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A study published in the New England Journal of Medicine (NEJM) reports data from phase 1 and phase 2-3 trial looking at the safety, immunogenicity, and efficacy of two doses of the Pfizer-BioNTech COVID-19 vaccine administered 21 days apart in children aged 5-to-11 years old.
Prof Adam Finn, Professor of Paediatrics, University of Bristol, said:
“This paper reports both dose finding (phase 1) results in a small number of 5-11 year old children and reactogenicity, immunogenicity and efficacy phase 2-3 results in a randomised placebo controlled study in more than 2000 children of the same age of whom two thirds received a low dose (10ug) of this mRNA vaccine and the rest placebo.
“The results are notable because they demonstrate good antibody responses and 90% efficacy at this lower dose with markedly less reactogenicity than is seen with the higher 30ug dose in older age groups and with no suggestion of the enhanced rates of local and systemic side effects after the second dose as compared to the first seen in adults. They suggest the vaccine is capable of preventing infection in children of this age and that it should be well tolerated although the study is not large enough to detect very rare adverse events. They also raise the question whether lower doses might be appropriately used in older age groups.
“SARS CoV2 infection is generally mild or asymptomatic in healthy children of this age, but vaccination might also contribute to broader epidemic control and thus reduce consequent disruption where the virus remains prevalent.”
Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“This paper describes phase 1, and phase 2-3 trial of Pfizer’s BNT162b2 vaccine in 5-11 year old children. (A phase 2-3 trial is when a vaccine is tried in a larger population to assess efficacy and safety).
“It explains that the earlier, phase 1 study, had suggested that the optimum dose for this age-group was a 10 microgram (μg) dose, and this was the dose used in the phase 2-3 trial. This is 1/3 the dose used in adults1.
“The study was not huge, compared to phase 3 trials in adults: there were over 40 thousand participants in the Pfizer adult vaccine trial1. This trial had only 2268 participants. A trial of this size is unlikely to detect rare vaccine associated adverse reactions (side effects); but again, taken with what we know about the level of side-effects in other age groups, and the likelihood that children in this age range will have those side effects, it provides fairly good estimates of vaccine safety: “No vaccine-related serious adverse events were noted.”
“Similarly, a trial of this size is unlikely to have many case outcomes, limiting its power (its ability to detect and quantify a true effect). That said, combined with laboratory data – we know a lot more about the lab measures that indicate immunity – and with data on other age groups, it is likely to provide a very strong estimate of vaccine efficacy.
“With respect to vaccine efficacy, the trial found that there were 3 cases of Covid-19 in the vaccinated group (7 days or more after the second dose), compared to 16 cases in placebo recipients. Note, however, that the vaccine group was twice as large as the placebo group, so this converts a rate of 3/1517 = 0.198% in vaccine recipients, and 16/751 = 2.130 in placebo recipients, from which the vaccine efficacy estimate of 90.7% is derived. The relatively large confidence interval (67.7 to 98.3) for this estimate is a consequence of the relatively small number of cases in the two groups. As the vaccine is rolled out in the population we would expect to see many more cases, and surveillance of vaccine effectiveness will give us more accurate figures.
“Cases in children are more likely to be relatively mild – fewer will require hospital admission, critical care admission, or die (although we should not dismiss the importance of vaccination on the heartless grounds that “not many die”). It is not clear what proportion of children in this age group will go on to develop “Long covid”; and the importance of reducing disruption to education and not transmitting the disease to vulnerable parents and grandparents will also benefit the children. This study is unlikely to have had enough serious cases to be able to assess the vaccine’s relative efficacy against infection (and potential infectiousness, even if asymptomatic), and more serious forms of disease. We cannot estimate, from it, the number of hospital admissions that would be directly prevented by vaccinating children of this age, for example.
“The abstract also refers to laboratory measures. In the Methods section it states: “Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-μg doses of BNT162b2.” The full paper explains this more clearly: “Effectiveness was inferred by an “immunobridging” approach, in which neutralizing titers [antibody levels to the vaccine]… in 5-to-11-year-olds were compared with titers elicited by BNT162b2 in 16-to-25-year-olds (in whom efficacy had been demonstrated), with formal noninferiority hypothesis testing. …” In other words, they looked to see if the antibody levels in blood samples from the younger children were as high as they were in older children, who had become immune. If the levels were equally high, they assumed that the younger children would be similarly immune.
“The results section of the abstract says: “One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8). This means that the concentration of neutralising antibodies in the blood of the 5-11 year olds was almost exactly the same as it was in the previous study on 16-25 year olds, suggesting that the vaccine’s efficacy is likely to be the same in both age groups.
“I would be surprised if Covid-19 vaccine regimes – at least with the sorts of vaccines currently in use – do not become three-dose priming regimes, possibly with subsequent boosters a year or more later. The 90% efficacy achieved in this trial can be expected to be considerably greater following a third dose. Real-world surveillance data will make this clear.
“This study provides reasonably good evidence that the vaccine is safe and effective in this age group. Taken together with the large amount of data from countries who are already vaccinating children of this age group (my 9-year-old nephew, who lives in New York, has recently been vaccinated!), the evidence is much stronger.
“Taking all of the evidence together we have very strong evidence of safety and efficacy in 5-11 years, and we should not procrastinate in starting to vaccinate children of this age group in the UK as we did with older children.”
Please note the following comments are based only on the abstract as the full paper was not yet available:
Prof Jonathan Ball, Professor of Molecular Virology, University of Nottingham, said:
“Based on the abstract: The data shows that the Pfizer mRNA vaccine is highly effective in young children, with a relatively low dose still giving around 90% protection from COVID-19. Importantly, none of the children recruited into the trial reported serious adverse effects.
“Whilst severe COVID-19 is rare in young people, it can happen, and cases and ensuing isolation has severely disrupted children’s education. Vaccination is an effective way to interrupt virus spread and reduce the overall disease burden.”
Dr James Doidge, Senior Statistician, Intensive Care National Audit & Research Centre (ICNARC); and Honorary Associate Professor, London School of Hygiene and Tropical Medicine, said:
“[Comments based on abstract only, as full paper unavailable] Questions about the risks and benefits of vaccinating children against COVID-19 are currently weighing heavily on the minds of most parents. Unfortunately, this trial does not provide the answers we seek. The reason for this is that severe outcomes of COVID-19 among children and severe complications from vaccination are both thankfully rare – too rare to be measured even in this study of over 2000 children. The main thing that this study tells us is that the Pfizer vaccine induces a similar immune response in children, provides a similar protection against infection as in adults, and was not so unsafe as to have been detectable in the 1517 participants who received the vaccine. These findings were to be expected. How much benefit they translate into with respect to rare but serious illness, and at what cost that comes in terms of rare but serious adverse reactions, will only be answered with much larger studies that are unlikely to be feasible as randomised controlled trials. To gauge the likely risks and benefits among younger children, we should look very carefully at the real-world data now emerging for adolescent and young adult populations. We should also consider the relevance of prior infection, with current evidence suggesting that the protection afforded by prior infection is at least comparable* to that provided by full vaccination. In the UK, where infections have been so prevalent among younger age groups, questions about the role of prior infection and the implications for the benefit of vaccinating those children are especially pertinent.
*While not perfect, some of the best data on the protection afforded by of prior infection versus vaccination come from the Coronavirus Infection Survey1,2 which indicates that, during the Delta wave, prior infection provided protection that was comparable to vaccination within the past 4 months and better than vaccination more than 4 months ago (with most infections having occurred even further in the past). However, these analyses appear to overestimate the risk of reinfection due to intermittent prolonged positivity in a significant minority of cases (as indicated by the sharp rise at the start of Figure 3 in [1]) and therefore underestimate the protection afforded by prior infection. Another key study comparing vaccination with prior infection—with notable differences in approach but a much more resounding conclusion—is from Israel [3]. It is important to note, however, that the question is not ‘which is better’ but ‘among those with prior infection, do the benefits still outweigh the risks’?”
[3] https://www.medrxiv.org/content/10.1101/2021.08.24.21262415v1.article-info”
Dr Peter English, Retired Consultant in Communicable Disease Control, Former Editor of Vaccines in Practice, Immediate past Chair of the BMA Public Health Medicine Committee, said:
“Thus far we have only seen the embargoed, pre-release version of the abstract (which, it says, may not be the final publication version). I rather hope it is not the final version, as it is one of the hardest abstracts to understand that I have encountered! They could communicate their findings far more effectively. Comments must be caveated on the basis that we are seeing only the abstract, and unable to read the full text, which would (one would hope) answer questions we may have having read the abstract.
“The abstract describes a phase 2-3 trial of Pfizer’s BNT162b2 vaccine in 5-11 year old children. (A phase 2-3 trial is when a vaccine is tried in a larger population to assess efficacy and safety).
“It explains that an earlier, phase 1 study, had suggested that the optimum dose for this age-group was a 10 microgram (μg) dose, and this was the dose used in the phase 2-3 trial. This is 1/3 the dose used in adults1.
“The study was not huge, compared to phase 3 trials in adults: there were over 40 thousand participants in the Pfizer adult vaccine trial1. This trial had only 2268 participants. A trial of this size is unlikely to detect rare vaccine associated adverse reactions (side effects); but again, taken with what we know about the level of side-effects in other age groups, and the likelihood that children in this age range will have those side effects, it provides fairly good estimates of vaccine safety: “No vaccine-related serious adverse events were noted.”
“Similarly, a trial of this size is unlikely to have many case outcomes, limiting its power (its ability to detect and quantify a true effect). That said, combined with laboratory data – we know a lot more about the lab measures that indicate immunity – and with data on other age groups, it is likely to provide a very strong estimate of vaccine efficacy.
“With respect to vaccine efficacy, the trial found that there were 3 cases of Covid-19 in the vaccinated group (7 days or more after the second dose), compared to 16 cases in placebo recipients. Note, however, that the vaccine group was twice as large as the placebo group, so this converts a rate of 3/1517 = 0.198% in vaccine recipients, and 16/751 = 2.130 in placebo recipients, from which the vaccine efficacy estimate of 90.7% is derived. The relatively large confidence interval (67.7 to 98.3) for this estimate is a consequence of the relatively small number of cases in the two groups. As the vaccine is rolled out in the population we would expect to see many more cases, and surveillance of vaccine effectiveness will give us more accurate figures.
“Cases in children are more likely to be relatively mild – fewer will require hospital admission, critical care admission, or die (although we should not dismiss the importance of vaccination on the heartless grounds that “not many die”). It is not clear what proportion of children in this age group will go on to develop “Long covid”; and the importance of reducing disruption to education and not transmitting the disease to vulnerable parents and grandparents will also benefit the children. This study is unlikely to have had enough serious cases to be able to assess the vaccine’s relative efficacy against infection (and potential infectiousness, even if asymptomatic), and more serious forms of disease. We cannot estimate, from it, the number of hospital admissions that would be directly prevented by vaccinating children of this age, for example.
“The abstract also refers to laboratory measures. In the Methods section it states: “Immune responses 1 month after the second dose of BNT162b2 were immunologically bridged to those in 16-to-25-year-olds from the pivotal trial of two 30-μg doses of BNT162b2.” It is not entirely clear what this means, but the results section makes it clearer. It says: “One month after the second dose, the geometric mean ratio of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing titers in 5-to-11-year-olds to those in 16-to-25-year-olds was 1.04 (95% confidence interval [CI], 0.93 to 1.18), a ratio meeting the prespecified immunogenicity success criterion (lower bound of two-sided 95% CI, >0.67; geometric mean ratio point estimate, ≥0.8).” This means that the concentration of neutralising antibodies in the blood of the 5-11 year olds was almost exactly the same as it was in the previous study on 16-25 year olds, suggesting that the vaccine’s efficacy is likely to be the same in both age groups.
“I would be surprised if Covid-19 vaccine regimes – at least with the sorts of vaccines currently in use – do not become three-dose priming regimes, possibly with subsequent boosters a year or more later. The 90% efficacy achieved in this can be expected to be considerably improved upon by a third dose. Real-world surveillance data will make this clear.
“This study provides reasonably good evidence that the vaccine is safe and effective in this age group. Taken together with the large amount of data from countries who are already vaccinating children of this age group (my 9-year-old nephew, who lives in New York, has recently been vaccinated!), the evidence is much stronger. We should not procrastinate in starting to vaccinate children of this age group in the UK as we did with older children.”
Abstract: ‘Evaluation of the BNT162b2 Covid-19 Vaccine in Children 5 to 11 Years of Age’ by E.B. Walter et al. was published in the New England Journal of Medicine at 17:00 UK time on Tuesday 9 November 2021.
DOI: 10.1056/NEJMoa2116298
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www.sciencemediacentre.org/tag/covid-19
Declared interests
Prof Adam Finn: “AF is an investigator in several COVID19 vaccine trials and studies including Oxford-AstraZeneca, Pfizer, Janssen and Valneva vaccines and several UK government-funded studies involving more than one vaccine. He is U.K. Chief Investigator Sanofi COVID19 booster vaccine trial. He is an advisor to the UK government as a member of JCVI. He chairs the WHO Euro Technical Advisory Group of Experts and is a member of the WHO Special Advisory Group of Experts Working Group on COVID19 vaccines. He undertakes consultancy work for several vaccine developers. He receives no personal remuneration for any of this work, owns no IP or stocks and shares and is paid only in his role as Professor of Paediatrics at the University of Bristol.”
Prof Jonathan Ball: “Receiving funding to develop and trial new generation COVID19 vaccines.”
Dr James Doidge: “None.”
Dr Peter English: “Dr English is on the editorial board of Vaccines Today: an unpaid, voluntary, position. While he is also a member of the BMA’s Public Health Medicine Committee, this comment is made in a personal capacity. Dr English sometimes receives honoraria for acting as a consultant to various vaccine manufacturers, most recently to Seqirus.”