Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently.
In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety.
A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups.
A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines.
A two-dose regimen of BNT162b2 (30 μg per dose, given 21 days apart) was found to be safe and 95% effective against Covid-19. The vaccine met both primary efficacy end points, with more than a 99.99% probability of a true vaccine efficacy greater than 30%. These results met our prespecified success criteria, which were to establish a probability above 98.6% of true vaccine efficacy being greater than 30%, and greatly exceeded the minimum FDA criteria for authorization.9 Although the study was not powered to definitively assess efficacy by subgroup, the 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 analyzed subgroups 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 among placebo and vaccine recipients begins to diverge by 12 days after the first dose, 7 days after the estimated median viral incubation period of 5 days,10 indicating the early onset of a partially protective effect of immunization. The study was not designed to assess the efficacy of a single-dose regimen. Nevertheless, in the interval between the first and second doses, the observed vaccine efficacy against Covid-19 was 52%, and in the first 7 days after dose 2, it was 91%, reaching full efficacy against disease with onset at least 7 days after dose 2. Of the 10 cases of severe Covid-19 that were observed after the first dose, only 1 occurred in the vaccine group. This finding is consistent with overall high efficacy against all Covid-19 cases. The severe case split provides preliminary evidence of vaccine-mediated protection against severe disease, alleviating many of the theoretical concerns over vaccine-mediated disease enhancement.
The favorable safety profile observed during phase 1 testing of BNT162b2 was confirmed in the phase 2/3 portion of the trial. As in phase 1, reactogenicity was generally mild or moderate, and reactions were less common and milder in older adults than in younger adults. Systemic reactogenicity was more common and severe after the second dose than after the first dose, although local reactogenicity was similar after the two doses. Severe fatigue was observed in approximately 4% of BNT162b2 recipients, which is higher than that observed in recipients of some vaccines recommended for older adults.This rate of severe fatigue is also lower than that observed in recipients of another approved viral vaccine for older adults.Overall, reactogenicity events were transient and resolved within a couple of days after onset. Lymphadenopathy, which generally resolved within 10 days, is likely to have resulted from a robust vaccine-elicited immune response. The incidence of serious adverse events was similar in the vaccine and placebo groups (0.6% and 0.5%, respectively).
This trial and its preliminary report have several limitations. With approximately 19,000 participants per group in the subset of participants with a median follow-up time of 2 months after the second dose, the study has more than 83% probability of detecting at least one adverse event, if the true incidence is 0.01%, but it is not large enough to detect less common adverse events reliably. This report includes 2 months of follow-up after the second dose of vaccine for half the trial participants and up to 14 weeks’ maximum follow-up for a smaller subset. Therefore, both the occurrence of adverse events more than 2 to 3.5 months after the second dose and more comprehensive 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 vaccine efficacy, ethical and practical barriers prevent following placebo recipients for 2 years without offering active immunization, once the vaccine is approved by regulators and recommended by public health authorities. Assessment of long-term safety and efficacy for this vaccine will occur, but it cannot be in the context of maintaining a placebo group for the planned follow-up period of 2 years after the second dose. These data do not address whether vaccination prevents asymptomatic infection; a serologic end point that can detect a history of infection regardless of whether symptoms were present (SARS-CoV-2 N-binding antibody) will be reported later. Furthermore, given the high vaccine efficacy and the low number of vaccine breakthrough cases, potential establishment of a correlate of protection has not been feasible at the time of this report.
This report does not address the prevention of Covid-19 in other populations, such as younger adolescents, children, and pregnant women. Safety and immune response data from this trial after immunization of adolescents 12 to 15 years of age will be reported subsequently, and additional studies are planned to evaluate BNT162b2 in pregnant women, children younger than 12 years, and those in special risk groups, such as immunocompromised persons. Although the vaccine can be stored for up to 5 days at standard refrigerator temperatures once ready for use, very cold temperatures are required for shipping and longer storage. The current cold storage requirement 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 for protecting humans against infectious diseases, and demonstrate the speed with which an RNA-based vaccine can be developed with a sufficient investment of resources. The development of BNT162b2 was initiated on January 10, 2020, when the SARS-CoV-2 genetic sequence was released by the Chinese Center for Disease Control and Prevention and disseminated globally by the GISAID (Global Initiative on Sharing All Influenza Data) initiative. This rigorous demonstration of safety and efficacy less than 11 months later provides a practical demonstration that RNA-based vaccines, which require only viral genetic sequence information to initiate development, are a major new tool to combat pandemics and other infectious disease outbreaks. The continuous phase 1/2/3 trial design may provide a model to reduce the protracted development timelines that have delayed the availability of vaccines against other infectious diseases of medical importance. In the context of the current, still expanding pandemic, the BNT162b2 vaccine, if approved, can contribute, together with other public health measures, to reducing the devastating loss of health, life, and economic and social well-being that has resulted from the global spread of Covid-19
Reference & source information: https://www.nejm.org/
Read More on: