This article is from the WeChat official account:Tencent Medical Encyclopedia (ID: Dr_TXyidian), Author: Wang Fengling; Reviewer: Lu Xuexin (Assistant Researcher, Ph.D. in Immunology, Institute for Viral Disease Prevention and Control, Chinese Center for Disease Control and Prevention). Original Title: “Last Night, Pfizer’s COVID-19 Vaccine Efficacy of 90% Dominated Headlines! Many Overlooked Three Key Issues.” Image credit: Visual China Group
On November 9, Pfizer and BioNTech announced major news.[1]：
Two jointly developed COVID-19 vaccine candidates have made significant progress in Phase III clinical trials, with efficacy exceeding 90% seven days after the second dose.
(Source: Pfizer official website)
If the vaccine’s safety and efficacy fully meet the required standards, they plan to submit an application to the U.S. Food and Drug Administration in the third week of November.（FDA）Submit Emergency Use Authorization.
Many people got excited when they heard the news—there were 43,538 volunteers participating in the trial. Does this mean that this vaccine is much more effective than others?
However, some readers may have noticed a detail: the “90% efficacy rate” was determined based on data from “94 participants infected with COVID-19,” and this represents only the conclusion from the first interim analysis.
Can vaccine efficacy be determined with such limited data in such a short period of time?
I. What is the trial protocol for the Pfizer COVID-19 vaccine?
As you may recall, in September this year, AstraZeneca suspended clinical trials of its COVID-19 vaccine due to a serious adverse event experienced by one participant.(Recap:Breaking: AstraZeneca Halts COVID-19 Vaccine Clinical Trials! Experts: Suspension Does Not Equal Failure）。
Subsequently, various sectors called for the public disclosure of COVID-19 vaccine trial protocols to enhance information transparency. The primary concern is that desperation may lead to indiscriminate acceptance of medical interventions; if a “problematic vaccine” from any manufacturer were to obtain emergency use authorization through unclear or unjustified means, the consequences would be unimaginable.
Indeed, Pfizer also unveiled the Phase I/II/III clinical trial protocol for its candidate vaccine BNT162b2 amid intense public scrutiny.[2], the Phase III trial you heard about today is part of it.
The participants enrolled in this clinical trial were healthy individuals with no prior history of SARS-CoV-2 infection. They were randomly assigned in a 1:1 ratio to two groups in a double-blind manner, receiving either the candidate COVID-19 vaccine or a placebo.("Double-blind" means that neither the person administering the vaccine to the participants nor the participants themselves know what is being injected, to prevent psychological effects from influencing the experimental results.), and then resume normal life(Contraception is advised), regular follow-up.
II. What are the primary endpoints of Phase III trials?
The efficacy of a respiratory virus vaccine is not determined by the number of individuals who remain uninfected after vaccination, but rather by the proportion of recipients of the candidate vaccine who develop symptomatic infection and test positive for viral nucleic acid.
Therefore,The “vaccine efficacy” mentioned here does not refer to “complete prevention of SARS-CoV-2 infection,” but rather to “prevention of symptomatic infection.”(Thus, "prevention of asymptomatic infection" is not included.). Some media outlets directly claimed that it “prevented 90% of infections,” which is imprecise wording.
Pfizer's trial is the same.The study assessed the number of participants who developed at least one symptom of COVID-19 infection and tested positive for SARS-CoV-2 via nasal swab nucleic acid testing within a specified period after receiving the second dose of the vaccine.
The U.S. FDA’s standard requires that COVID-19 vaccines demonstrate a minimum efficacy of 50% to obtain Emergency Use Authorization.(Of course, this is the minimum passing threshold; under normal circumstances, higher standards are required for vaccine market approval.)
Pfizer has set a slightly higher modest target for itself—60%.
What Does a 60% Efficacy Rate Mean?
Suppose the individuals who received the placebo injection(i.e., without vaccine protection)The one-year prevalence rate is 1.3%.Therefore, vaccinated individuals can achieve an additional 60% reduction in infection risk, resulting in a disease prevalence of only 0.52%.
III. Can Interim Analysis Predict Efficacy Rates? Is It Reliable?
During this process, whenever the number of symptomatic infected individuals reaches a certain threshold, researchers will conduct an interim analysis.（interim analysis）。
They had originally planned to conduct four interim analyses, but after discussions with the FDA, this was revised to three. When the number of symptomatic infected individuals:
● Conduct the first interim analysis when 62 participants are enrolled;
● The second interim analysis will be conducted when the number of participants reaches 92;
● The third interim analysis will be conducted when the sample size reaches 120 participants.
Why conduct an analysis when the number of infections is so low?
In fact, this is to evaluate the vaccine’s efficacy at an early stage and determine whether it meets the required criteria.. Conducted in phases; the decision to continue the trial is made only after each small step meets the established criteria.
However, plans often fail to keep pace with changing circumstances. After their discussion, they found that the actual number of collected infection cases had already reached 94... Therefore, they decided to include all of them in the first interim analysis.
So, how is the 90% efficacy rate calculated?
The trial protocol includes a table outlining the success and futility criteria for each interim analysis, with the corresponding vaccine efficacy rates as follows:
(Source: Pfizer official website; IA = interim analysis; VE = vaccine efficacy. The ratio in parentheses represents the ratio of the number of infected individuals in the vaccine group to that in the placebo group.)
For example, the original plan for the third interim analysis was 92 cases, assuming 25 infections in the vaccine group and 67 infections in the placebo group.(The number of participants in both groups is the same), indicating that vaccination reduced the number of infections by (67-25)/67=62.7%, i.e., the vaccine efficacy was 62.7%.
Once the efficacy success criteria outlined in the table above are met, a plan will be made to submit an Emergency Use Authorization (EUA) application to the FDA; if the criteria are not met, the trial will continue; however, if the results fall below the futility boundary, the trial will be terminated.
If the protective efficacy were higher than this, the number of infections in the vaccine group would be fewer than 25.
Therefore, concluding an efficacy rate as high as 90% based on only 94 infections is not an exaggeration but a calculation grounded in solid evidence.
Given that the vaccine’s efficacy has far exceeded expectations, it is reasonable to apply for an Emergency Use Authorization at this time, thereby enabling high-risk, susceptible populations to receive the vaccine as early as possible and reducing infections.
However, until the clinical trials are concluded, anything is possible.
Currently, the COVID-19 vaccines in China that have entered Phase III clinical trials are inactivated vaccines and adenovirus vector vaccines. The Pfizer vaccine is an mRNA vaccine, and its safety and long-term protective efficacy still require continued monitoring. Let us look forward to more updates!
Finally, here are a few key points distilled for you:
● Pfizer’s COVID-19 vaccine candidate demonstrated an efficacy rate of up to 90%; this is not a final conclusion, but rather the result derived from the first interim analysis based on 94 confirmed infections among participants.
● The efficacy rate here does not refer to “completely preventing SARS-CoV-2 infection,” but rather to “preventing symptomatic infection,” and does not include “preventing asymptomatic infection.”
● The vaccine may thereby seek Emergency Use Authorization from the U.S. FDA; however, as clinical trials are not yet complete, continued observation is required to determine its long-term safety and the duration of protective efficacy.
References
[1]https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against
[2]https://pfe-pfizercom-d8-prod.s3.amazonaws.com/2020-11/C4591001_Clinical_Protocol_Nov2020.pdf
This article is from the WeChat official account:Tencent Medical Encyclopedia (ID: Dr_TXyidian), Author: Wang Fengling; Reviewer: Lu Xuexin (Assistant Researcher, Ph.D. in Immunology, Institute for Viral Disease Prevention and Control, Chinese Center for Disease Control and Prevention)