The results of the most recent study published in The New England Journal of Medicine led by Argentine physician Fernando Polack are the basis for an emergency use authorization request.
Anxiety about obtaining safe treatment or effective vaccines to combat the pandemic is growing. In view of the second wave of infections already observed in Europe, the need for safe and effective prophylactics to contain the pandemic that has had devastating medical, economic and social consequences is growing.
In the past, it had already been reported reported immunogenicity and safety results from Phase 1 clinical trials of Pfizer and BioNTech's vaccine candidate, known as BNT162b2. The results of studies conducted in the United States and Germany among healthy men and women showed that two doses of 30 μg of BNT162b2 elicited high titers of SARS-CoV-2 neutralizing antibodies and robust antigen-specific CD8+ and CD4+ Th1-type Th1 T-cell responses.
The 50% geometric mean neutralizing titers in older and younger adults exceeded the geometric mean titer measured in a human convalescent serum panel, despite a lower neutralizing response in older adults than in younger adults. Furthermore, the reactogenicity profile of TNB162b2 represented primarily local (i.e., injection site) and short-term systemic responses. These findings supported the progression of the BNT162b2 vaccine candidate BNT162b2 to Phase3.
A team led by the Argentine doctor Fernando Polack, from the INFANT Foundation (F.P.P.) and the Central Military Hospital (G.P.M.) in Buenos Aires, reports safety and efficacy findings from a Phase2/3 global Phase1/2/3 trial evaluating the safety, immunogenicity and efficacy of 30 μg of BNT162b2 to prevent COVID-19 in people 16 years of age and older. This data set and the results of these trials are the basis for a request for authorization for emergency use.
Figures of the analysis
Among the 36,523 participants who had no evidence of existing or previous SARS-CoV-2 infection, 8 cases of COVID-19 with onset at least 7 days after the second dose were observed among those who received the vaccine and 162 among those who received placebo. This division of cases corresponds to a vaccine efficacy of 95.0%.
Among participants with and without evidence of prior SARS CoV-2 infection, 9 cases of COVID-19 were observed at least 7 days after the second dose among those who received the vaccine and 169 among those who received placebo, corresponding to a vaccine efficacy of 94.6%. Supplemental analyses indicated that vaccine efficacy among subgroups defined by age, sex, race, ethnicity, obesity, and presence of a coexisting condition was generally consistent with that observed in the general population.
Vaccine efficacy among participants with hypertension was analyzed separately, but was consistent with the other subgroup analyses (vaccine efficacy, 94.6%). Between the first and second doses, 39 cases were observed in the BNT162b2 group and 82 cases in the placebo group, resulting in a vaccine efficacy of 52% during this interval and indicating early protection by the vaccine, starting as early as 12 days after the first dose.
A two-dose regimen of BNT162b2 (30 μg per dose, administered 21 days apart) was found to be safe and had 95% efficacy against COVID-19. The vaccine met the two primary efficacy endpoints, with greater than 99.99% probability of true vaccine efficacy greater than 30%. These results met the pre-specified success criteria set by the task force, which were to establish a greater than 98.6% probability of greater than 30% true vaccine efficacy, and greatly exceeded the FDA's minimum clearance criteria.
Although the study was not powered to definitively assess efficacy by subgroup, point estimates of efficacy for subgroups based on age, sex, race, ethnicity, body mass index, or the presence of an underlying condition associated with a high risk of COVID-19 complications are also high. For all subgroups analyzed in which more than 10 cases of COVID-19 occurred, the lower limit of the 95% confidence interval for efficacy was more than 30%.
The cumulative incidence of COVID-19 cases over time between placebo and vaccine recipients begins to diverge 12 days after the first dose, 7 days after the estimated mean viral incubation period of 5 days, indicating the early onset of a partially protective effect of immunization.
The study was not designed to evaluate the efficacy of a single-dose regimen. However, in the interval between the first and second dose, the observed vaccine efficacy against COVID-19 was 52%, and in the first 7 days after dose 2 was 91%, reaching maximum efficacy against disease onset at least 7 days after dose 2.
Of the 10 cases of severe COVID-19 observed after the first dose, only one occurred in the vaccine group. This finding is consistent with an overall high efficacy against all cases of COVID-19. The division of severe cases provides preliminary evidence of vaccine-mediated protection against severe disease, alleviating many of the theoretical concerns about vaccine-mediated disease enhancement.
The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).
Forward-looking information
With approximately 19,000 participants per group in the subset of subjects with a median follow-up of 2 months after the second dose, the study has more than an 83% chance of detecting at least one adverse event, if the true incidence is 0.01%, but is not large enough to reliably detect less common adverse events.
This paper includes 2 months of follow-up after the second dose of vaccine for half of the trial participants and up to 14 weeks of maximum follow-up for a smaller subset. Thus, both the occurrence of adverse events more than 2 to 3.5 months after the second dose and more complete information on the duration of protection remain to be determined. Although the study was designed to follow participants for safety and efficacy for 2 years after the second dose, given the high efficacy of the vaccine, ethical and practical barriers preclude following placebo recipients for 2 years without offering active immunization once the vaccine is approved by regulators and recommended by public health authorities.
This report does not address COVID-19 prevention in other populations, such as younger adolescents, children, and pregnant women.
Another caveat highlighted by the researchers is that although the vaccine can be stored for up to 5 days at standard refrigerator temperature once ready for use, very cold temperatures are required for shipping and longer storage. The current requirement for cold storage may be alleviated by ongoing stability studies and formulation optimization, which may also be described in subsequent reports.
The data presented in this report have significance beyond the performance of this vaccine candidate. The results demonstrate that COVID-19 can be prevented by immunization, provide proof of concept that RNA-based vaccines are a promising new approach to protect humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with sufficient investment of resources.
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