines available: conjugated polysaccharide pneumococcal vaccine (PCV) and non-conjugated polysaccharide pneumococcal vaccine (PPSV). Both vaccines are designed to elicit immune responses against multiple serotypes of pneumococcus, which are defined by the different immune responses to the sugars found on the bacterial surface.⁶⁹ To be broadly effective, the vaccines need to protect against a certain number of these pneumococcal serotypes, but it is not necessary to include all possible serotypes because only a limited subset is responsible for 70%-80% of invasive pneumococcal disease.⁷⁰ However, as we'll discuss later, this variety of different pneumococcal serotypes is important to keep in mind because as vaccine coverage increases we may see a replacement of the vaccine-included serotypes with the less dominant ones, which will mean new vaccine versions will be required.

While there are two types of pneumococcal vaccines available, for children under two years old only the conjugated (i.e. PCV) vaccines are recommended because the non-conjugated versions (i.e. PPSV) are not effective at such a young age.⁷¹

In clinical trials PCV has shown 80% efficacy in reducing invasive pneumococcal disease caused by the bacterial serotypes included in the vaccine formulation. Vaccinated children are 27% less likely to be diagnosed with pneumonia and 11% less likely to die from it.⁷²

Several studies have attempted to estimate how many lives PCV vaccination has saved and could possibly save. One Lancet study concluded that between 2000 and 2015, in 120 countries the number of childhood deaths caused by pneumococcus fell from 600,000 to 294,000 - a decline of 54%. Most of this decline was attributed to the PCV vaccines: over this period, it's estimated these vaccines saved the lives of 250,000 children. The majority of these deaths would have been caused by pneumonia, but the vaccine also prevented deaths from pneumococcal meningitis and other diseases.⁷³

The chart shows how estimates of the potential impact of the pneumococcal vaccine.

It is based on a recent study published in The Lancet Global Health journal, which calculated that if the PCV vaccine coverage would reach at least the levels of the vaccination against diphtheria, tetanus and pertussis (DTP3), the lives of 399,000 children under 5 could be saved.⁷⁴ Additionally the researchers estimate that 54.6 million pneumonia episodes annually could be averted.

These number estimate the impact of the PCV vaccination relative to a world without that vaccine - since the vaccine is already used it means that some of these lives are already being saved by the PVC vaccination. However, in many countries PCV vaccination rates still fall far below the DTP3 rates, making clear that we still haven't used the pneumococcal vaccine to its full potential.

A continued increase in immunization coverage and the introduction of PCV vaccines into countries which don't yet use them is important if we want to make use of the full potential of pneumococcal vaccines.

PCV vaccines are amongst the most expensive vaccines in national immunisation programmes. The price ranges from $3.05 per dose in GAVI⁷⁵ supported low-income countries to $169 in high-income countries such as the United States.⁷⁶ For low-middle-income countries who are transitioning from GAVI support the increasing future costs of vaccination place a considerable strain on national healthcare budgets.⁷⁷

But given the high burden of pneumococcal diseases, even at high prices, PCV vaccines are considered to be cost-effective, with an estimated return of investment in low- and middle-income countries of around 3.⁷⁸

PCV vaccines include a limited subset of possible pneumococcal serotypes. The distribution of pneumococcal serotypes is known to vary between countries and PCV vaccines include the ones that are most common globally.

Which non-vaccine serotypes are most common in a particular country, may affect the potential for a particular vaccine's impact. However, not all countries collect data on serotype distribution, and an assessment of the potential impact is therefore compromised.⁷⁹ ⁸⁰ ⁸¹ Notably, since the PCV vaccine was introduced, there has been a rise in pneumococcal invasive disease incidences caused by the less common serotypes. This suggests that, by reducing the prevalence of vaccine-included serotypes, the vaccine unintentionally provides space for non-vaccine serotypes, against which it works less well.⁸² This means that the vaccine's effectiveness may decrease over time, if the serotype formulation of PCV is not continually reevaluated. In the future, new versions of pneumococcal vaccines may be needed that work better independently of the bacterial serotype. Such vaccines are already in development.⁸³ ⁸⁴

The chart here shows the coverage for Hepatitis B vaccination.

Hepatitis B (HepB) is a highly contagious viral infection that attacks the liver and is transmitted through contact with the blood or other body fluids of an infected person. As the chart shows, it is estimated that about 100,000 people die each year of chronic liver disease due to hepatitis B. The WHO recommends that all infants should receive their first dose of vaccine as soon as possible after birth, preferably within 24 hours.

Haemophilus influenzae type b (Hib) is a bacterial infection that causes meningitis and pneumonia transmitted through the respiratory tract from infected to susceptible individuals. The chart here shows the coverage for Hib vaccination.

The chart here shows the coverage of the polio vaccine.

Poliomyelitis (OPV, IPV) is a highly infectious viral disease. Once the poliovirus invades the nervous system it can cause irreversible paralysis in a matter of hours. No cure exists for polio, only treatment to alleviate symptoms. As we detail in our entry on polio the world is on its way to eradicate the disease thanks to the vaccine against the virus: While in the 1980s there were 350,000 paralytic cases of polio every year, the world saw only 42 cases in 2016.

The chart here shows the coverage of the BCG vaccine, which protects against tuberculosis.

Developed more than a century ago, bacille Calmette-Guérin vaccine (BCG) is currently the only vaccine available against tuberculosis (TB).

Close to 4 billion people have been vaccinated with BCG - this makes it the most widely used vaccine in the world.⁸⁵

BCG vaccine is based on a reduced-virulence strain of Mycobacterium bovis, a bacterium that is closely related to Mycobacterium tuberculosis - the pathogen that causes TB. BCG vaccine was already used in the 1920s in Belgium and France in small trials and after the Second World War its use was expanded to vaccinate children across Europe. In 1950s the WHO started recommending the use of BCG globally.

BCG is effective at protecting children and adolescents from severe forms of TB and meningitis.⁸⁶ ⁸⁷ However, studies have shown that the length of protection provided by the vaccine varies greatly depending on the populations studied: from 15 years in the UK to 50-60 years in Alaska.⁸⁸ ⁸⁹ The reason for such variability is not clear, but factors such as different vaccine seed strains used for immunization and pre-existing immunity in people already exposed to other mycobacteria strains may be important.
Notably, BCG vaccine does not protect people from primary infections, that is it does not prevent people from getting infected with M. tuberculosis bacterium in the first place. BCG also does not prevent activation of latent TB if a person has already been infected. Therefore, the vaccine has limited effect on prevention of M. tuberculosis spread in a population.⁹⁰

The chart here shows the coverage of the yellow fever vaccine.

Yellow fever (YF) is a viral disease transmitted by infected mosquitoes. There are 40 countries and territories at risk for yellow fever in Africa and the Americas and of these 36 include yellow fever vaccination in their routine immunization schedules. Total, vaccine coverage in 2018 was estimated at 49%.⁹¹

Definitions and Measurement

The coverage is calculated as the proportion of persons in a target age group who received a vaccine dose. Dates of vaccination are either taken from a child's home-based record, recorded based on caregiver recall, or from health facility records.

While appearing straightforward enough, several methodological problems of household survey respondent data on vaccination have been well documented.⁹²

Questions have arisen about how accurately parents can recall child immunization history and the limitations of phone calls to collect data.

Even accurately estimating target populations in low-income settings can be difficult and discrepancies have been found when comparing country-reported figures with independent surveys.⁹³

Furthermore, childhood vaccinations are rarely considered altogether. The DTP3 vaccination tends to be the vaccination most often used as a marker of strength in a country's immunization programs, since three administrations of the vaccination are required.⁹⁴

National coverage rates are what is focused upon, but even when national coverage are high, subnational coverage can reveal inequities, which is why the WHO and UNICEF are increasing efforts to gather high quality subnational coverage data.⁹⁵

In 2015 coverage estimates at the district level were only reported for 158 of the 194 WHO Member States. National data only provides part of the picture of immunization coverage. Different levels of coverage data, including at sub-national or district level is useful for gaining an understanding of where there might be clusters of under- or un-vaccinated children.

Data: Immunization coverage, system indicators and schedule, and disease incidence

Geographical coverage: WHO member nations

Time span: 1980 onwards for many countries

Available at: Online here

Data: Percent of one-year-olds immunized

Geographical coverage: UN member nations

Time span: 1980 onwards for many countries

Available at: Online from UNICEF here. Also available via Gapminder here (search "vaccine" to find the data).

More information about vaccines in general can be found on the World Health Organization (WHO) page on immunization.

Endnotes

1. This and other numbers in this entry are based on the estimates by the World Health Organisation. The coverage estimates are calculated by dividing the total number of vaccinations given by the number of children in the target population. Target population size is usually based on census population projections.

This means that there may be children in the target population that for medical reasons should be exempt from vaccination. These medical reasons may include factors such as allergies to vaccine components or severe immunodeficiencies.

Notably, such cases are very rare and would have little effect on global coverage numbers. For example, a study from 2003 identified severe allergic reaction in only 0.000063% of all vaccinations, that's 0.63 cases per million vaccinations. In addition, vaccines are always being improved with fewer ingredients that may cause allergic reactions.

Vaccination of children with immunodeficiencies generally needs to be assessed by a specialist. Especially, for vaccine that are based on a live pathogens. For example, WHO recommends vaccinating HIV-positive children with measles vaccine if child's HIV infection is asymptomatic or not severe. Similarly, children with severe immunodeficiency syndrome (SCID), a genetic disorder that causes defects in immune system, are safely vaccinated with many vaccines before SCID is even diagnosed, but it's recommended not to vaccinate them with live vaccines.

In fact, one of the reasons it is important to increase vaccination rates is that those children and adults who for medical reasons cannot be vaccinated would still be protected from diseases through herd immunity.

2. https://www.who.int/en/news-room/fact-sheets/detail/immunization-coverage

3. UNICEF (1996) and Hinman, A. R. (1998) estimate that in the absence of a vaccine the world would have seen 5 million deaths due to smallpox every year in the mid-1990s.

Assuming that the estimate for the mid-1990s provides a midpoint estimate for the period since 1980 and therefore multiplying the 5 million per year estimate by the number of years between 1980 and 2018 means that since the eradication of the disease 190 million people's lives were saved.

UNICEF (1996) - Vaccines bring 7 diseases under control. Online here.

4. See Oxford's Vaccine Knowledge Project for an explanation here: http://vk.ovg.ox.ac.uk/herd-immunity.

5. Beutels P, Van Damme P, Van Casteren V, Gay NJ, De Schrijver K, Meheus A. The difficult quest for data on "vanishing" vaccine-preventable infections in Europe: the case of measles in Flanders ( Belgium). Vaccine. 2002 Oct 4;20(29-
30):3551-9 here

6. This table is taken from Wikipedia's entry on Herd Immunity - the original sources are listed there.

7. Cholera, Dengue fever, Diphtheria, Haemophilus influenzae type b, Hepatitis A, Hepatitis B, Hepatitis E, Human papilloma-virus, Influenza, Japanese encephalitis, Malaria, Measles, Meningococcal disease, Mumps, Pneumococcal disease, Pertussis, Poliomyelitis, Rabies, Rotavirus gastroenteritis, Rubella, Tetanus, Tick-borne encephalitis, Tuberculosis, Typhoid fever, Varicella, Yellow fever, Shingles (Herpes Zoster), and Smallpox.
See https://en.wikipedia.org/wiki/Vaccine-preventable_diseases and https://www.who.int/immunization/global_vaccine_action_plan/GVAP_doc_2011_2020/en/

8. Roush and Murphy (2007) - Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. In the Journal of the American Medical Association, 298, 18, 2155-2163. here

9. These data are taken from the research paper Roush and Murphy (2007) - Historical comparisons of morbidity and mortality for vaccine-preventable diseases in the United States. In the Journal of the American Medical Association, 298, 18, 2155-2163 here.
The vaccines against the diseases up till 'Tetanus' were vaccines licensed or recommended before 1980. The vaccines against the last 5 diseases were only licensed or recommended between 1980 and 2005.

10. See also 'Graphical proof that vaccines work (with sources)' in Medium online here.

To account for such long-term changes, Roush and Murphy (2007) report data from the period shortly before the introduction of the respective vaccine. here

11. In our graphics and visualizations we rely on the Institute for Health Metrics (IHME) ' Global Burden of Disease Study 2016 ' estimates of child death rates from individual VPDs (compared with other causes), TB death rates across countries, and death rates from individual VPDs; this dataset extends back to 1990 and therefore provides a longer-term perspective on these changes over time. However, lack of estimates from the IHME on the role of vaccination in the prevention of deaths means we rely on WHO data for the number of deaths prevented each year through vaccination and the total amount of deaths VPDs are responsible for.

The rates reported by the WHO and IHME are in a similar range but do differ slightly. WHO data on individual disease death rates can be found here: http://www.who.int/gho/mortality_burden_disease/en/

12. Note that, as discussed later in this post, the role of vaccines in prevention varies between these causes of death. Measles, for example, has the capacity to be eliminated through vaccination. Diarrheal deaths, in contrast, cannot be eliminated through vaccination alone; hygiene, water services, and nutrition must also be prioritised.

13. Some countries only give measles vaccines combined with rubella (MR) or with varicella in addition (MMRV).

14. Highlighted are 10 countries where approximately 60% of these infants live in: Angola, Brazil, the Democratic Republic of the Congo, Ethiopia, India, Indonesia, Iraq, Nigeria, Pakistan, and South Africa.

15. An affordable MenACWYX vaccine is being developed to cover all the types of meningococcal disease (with the exception of meningitis B, which is available through a separate vaccine) and will also have the ability to be transported at higher temperatures. It is currently in phase 1 clinical trial, with the hope that it will be available for use in 2020-2022.

16. Susan T Goldstein, Fangjun Zhou, Stephen C Hadler, Beth P Bell, Eric E Mast, Harold S Margolis; A mathematical model to estimate global hepatitis B disease burden and vaccination impact, International Journal of Epidemiology, Volume 34, Issue 6, 1 December 2005, Pages 1329-1339, https://doi.org/10.1093/ije/dyi206. Available here.

17. Smallpox is the only disease that affects humans which has been eradicated through vaccination. Rinderpest, a disease that affected cattle, has also been eradicated. Polio is getting close to being eradicated.

18. This survey result is in line with the finding of the Gapminder Ignorance Project, which studied Americans' perception of global vaccination efforts. Just as in the Ipsos Mori survey, the answers that most Americans gave were far off from the truth.

More information on the Gapminder 'Ignorance Test' can be found here. The results for the US are here on Gapminder's site.

19. The survey results are from Chris Jackson (2017) - Global Perceptions of Development Progress: 'Perils of Perceptions' Research', published by Ipsos MORI, 18 September 2017. Online here.

20. Terminology: vaccination and immunization
There is a technical difference between vaccination and immunization, as the National Health Service (NHS) explains: "Vaccination means having a vaccine - that is actually getting the injection, or nasal spray or oral vaccine. Immunization means both receiving a vaccine and then becoming immune to a disease". The distinction is made because in a very small number of those who are vaccinated the vaccination will not 'take' and therefore that vaccinated person will not be immunized (i.e. will not be immune to the disease). However, as this refers to a very small number of people both terms are often used interchangeably across the academic literature and in media reporting and we follow this convention in this entry.

21. For the WHO recommendations see http://www.who.int/ith/vaccines/en/

The Bacille Calmette-Guerin (BCG) vaccine for tuberculosis (TB) is recommended in countries where TB is common. BCG policies and practices have varied considerably across time and countries. The BCG World Atlas is an online resource that tracks these changes comprehensively.

22. It provides data on topics such as trust in science and scientists; trust in sources of information about health; public understanding of the word 'science'; the intersection between religious teachings and science; and attitudes to vaccines. In this post, we focus on how attitudes to vaccination vary across the world.

23. This is a stark result for Venezuela in particular (although perhaps unsurprising) since the availability and coverage of child vaccination has fallen significantly over the last few years.

24. Navin M. Largent, improving non-medical exemption vaccine policies: three case studies. Public Health Ethics. 2017; 10: 225-234. Available here

25. See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1449224/

26. Stern, M., Alexandra. (2010). Better Off in School: School Medical Inspection as a Public Health Strategy During the 1918-1919 Influenza Pandemic in the United States

27. Amin, A.N.E., Parra, M.T., Kim-Farley, R. et al. (2012) - Ethical Issues Concerning Vaccination Requirements. In Public Health Reviews (2012) 34: 14. https://doi.org/10.1007/BF03391666. Online here: https://link.springer.com/article/10.1007/BF03391666

28. See: http://www.who.int/csr/ihr/icvp/en/index.html

29. Salmon, Daniel A et al., Compulsory vaccination and conscientious or philosophical exemptions: past, present, and future, The Lancet, Volume 367, Issue 9508, 436 - 442

30. The data source for vaccination coverage: School Vaccination Assessment Report, 2016-17 school year.
Estimated vaccination coverage with 5 doses of Childhood Diphtheria toxoid, Tetanus toxoid, acellular Pertussis (DTaP) vaccination for kindergartners (typical age range is 4-6 years).

The data source for exemptions is: Immunization Action Coalition, "Exemptions Permitted for State Immunization Requirements," 2017; LexisNexis; StateNet 2017

Regarding the school vaccination coverage and exemption methods the source notes: "Each school year, school nurses, other school personnel, or health department personnel check the vaccination and exemption status of kindergartners enrolled in public and private schools as required by state law or regulation. State and local immunization programs measure vaccination coverage among children entering kindergarten annually. This may be done for every student or for a sample of students.

State and local areas set the vaccination requirements. Immunization information systems (IISs) may be used as one source of data for school vaccination assessment. The school-level data are reported to the health department. The aggregate data are reported to CDC for public and private schools. Data for home-schooled students are not routinely reported to CDC."

The types of permitted exemptions vary by state. For specific details refer to School Vaccination Requirements and Exemptions.

31. See the WHO here.

32. See here.

33. In 2014 their vaccine business was acquired by GlaxoSmithKline, as reported here.

34. There are exceptions however. A vaccine for tetanus and diphtheria (td) for example, has a large number of suppliers (13, and 7 for the paediatric formulation).

35. Review of vaccine price data. Submitted by WHO European Region Member States through the WHO/UNICEF. Joint Reporting Form for 2013. Online here.

36. The Economist. (2010). A smarter jab. Available online

37. The Economist. (2010). A smarter jab. Available online

38. See WHO guidance for more information at: https://www.who.int/vaccine_safety/initiative/tools/DTP_vaccine_rates_information_sheet.pdf

39. The source of the data is the International drug price indicator guide

40. Bonanni et al. 2009; Bonanni P., Breuer J., Gershon A., Gershon M., Hryniewicz W., Papaevangelou V., et al. (2009) - Varicella vaccination in Europe - taking the practical approach. BMC Med 7: 26 here.

41. See the WHO here: http://www.who.int/mediacentre/factsheets/fs378/en/

42. Holt, Ed., Ukraine at risk of polio outbreak, The Lancet , Volume 381 , Issue 9885 , 2244 here

43. Figures are updated by the WHO here: http://www.who.int/news-room/fact-sheets/detail/measles

44. See the WHO here: http://www.who.int/mediacentre/factsheets/fs286/en/

45. In 2014 there were 135.2 million one-year olds. Of these 84.52% received the vaccine against measles.
This means that 135.2 *0.8452 = 114.27 million children were vaccinated.

46. Gaston De Serres, Jill Sciberras, Monika Naus, Nicole Boulianne, Bernard Duval, and Louis Rochette (1999) - Protection after Two Doses of Measles Vaccine Is Independent of Interval between Doses. In The Journal of Infectious Diseases, Volume 180, Issue 1, 1 July 1999, Pages 187-190, https://doi.org/10.1086/314847 Online here: https://academic.oup.com/jid/article/180/1/187/990623.

47. For guidelines on recommendations for the second dose of measles vaccine see here https://www.who.int/immunization/sage/meetings/2016/october/Session6-MCV2-Introduction-criteria.pdf

48. Aliabadi, Negar, et al. "Global impact of rotavirus vaccine introduction on rotavirus hospitalisations among children under 5 years of age, 2008-16: findings from the Global Rotavirus Surveillance Network." The Lancet Global Health 7.7 (2019): e893-e903.

49. The cost of rotavirus vaccines varies by country. For example, countries with a gross national income per capita of less than US$1,000 receive subsidies from the Global Alliance for Vaccines and Immunisation, and there the cost per dose is set between US$2.10 - 3.20. With additional co-financing options can reduce the costs down to US$0.13. In high-income countries, such as the US, the cost per dose is between US$70 and 95

Countries are more likely to introduce the vaccine if the political environment is favourably disposed towards them. For example, if a country has set a high priority on achieving the Millennium Development Goal targets or the introduction of vaccines is seen as a positive news story, especially during election years.

50. Clark, Andrew, et al. "Efficacy of live oral rotavirus vaccines by duration of follow-up: a meta-regression of randomised controlled trials." The Lancet Infectious Diseases (2019).

51. The Clark et al. (2019) study defined low child mortality rate as less than 1.3% of newborns; medium mortality rate as between 1.35% and 2.81%; and high mortality rate as more than 2.81%

52. Who.int. (2019) - Immunization coverage. [online] [Accessed 10 Sep. 2019]. http://view-hub.org/viz/ (Go to PCV -> PCV - Vaccine Access -> Children without Access)

53. The number of serotypes included in the vaccine is generally indicated in its name, e.g. PCV13 is pneumococcal conjugate vaccine effective against 13 bacterial serotypes. Vaccines including progressively more serotypes have been introduced over the years, PCV7 was introduced in 2000 and today the most commonly used PCV13 was introduced in 2010.

54. The current non-conjugate vaccine, PPSV23, is generally only given to adults or as a single dose following two immunisations with PCV13 in children older than 2.

Golos, M., Eliakim‐Raz, N., Stern, A., Leibovici, L., & Paul, M. (2016). Conjugated pneumococcal vaccine versus polysaccharide pneumococcal vaccine for prevention of pneumonia and invasive pneumococcal disease in immunocompetent and immunocompromised adults and children. Cochrane Database of Systematic Reviews, (8).

55. The 27% refers to X-ray-defined cases of pneumonia. For clinically defined pneumonia, a less accurate diagnosis than X-ray-defined cases, the number is 6%. Both of these indicators refer to cases of pneumonia caused by any pathogen not only pneumococcus. Lucero, M. G., Dulalia, V. E., Nillos, L. T., Williams, G., Parreño, R. A. N., Nohynek, H., ... & Makela, H. (2009). Pneumococcal conjugate vaccines for preventing vaccine‐type invasive pneumococcal disease and X‐ray defined pneumonia in children less than two years of age. Cochrane Database of Systematic Reviews, (4).

56. GAVI (Global Alliance for Vaccines and Immunisation) is a non-profit organisation that provides access to vaccination programs for low-income countries by providing financial support and individual expertise.

57. For example Kenya has recently entered a transition phase during which it will pay a larger and larger portion of the PCV vaccine cost. By 2027 Kenya will have to pay the full $9 price for a three-dose course child vaccination. The 2016 per capita healthcare expenditure in Kenya was around $66 (5% of the GDP), clearly $9 per child is not a trivial cost.

58. The return of investment was estimated for a projected coverage for individual countries for the decade between 2011 and 2020. It means that the economic benefits (as measured by the costs of vaccination program subtracted from the reduced costs of treatment and productivity loss) of using the vaccine are 3 times higher than no vaccine use.
To reduce costs, some countries may also consider switching to a two rather than three dose immunization schedule, but more research on the effectiveness of this schedule in different countries is needed. See O'Brien et al. (2018) reference.

Nakamura, M. M., Tasslimi, A., Lieu, T. A., Levine, O., Knoll, M. D., Russell, L. B., & Sinha, A. (2011). Cost effectiveness of child pneumococcal conjugate vaccination in middle-income countries. International health, 3(4), 270-281.

Ozawa, S., Clark, S., Portnoy, A., Grewal, S., Brenzel, L., & Walker, D. G. (2016). Return on investment from childhood immunization in low-and middle-income countries, 2011-20. Health Affairs, 35(2), 199-207.

Center, I. V. A. (2017). The evidence base for pneumococcal conjugate vaccines (PCVs): data for decision-making around PCV use in childhood. Baltimore (MD): Johns Hopkins University.

O'Brien, K. L. (2018). When less is more: how many doses of PCV are enough?.The Lancet Infectious Diseases, 18(2), 127-128.

59. Ginsburg, A. S., Nahm, M. H., Khambaty, F. M., & Alderson, M. R. (2012). Issues and challenges in the development of pneumococcal protein vaccines. Expert review of vaccines, 11(3), 279-285

60. Kendig, E. L., Wilmott, R. W., & Chernick, V. (2012). Kendig and Chernick's disorders of the respiratory tract in children. 9th ed. Elsevier Health Sciences.

61. Aronson, N. E., Santosham, M., Comstock, G. W., Howard, R. S., Moulton, L. H., Rhoades, E. R., & Harrison, L. H. (2004). Long-t erm efficacy of BCG vaccine in American Indians and Alaska Natives: a 60-year follow-up study. Jama, 291(17), 2086-2091.

62. https://www.who.int/biologicals/areas/vaccines/bcg/en/

63. https://www.who.int/news-room/fact-sheets/detail/immunization-coverage

64. "Global childhood immunization coverage growing at only half the officially reported rate, IHME study" online here: http://www.healthdata.org/news-release/global-childhood-immunization-coverage-growing-only-half-officially-reported-rate-ihme

65. Other vaccines measured by the WHO and UNICEF are HepB3, Hib3, MCV and PAB.

66. See: http://www.who.int/immunization/newsroom/press/immunization_coverage_july_2016/en/

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Citation

Our articles and data visualizations rely on work from many different people and organizations. When citing this entry, please also cite the underlying data sources. This entry can be cited as:

Samantha Vanderslott and Bernadeta Dadonaite (2013) - "Vaccination".Published online at OurWorldInData.org. Retrieved from: 'https://ourworldindata.org/vaccination' [Online Resource]

BibTeX citation

@article{owidvaccination,
    author = {Samantha Vanderslott and Bernadeta Dadonaite},
    title = {Vaccination},
    journal = {Our World in Data},
    year = {2013},
    note = {https://ourworldindata.org/vaccination}
}

# data[].attributes.attachment_link.description
Since the invention of the smallpox vaccine, vaccines have greatly reduced the prevalence of diseases everywhere in the world. This research article explains which vaccines are available and where they are, what their impact on global health is, and how the world can make more progress against early death and disease with the help of vaccines.

# data[].attributes.attachment_link.readable_text
A vaccine is a type of medicine that trains the body's immune system so that it can fight a disease it has not come into contact with before. Vaccines are designed to prevent disease, rather than treat a disease once you have caught it.

To understand how vaccines work, it helps to look first at how the immune system works, because vaccines harness the natural activity of your immune system. This short animation explains how vaccines enable the body to make the right sort of antibodies to fight a particular disease. Click here to download the script of the animation.

# data[].attributes.attachment_link.title
What is a vaccine, and how do vaccines work?

# data[].attributes.attachment_link.description
A vaccine is a type of medicine that trains the body's immune system so that it can fight a disease it has not come into contact with before. Vaccines are designed to prevent disease, rather than treat a disease once you have caught it.

# data[].attributes.attachment_link.title
Prevalence of Polio Rates in the United States

# data[].attributes.attachment_link.description
The reported rates are per 100,000 US population and include both wild- and vaccine-derived type polio infections that occurred indigenously and as imported cases.

# data[].attributes.attachment_link.title
The Cutter Incident: How America's First Polio Vaccine Led to a Growing Vaccine Crisis

# data[].attributes.attachment_link.description
The Cutter incident had an ambivalent legacy. On the one hand, it led to the effective federal regulation of vaccines, which today enjoy a record of safety `unmatched by any other medical product'.

# data[].attributes.attachment_link.readable_text
Nature Biotechnology 28, 910-916(2010) Cite this article

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Several factors should be taken into account when it comes to the first exposure of humans to a novel vaccine.

Vaccines have a long history of excellent safety and a highly positive benefit/risk profile. Even so, the lack of specific guidance from regulatory agencies specifically relating to the first application of a new experimental vaccine in humans has hampered product development. Most of the regulatory guidance documents for manufacturers are too broad and sometimes only vague where vaccines are concerned. As regulators deeply involved both in the development of the European Medicines Agency's (EMA; London) new regulatory framework on risk identification and mitigation, and in assessment and authorization of clinical trial applications for biotechnological and biological products (especially vaccines), we have been repeatedly approached by companies and vaccine developers regarding regulatory issues for first-in-human clinical trials. Here, we discuss these considerations as they relate to vaccines within the context of the current EMA guideline for risk identification and mitigation for first-in-human clinical trials based on the apparently considerable uncertainty among developers. We describe how regulators apply the guideline and where we see the limitations or the need to take alternative approaches. The discussion primarily focuses on prophylactic and therapeutic vaccines against infectious diseases as this classic field of products is associated with particular uncertainty.

Unfortunately, little if any specific guidance is available for first-in-human trials specific to vaccines. The guidance for industry issued by the US Food and Drug Administration (FDA) concerning dose calculation for a first-in-human clinical study2 describes in detail the initial dose finding but states explicitly that it is not pertinent for vaccines. Only general guidance concerning the principles for conduct of clinical studies is available from the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). EMA guidance specific to nonclinical and clinical evaluation of vaccines is available but also includes only limited guidance specific to first-in-human studies3,4,5.

Because vaccines resemble pathogen antigens, which usually have antigenic features distinct from physiological structures found in human tissues, the risk accompanied with administration of these products is usually considered relatively low; frequently reported adverse events in clinical trials are in most cases manageable and transient (e.g., fever and local reactogenicity). In addition, knowledge of immunological processes and the role of specific cells and mediators in this context continues to advance, facilitating our understanding of the mechanism of action of individual components of vaccines.

The overall safety of vaccines is corroborated by the fact that during decades of vaccine development and application, cases of severe damage caused by these products have been uncommon. However, rare examples of adverse events have been observed. In 1955, for example, insufficiently inactivated batches of polio vaccine caused an outbreak of polio due to the presence of wild-type poliovirus strains. This became known world wide as the Cutter incident, in which 40,000 children developed mild polio, 200 were permanently paralyzed and 10 died6. Another example is an aggravated or atypical disease following vaccination and exposure to wild-type viruses caused by a measles and respiratory syncitial virus7 or experimental severe acute respiratory syndrome (SARS)8 vaccine. Regarding live-attenuated vaccines, data suggesting elevated mortality observed in developing countries following vaccination with medium- and high-titer measles vaccines demonstrate again the need for cautious approaches when entering into early clinical trial phase9. But these examples also highlight that root causes for problems can often be identified, and principles for risk identification and mitigation can be developed.

Infections themselves can trigger immunological sequelae that can even be more harmful than the actual infection itself (e.g., rheumatic fever after infection with group A streptococci, such as strep throat or scarlet fever, or Guillain-Barré syndrome (GBS) following viral infections or infection with Campylobacter jejuni or certain other bacteria). Guillain-Barré syndrome is a rapidly progressing ascending paralysis, mediated by a cross-reactive attack of antibodies (e.g., cross-reacting against the GM1 ganglioside)10. Such knowledge is relevant to the risk assessment of a novel vaccine against an infection for the following reasons: first, vaccines often present an antigen in an artificial context (that is, as repetitive structures, such as in virus-like particles, as fragments of epitopes or as capsules); second, in many cases, vaccines are administered together with an adjuvant that enhances or modulates the immune response (see below); and third, vaccines provide an antigen dose that is both different from that seen in a natural infection and most times presented to the immune system by a different route. It may, thus, be (theoretically) possible that a vaccine could lead to clinical symptoms similar to infections that trigger downstream immunological sequelae and thus study protocols could benefit from implementing respective endpoints. This is borne out by the observation that especially in live vaccines, but also in some others, there have been sporadic reports of rheumatic fever and Guillain-Barré syndrome. At the same time, such complications are very rare and the causality is not always clear. For instance, sometimes concomitant minimal (respiratory) infections are present in a subject when an experimental vaccine is tested, but these are, of course, no reason to delay a vaccination. Thus, for the time being, there are doubts of a causal relation between vaccination and the onset of autoimmune diseases, apart from isolated cases.

On the other hand, vaccines have an excellent safety record and most new vaccines can a priori be considered low-risk medicinal products. It needs to be emphasized that we do not have to assume that a vaccine with a new mechanism of action or a novel structure is a high-risk vaccine. Likewise, not every new medicinal product should automatically be considered a high-risk medicinal product13. The first-in-human trial is a critical turning point between preclinical studies and first human exposure and subsequent larger clinical trials in hundreds or (for many vaccines) thousands of subjects. For sponsors, relevant risk assessment for first-in-human clinical studies means careful design and conduct of studies that reduce potential risk to humans. In comparison to therapeutic proteins or other medicinal products, however, the prophylactic character and mechanism of action of vaccines warrant particular attention. Indeed, some of the concepts introduced in the aforementioned EMA guideline1 may not even be readily applicable.

First, pharmacokinetics should be considered relevant only if, for example, a vaccination approach involves either a novel or different means of delivery (the first pass effect for oral application versus the usual intramuscular route) or a novel live vaccine (where shedding rates can differ). Pharmacodynamics in vaccines is usually gauged by immunogenicity (appearance and increase of antibody titers).

Second, vaccines often include an adjuvant or are administered concomitantly with an immunomodulator that has its own impact on the overall risk assessment. As such agents can influence the behavior of a vaccine or the host's responses to a vaccine14,15, it is often important to assess their effects (including, for instance, pharmacokinetics and pharmacodynamics) both separately from the vaccine antigen (as its own entity) and in combination with the antigen.

Third, the target population for vaccine trials is usually healthy and young-often infants from six weeks of age and up, children or adolescents. This requires special diligence concerning benefit/risk assessment.

Fourth, unlike other medicinal products, efficacy measurements are often indirect; thus, the elicited immune response is the active principle of a vaccine and needs to be part of the risk assessment.

And finally, the risk profile of a vaccine may be different over time and dependent on exposure to both vaccine and pathogen infection. For vaccines, acute risks have to be distinguished from sub-acute or chronic (long-term) risks after (repeated) product administration.

Although the general criteria and considerations mentioned in the EMA guideline1 should always be taken into account, Figure 1 displays criteria that are more specific to vaccines and may be helpful for developers. The relative importance of these criteria should be decided on a case-by-case basis for each product; if developers are in doubt, they should consult with regulators (either the national agencies of EU member states or the EMA) when designing a trial.

Risk assessment for a vaccine intended for first-in-human administration.

The safe starting dose: is the MABEL relevant?

The calculation of a safe starting dose is a central aspect for a first-in-human trial. The classic approach to calculate the starting dose for a first-in-human trial for a classic medicinal product (not a vaccine) is based on toxicity in the relevant animal model specifically on the no-observed-adverse-effect level (NOAEL). This approach was also chosen for the agonistic anti-CD28 monoclonal antibody TGN1412, but was apparently insufficient to prevent the highly elevated pharmacodynamic effect, a massive cytokine-release syndrome16. Thus, the EMA guideline advocates an alternative approach, that is, a calculation based on the minimal-anticipated-biological-effect level (MABEL), being the dose level at which a minimal biological effect in humans is expected by in vitro or in vivo data. It is based on the occurrence of any biological effect, not only toxicity. Thus, the MABEL approach usually results in a much lower dose than that calculated with the NOAEL approach, which relates to toxicity findings. Here, the classic paradigm of a dose-dependent effect (including toxicity) is implicitly assumed-a principle already questionable for certain biotechnological medicinal products that can exhibit distinct pharmacodynamic effects at a low dose. For vaccines, additional-or even alternative-considerations need to be made because often thresholds for eliciting an immune response exist. Thus, the principle of little dose increases in cohorts might not be applicable here regarding the toxicity (if any) of the vaccine itself and consequences of the elicited immune response. In addition, if no correlate of clinical protection yet exists for the respective vaccination or if thresholds of antibodies are different between serotypes included in a vaccine (e.g., pneumococcal vaccines), the respective dose for a MABEL would be difficult to determine.

If a similar vaccine exists, for instance, a conventional Bacillus Calmette Guérin (BCG) vaccine in relation to new BCG-based tuberculosis-vaccine developments, information about the immunological pathways and clinical effects (efficacy and safety) may be extrapolated to indicate a safe starting dose and a possible test setting for the first-in-human clinical trial. If such a 'prototype' product is not available, a safe starting dose can be achieved by dissecting the different aspects that characterize a vaccine ( Fig. 2), which are discussed below.

Factors to be considered for the starting dose of a vaccine for first-in-human administration.

Vaccine antigen. Traditionally, the vaccine antigen consists of a live-attenuated pathogen, an inactivated pathogen or a recombinant or chemically synthesized antigen that resembles the natural antigen of the pathogen. An attenuated vaccine strain has impaired replication competence in humans. Here, a dose escalation starting from a low dose of the vaccine can indeed be feasible when it comes to test safety of the pathogen itself. But for inactivated pathogens and synthetic antigens, this may be less feasible because the protein or polysaccharide in itself might not exert any toxicity at all. These considerations apply both to dose escalation in nonclinical safety studies and for first-in-human trials. A MABEL approach may well be feasible only for certain types of antigens and may produce misleading results and even a false feeling of safety for other types.

Concerning direct toxicity, nonclinical studies might already be of help here. If there is a direct toxicity of the antigen, for instance, this normally will be apparent in nonclinical toxicity studies.

Adjuvants and immunomodulators. Adjuvants are an important component of a vaccine and a rapidly growing number of new adjuvant systems are used to enhance the immune response either through ideal presentation of the antigen or by immunomodulating effects. They are traditionally composed of mineral salts (e.g., alum), or more advanced developments derived from microorganisms like muramyl dipeptide, monophosphoryl lipid A or trehalose dimycolate. The mechanism of action of adjuvant emulsions includes the formation of a depot at the injection site enabling the slow release of antigen and the stimulation of antibody-producing plasma cells. Other adjuvants may be particulate antigen delivery systems (that is, liposomes, polymeric microspheres, nano-beads, immunostimulating complexes and virus-like particles), polysaccharides or nucleic acid-based adjuvants17. They may consist of combinations of two or more adjuvant systems (e.g., AS04) or not even be part of the formulation at all but concomitantly administered (that is, cytokines).

Some of these adjuvants are well known or at least 'established' through their long use. For newer adjuvants, however, less exposure data are available and the ideal dose of adjuvant with a certain antigen (content) has to be sought each time a novel vaccine is developed.

The dose of a novel adjuvant may feasibly be found through a MABEL approach. For example, a dose-dependent effect might exist for adjuvants targeting Toll-like receptors. A MABEL approach could also be used for immunomodulating adjuvants like cytokines. However, a threshold effect could exist here as for some antigens or other adjuvants.

Novel adjuvants can be species specific (e.g., cytokines), posing an additional challenge to find a relevant animal model (see discussion further below). Thus, even individual testing of the adjuvant or the immunomodulator in a separate first-in-human study might become necessary. Experience gained with a specific adjuvant in another vaccine could be considered supportive data, but it cannot be excluded that the same adjuvant causes serious side effects in combination with a different antigen. In any case, a thorough risk assessment is necessary also for the adjuvant.

The elicited immune response. The elicited immune response surely represents the main 'active' principle of vaccination. The vaccine antigen (such as a protein or polysaccharide) may in itself be harmless (and cause only unspecific local reactions), but the immune response against it could be harmful. Antibodies can cross-react with physiological structures and the concept of 'molecular mimicry'18 is one of the hypotheses by which autoimmunity is explained. Antibodies, as well as CD4⁺ T-helper cells that are part of activating and promoting a specific immune response against an antigen, might not only detect the target antigen they are intended for (that is, the pathogen) but also cross-react in an unwanted fashion with other structures that have a similar formation. T-cell recognition is 'degenerate'19, meaning that T cells also react with structures that have less than 100% identity with the T-cell receptor's primary target.

Thus, for risk estimation of a novel vaccine candidate one needs to consider the immune response that is elicited by a vaccine as a potentially 'toxic' principle. Because activation of the immune system and the resulting immune response is not necessarily dose dependent and may be associated with particular threshold considerations, MABEL might also not be feasible here. One possible solution could be nonclinical studies. Unfortunately, for observation of a potential cross-reactivity animal toxicology data might not always be sufficiently helpful because the biological structures of animal and human organs regarding epitopes are different. Cross-reactivity of the sera of accinated animals with animal organs might not necessarily imply that the same would happen in humans and, likewise, absence of cross-reactivity or autoimmunity in animals would not imply safety in humans.

On the other hand, in vitro tissue cross-reactivity studies performed with animal sera can be helpful. This approach, in which animals are vaccinated and their sera tested for cross-reactivity with human tissue sections, is routinely carried out in nonclinical toxicology testing of monoclonal antibodies. In the case of a vaccine product, the animal species might not necessarily have to be 'relevant' (see discussion below) because the animals are used rather to obtain the antibodies that can then be tested for toxicity. In addition, for the choice of the species, one may have to take into account that unrelated species may produce cross-reactive antibodies. These might be deleted in highly related species due to a tolerance for self that is shared by related but not by unrelated species. Nevertheless, such results can be useful to create a 'worst-case scenario' for cross-reactivity and may be helpful when considering risks. It is acknowledged that cross-reactivity studies have their inherent difficulties as data may be misleading if artifacts arise due to tissue preparation and fixation procedures. Even if true binding or cross-reactivity is observed, this might not necessarily point to a safety concern as the tissue structure may not be accessible under physiological conditions in humans. A shortcoming of this approach is that it tests only the antibody response; a T-cell response cannot be tested. This is problematic as T cells might be the main driver for toxicity in humans. Even so, such findings should be regarded as potential safety signals and will be helpful in assessing risks. For a first-in-human study (and subsequent clinical studies), such signals trigger the implementation of relevant clinical safety endpoints to detect potential clinical manifestations of such bindings or confirm that it does not occur in patients. These will be aimed mostly at subclinical changes, for instance, echocardiography in case binding to human cardiac tissue sections had been observed. It is fully acknowledged that such events can be rare and that the true risk of occurrence might not even become apparent before marketing authorization and use in large numbers of people. Nevertheless, for novel vaccination, principles such as precautionary measures are helpful in risk identification and mitigation strategies.

The vaccination schedule. For most vaccines, single-dose administration is insufficient to establish immune protection as well as boosterable long-term persistence of the immune response. Adverse effects not triggered by a first dose might be triggered or will become detectable only during completion of the primary vaccination regimen or at the time of booster vaccination. These phenomena are known as positive re-exposure. The risk might then increase with the frequency of administration of a specific vaccine to achieve an acceptable immune response and might be particularly high for vaccines that must be administered at regular intervals. In view of these effects, the vaccination schedule also needs to be taken into consideration for the definition of the safe starting dose. As such safety issues cannot readily be predicted, a simulation of the vaccination schedule in animals should be made. In addition, appropriate safety evaluations in vaccinees and regular and extensive follow-up visits suitable to detect late effects (up to several months) must be implemented.

Quality/CMC considerations

At the time the step from animals to humans is made in drug development, the product should already be very well characterized. The potency of bacterial or viral antigens in the vaccine should be given special attention as this is a crucial factor to mediate toxicity and other adverse reactions. Therefore, specifications for potency should ideally be set sufficiently narrow. Specifications being too wide might project into false dose estimations, thus leaving room for uncertainty regarding the validity of dosing assumptions defining the starting dose. Assays measuring impurities, sterility and inactivation of biological agents have to be available at this early point in development. If possible, components (e.g., reagents, adjuvant and excipients) should be referenced (for trials in Europe) to the European Pharmacopoeia where monographs are available.

Nonclinical considerations

Although animals present 'good models' for a variety of human physiological functions, they also have significant limitations when it comes to species-specific aspects; diseases induced by infectious agents relevant to humans may not exist in animals or may cause different symptoms. Likewise, certain adverse reactions can be seen only in humans and some adverse events of special interest cannot be predicted or reproduced in animals (e.g., a potential impact on functions of the central nervous system, especially learning difficulties or development of speech). Thus, a 'relevant' animal model is needed that maps the respective disease to be prevented as well as organ systems influenced by the new agent. In this respect, it is important to discuss the concept of the 'relevant species' specifically for vaccines. For a vaccine as well as for certain other biologicals, there needs to be a distinction of 'relevance' in respect of susceptibility and the clinical course of infection with the pathogen (proof of concept) and in respect of reliable prediction of safety and toxicology of the vaccine in humans.

When it comes to proof of concept, the relevant species might have to be defined differently. Here, the relevant species is one that is susceptible to infection with the pathogen and at best also resembles clinical features of humans suffering from infection and its subsequent resolution. Relevant animal models for most kinds of vaccine-targeted diseases exist (e.g., ferrets for influenza and chimpanzees for hepatitis A and B), but for specific scenarios investigators might have to combine different approaches to describe the human infection and the way the vaccine will prevent it. When selecting an animal model, which type of immune response is elicited in conjunction with the adjuvant, for example, the kind of T-cell response (cytotoxic T cells or T-helper cell responses), is also among the factors to be considered.

Usually, only single and repeated dose toxicity studies in at least one animal species are required before first-in-human administration (repeat dose toxicity for most vaccines that are applied at least twice). For vaccines that target children and/or women of child-bearing potential, the influence on the reproductive system has to be explored. Here, different animal models might be defined as 'relevant' compared with the other nonclinical studies. For the emerging class of genetically modified biological systems, the risk of possible gene transfer into humans (or the human germ line) also needs to be quantified. Reproductive toxicity includes male and female reproductive capacity as well as the possible influence of transferred genes on the development of the embryo/fetus during pregnancy. This might indeed be an issue, given the complex changes to the maternal organism during pregnancy, including maternal-fetal exchange (hormones, antibodies and so forth). Therefore, the possible influence on fetal development (bone structure, central nervous system, organs and so forth) has to be closely surveyed as well.

Clinical trial design considerations

One central aspect of clinical trial design is the translation of potential findings from the nonclinical and in vitro studies (e.g., unexpected cross-reactivity of induced antibodies in animals with human tissue, to suitable clinical endpoints). As discussed, surveillance of subjects should be designed on a risk-based approach including acute and chronic risks ( Figs. 1 and 2). Because they can affect immunological responses, several intrinsic and extrinsic factors influence the conduct and structure of a clinical trial design.

Intrinsic factors derive from subjects enrolled in the trial. They can cover, for example, concurrent diseases (e.g., HIV and malaria) and genetic polymorphisms, including major histocompatibility complex (MHC) haplotypes, receptor sensitivity or organ function. Ethnic factors, drug habits and nutritional status also directly affect the immune system.

Extrinsic factors derive from the socioeconomic background of the region where a trial takes place. Crucial factors for vaccines are the climate (that is, the ability to maintain the cold chain for the product), diagnostic and case definition practices. Drug compliance influences the trial subjects' view on multi-dose vaccinations as well as repeated visits for blood draws and adverse event checks. Some of these factors cannot be controlled or avoided (e.g., MHC haplotypes), but should nevertheless be considered in clinical trial protocol design as relevant. For example, developers elect to conduct a trial in a region where disease incidence or prevalence is high because only in this region would subjects be sufficiently motivated to comply with the trial protocol. Also crucial are local views on regulatory practice and good clinical practice as well as methodology and endpoints for the trial. This last instance, of course, influences all drug trials and is not unique for vaccines, but local ethical or religious views determine the acceptability of certain vaccines, as can be seen by the difficulty in eradicating polio, and might even be more an issue with vaccines preventing sexually transmittable diseases. To take into account these factors, the EMA has drafted a reflection paper containing examples of product groups and special extrinsic factors influencing studies23 and the ICH has issued 'frequently asked question' paper E5 (ref. 24).

Statistical methods for limiting trial size. In first-in-human studies, only a very small number of participants are enrolled to minimize risk in light of the usually-at this point-nonexisting benefit for the enrolled study subjects (if, for example, the vaccine dose when deciding to follow the MABEL approach is too low and is maybe immunogenic but not yet protective). As most first-in-human studies have dose escalation in their procedure reliable measures for proceeding to the next dose cohort have to be implemented. Besides orientation from nonclinical animal challenge studies, several statistical methods limit the number of study subjects while at the same time allowing good estimates of nontoxic (minimal toxicity dose, MTD) and beginning effect (minimal effective dose, MED) levels. This includes, for example, the standard 3+3 cohort analysis and the continual reassessment method (CRM). The CRM is usually used to estimate the maximum tolerated dose but might be used as well to define the MED and MTD when starting from a dose level estimated to be between nontoxic and a beginning effect, as previously observed in nonclinical studies25,26.

Surveillance of subjects. Safety is not restricted to 'tolerability' as this rather relates to local tolerance of the vaccine only. First, as usually only healthy participants are included in these studies, all possible control mechanisms must be applied. These include recording of routine laboratory parameters, including those specific to the expected interaction of the vaccine with the physiological environment, such as differential blood count and blood chemistry. Systematic evaluation should also include the recording of parameters in organs previously observed to be affected in animals (e.g., liver enzyme levels associated with hepatotoxicity) and those deduced from tissue cross-reactivity studies. Imaging techniques like (contrast) magnetic resonance imaging, computer tomography, ultrasound or X-ray of suspected vulnerable tissues as well as regular medical surveillance (electrocardiography or clinical examination) before, during and after the application of the new vaccine are also common. In addition, a first-in-human administration should not only be performed in a suitable hospital environment that provides the investigator with all necessary equipment, including an adjourning intensive care unit, but also cover a time span estimated to include all possible short-term adverse events and/or serious adverse events. After this period has elapsed, subjects are released from the trial center and examined as outpatients at regular intervals until the end of the expected interference induced by the vaccine (that is, long-term adverse events). Agencies often request long-term follow-up visits up to six months from the start of the trial, depending on the perceived potential risk for long-term events like autoimmunity.

Pediatric studies. In contrast with most conventional pharmaceuticals, the target population for many vaccines is infants and children. First use in a pediatric population is, therefore, a particularly critical step that again needs careful consideration with respect to additional animal studies that might potentially be required (juvenile animals), further dose reduction and different dosing schemes. In addition, studies in children regardless of age are ethically difficult if no comparator yet exists and the disease to be prevented is at the same time not life threatening. Thus, justification of the trial design has to be very thorough, covering availability of a comparator (at least established medicinal use), impact and epidemiology of the disease as well as resulting age escalation/de-escalation planned.

Guidance for this field is provided in various documents by EMA ( http://www.ema.europa.eu/htms/human/paediatrics/sci_gui.htm). As in the EU, all different pediatric age groups (up to 18 years of age) will usually have to be evaluated separately in accordance with the European Paediatric Regulation; possibly only very small numbers for the individual trials will be available.

Most vaccines have an excellent safety record. As vaccination against infectious diseases contributes hugely to public and individual health all over the world, one needs to exercise caution when discussing risks associated with vaccines so as to avoid false and misleading signals for the public and politicians. Such a balanced view is particularly important with the emergence of new infectious agents (e.g., SARS and H1N1 influenza), the continued battle against neglected (tropical) diseases and the re-emergence of pathogens and vectors worldwide displaying increasing resistance to existing therapeutic agents. In this context, the establishment of new vaccines both against known and novel infectious diseases, as well as the improvement of established vaccines through novel techniques (e.g., genetic modification), is of the utmost importance. In addition, vaccination usually represents the cheapest and at the same time the most effective means of disease prevention worldwide.

In this context, a balanced and reasonable approach for first-in-human studies of a novel vaccine candidate is crucial to ensure safety of trial participants. The principles of the EMA guideline need to be applied in a reasonable and scientific way based on how prophylactic and therapeutic vaccines against infectious diseases function. Some principles, like the MABEL or NOAEL approaches, might require very careful adaptation to the specific needs and/or aspects of any given product, including a novel vaccine, as we discuss above. If a first-in-human trial for a vaccine does apply the MABEL strategy (e.g., for a novel adjuvant) and implements gradual dose increases, this merely represents the first step in defining the safety of administration. It must not be mistaken as 'dose finding' for immunogenicity, safety and tolerability. These are integral parts of further vaccine development to arrive at a dose that is maximally safe and immunogenic.

The principles discussed in this article apply primarily to prophylactic and therapeutic vaccines against infectious agents. However, many of the principles discussed here might also readily be applied to other classes of vaccines, including therapeutic 'anti-tumor vaccines'. Because of their different immunological mode of action, these products should not be grouped with traditional vaccines and thus, according to their specific mode of action and nonprophylactic timing of use, have been classified as 'immunotherapy medicinal products'.

It is important to emphasize that not every novel vaccine or adjuvant system bears a high risk and 'higher risk' might likewise imply 'more effective' concepts (e.g., enhanced immunogenicity or protection against pathogens where no functional vaccine principle exists yet). The European guideline for first-in-human trials is intended to be a step forward to develop innovative compounds more safely. It is a certainty that even this guideline and all precautionary principles will never reduce the risk to zero. Transition from nonclinical studies will always be a risk but is also a necessity to develop more efficacious medicines against human diseases.

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First-in-human clinical trials with vaccines-what regulators want

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Nature Biotechnology 28, 910-916(2010) Cite this article 1977 Accesses 15 Citations 3 Altmetric Metrics Several factors should be taken into account when it comes to the first exposure of humans to a novel vaccine. Vaccines have a long history of excellent safety and a highly positive benefit/risk profile.

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Introduction

The 20th century saw great successes at developing vaccines for many acute infectious diseases such that we now have an arsenal of 31 vaccines that are licensed in the United States to prevent infectious diseases [ 1, 2]. The 21st century is seeing vaccine development take on the challenge of developing vaccines for chronic infectious and noninfectious diseases as morbidity and mortality owing to these conditions is becoming an ever-increasing public health problem and economic cost. This is a tough challenge due to the complexity of these chronic diseases.

In this volume, we describe the current status of two well-established vaccines, yellow fever and smallpox, as examples of hugely successful vaccines at controlling two major infectious diseases. Surprisingly, even though these vaccines are very successful our knowledge regarding how these vaccines work is relatively rudimentary and both still have problems with rare, but important, side effects. We also include malaria and tuberculosis as examples of two chronic infectious diseases where vaccine development has proved to be very complex yet is crucial for public health in the 21st century. An important approach in the 21st century will be enhancing the immune response of candidate vaccines and this volume also describes research on three approaches: adjuvants, prime-boost strategies, and mucosal immunity. Finally, chronic noninfectious diseases continue to become an ever-increasing cause of morbidity and therapeutic vaccines offer a potentially attractive route to controlling these conditions. We use Alzheimer's disease as a prime example of the problems and hopes for a vaccine to control such conditions. A brief summary of the articles in this volume is provided below.

Yellow fever

The yellow fever 17D vaccine was developed in the 1930s and played a major role in controlling the mosquito-borne disease yellow fever. Barrett and Teuwen review the progress that has been made recently in understanding the mechanism of immunity by the 17D vaccine but there are still major gaps in our knowledge. Although a very successful and efficacious vaccine, there are still rare cases of severe adverse events (SAEs) following immunization. The mechanism of these SAEs is not understood at present but advances in understanding the mechanism of immunity hold promise to help reveal why such events occur.

Smallpox

The smallpox vaccine is one of the oldest vaccines and has been very successful, resulting in eradication of smallpox in the 1980s. Even though we have other vaccines that target diseases only found in humans and do not have animal reservoirs (e.g. measles), smallpox is the only disease where the various arms of public health have successfully worked together to eradicate a disease and the agent that causes it. Kennedy and colleagues review our knowledge and gaps regarding the mechanism of action of this vaccine. In particular, they describe the role of host genetics in the induction of the host immune response. Such genetic profiling may help in elucidating why smallpox vaccine causes rare SAEs, and in informing new vaccine development.

Malaria

Malaria is the prototypical parasitic disease where vaccines are crucial to controlling this chronic disease. Great strides in our knowledge of malaria has been made in recent years yet the complexity of the plasmodium life cycle has made vaccine development challenging. Casares and Richie review the challenges and novel approaches needed to successfully develop a malaria vaccine. The sophistication of plasmodium, including its ability to escape the innate and adaptive immune response, is a lesson to all vaccine researchers. Although there are some promising candidate vaccines, the ability of the parasite to evade the immune response is a major concern and novel approaches to immunogenicity will be needed.

Tuberculosis

Tuberculosis is an age-old scourge that continues to ravage developing countries and persons in the developed world with immunocompromising conditions. Barker and colleagues provide an overview of current TB vaccine developments and in particular focus on new immunologic insights that will enhance the development of a TB vaccine. Novel vaccine approaches, and new tools to identify immunogenic TB proteins and cell-mediated immune responses will facilitate TB vaccine development.

Approaches to improving immunogenicity: adjuvants

Crucial to advancing vaccine development in the 21st century will be the development of novel adjuvants designed to enhance the immunogenicity of novel antigens. Both TLR-dependent and TLR-independent pathways appear to be important. De Gregorio and colleagues provide a succinct summary of the immunology of TLR-independent vaccine adjuvants, particularly those that activate dendritic cells, which play a crucial role in the development of an effective immune response.

Approaches to improving immunogenicity: prime-boost regimens

The last two decades of the 20th century saw the utilization of prime-boost regimens to improve immunogenicity of vaccines. Shan Lu reviews various prime-boost regimens that have been used for traditional vaccines in the 20th century, including homologous and heterologous approaches. He also discusses current approaches of heterologous prime-boost regimens that are being investigated in the 21st century to improve immunogenicity of current candidate vaccines. This approach has broad application to the development of both chronic infectious disease and chronic noninfectious disease vaccines.

Approaches to improving immunogenicity: mucosal immunity

The last 25 years have revealed the major role and importance of the mucosal immune response. Takahashi and colleagues review the various components of mucosal immunity focusing on the gastrointestinal tract and oral delivery of vaccines. They use cholera vaccine as an example, describe the limitations of cholera vaccines, and show how novel delivery systems, such as plant-based immunogens, can be used to enhance the immune response.

Alzheimer's disease

In the 21st century chronic noninfectious diseases are becoming a major problem for society and this is exemplified by Alzheimer's disease, the most common neurode-generative disorder. To date the major vaccine approach has been to develop therapeutic vaccines based on amyloid beta (Aβ) peptide, a component of senile plaques. Despite immense efforts involving multiple 'immunizations,' success has been limited for either passive or active vaccination regimens. The review by Kayed and Jackson describes the complexities of Alzheimer's disease and recent approaches to the development of an Alzheimer's vaccine; in particular those that are focusing on the microtubule binding protein tau, a component of the neurofibrillary tangles. Tau plays an important role in the normal function of regulating axonal transport in neurons but a pathological hallmark of Alzheimer's disease is deposition of tau. Furthermore, tau is associated with a number of neurode generative conditions, which suggests that targeting tau for vaccine development may have many applications. Kayed and Jackson provide a description of the complexities of vaccine development for a disease characterized by pathogenesis associated with protein misfolding and aggregation.

Summary

Overall, the success of developing vaccines against acute diseases in the 20th century has laid the groundwork for vaccine development for chronic diseases in the 21st century. It is clear that we are still identifying the appropriate immunogens for inclusion in vaccines for chronic diseases and once identified our progress in enhancing the immune response is crucial for controlling these conditions either as prophylactic or therapeutic vaccines. We now enter a second 'golden age' of vaccinology in the enhanced understanding of common diseases, vaccine development against chronic noninfectious diseases, and in better integrating advances in biology, genomics, immunology, molecular biology, and virology.

Acknowledgments

We are very grateful to our colleagues who participated in writing the various reviews for this volume and identifying exciting areas for vaccine development in the 21st century. We trust our readers will find this information useful in the cause of decreasing human suffering due to preventable diseases.

Biographies

Greg Poland, MD, is a professor of medicine and infectious diseases, and director of the Mayo Vaccine Research Group, and the Program in Translational Immunovirology and Biodefense at the Mayo Clinic. His lab has defined immunogenetic markers for viral vaccine immune responses in multiple viral vaccine models, and works on development of new biodefense and viral vaccine candidates.

Alan Barrett, PhD, is a professor of Pathology and Microbiology & Immunology, and director of the Sealy Center for Vaccine Development at the University of Texas Medical Branch. His lab has had a long standing interest in vaccines for flavivirus diseases, including how the current yellow fever and Japanese encephalitis vaccines work and the development of vaccines for dengue and West Nile.

Contributor Information

Gregory Poland, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.

Alan Barrett, Department of Pathology and Sealy Center for Vaccine Development, University of Texas Medical Branch, Galveston, TX 77555-0436, USA.

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The Old and the New: successful vaccines of the 20th century and approaches to making vaccines for the important diseases of the 21st century: Editorial overview

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The 20th century saw great successes at developing vaccines for many acute infectious diseases such that we now have an arsenal of 31 vaccines that are licensed in the United States to prevent infectious diseases [ 1, 2].