I spent most of my day December 10 trying to catch as much of the FDA Center for Biologics Evaluation and Research (CBER) meeting of the Vaccines and Related Biological Products Advisory Committee (VRBPAC) discussion of the Pfizer/BioNTech COVID-19 vaccine. Although I had some interruptions and much multi-tasking, I was able to watch most of the proceedings, plus I did have a chance to review the detailed briefings from FDA and Pfizer as well as all of the presentation slides, posted online for everyone. Overall I came away feeling that we now have a very clear picture of the data, certainly enough to make decisions about this vaccine for the short term. Obviously they covered a ton of information, but I'll try to distill down to the essentials.
First, the overview and major take-home messages. As you may already know, this is a messenger RNA vaccine; the technology and science for making these vaccines has been around for quite a while and been tested in small numbers of humans for different purposes. However, this is the first mRNA vaccine to undergo widespread testing and presumably use in people. The cartoon below is from the Pfizer slides and I think shows you how this works. The modified mRNA is contained in lipid nanoparticles (LNP) and when injected ends up in cells where the mRNA instructs the cell to make the SARS-CoV-2 spike protein. The protein then triggers an inflammatory response such that the recipient makes antibody to the protein as well as memory T and B cells, then lies in wait to attack anything possessing the spike protein to enter the body.
In terms of safety, bottom line is that no serious concerns were raised in the 20,000+ individuals who received the vaccine (the other half of the subjects received saline placebo injections). Local side effects such as pain and swelling at the injection site occurred but nothing dramatic there. Systemic reactions like fatigue and chills were reported by a few percent of vaccine recipients; fever also occurred and usually of short duration. Side effects were more common after the second vaccine dose. Efficacy was as you have heard in news reports, in the mid-90s% range and much higher than I had hoped originally.
Now for the nuances and special populations. You've probably heard about the 2 vaccine recipients in England who may have experienced severe allergic reactions to the vaccine. Pfizer presented what little is known so far about this, and the best I can say is that it is still pretty murky. It didn't really sound like true anaphylaxis to me, but we'll just need to wait for more details, I'm hoping in the next few days. The current trial did not include individuals with severe allergy profiles, unlike the 2 British recipients this week.
A couple other caveats from the safety aspect. Regional lymphadenopathy occurred in 64 individuals in the vaccine group versus 6 in the control group, nothing worrisome but certainly plausible as an uncommon side effect. Bell's palsy occurred in 4 vaccine recipients versus none of the controls, but that level is within the rate of Bell's palsy that would be expected in the general population not receiving any vaccine, so difficult to know if any connection to the Pfizer vaccine.
The immune response to this vaccine is what is termed "Th-1 biased." That's a good thing, because in the past (e.g. an RSV vaccine trial in the 1970s), vaccines have the capability to produce an exaggerated immune response by the host when exposed to the virus. The immunology of that process is now understood, and a Th-1 biased immune profile protects against this. The few vaccine recipients in the Pfizer trial who did develop subsequent infection with SARS-CoV-2 did not show evidence of severe disease; in fact it was very mild.
In terms of special populations, the trial did not enroll immunocompromised individuals though this is planned for the future. They might need a different vaccine dose; this will take a while to figure out. Similarly, pregnant women were not enrolled. However, 23 women subsequently became pregnant, 12 in the vaccine group and 11 in the placebo group. The only known outcome so far is 2 women in the placebo group experienced a spontaneous abortion. The remainder of the pregnancies are still ongoing so we'll hear more about that later. In the meantime, the language of what to do about guidance for pregnant women will come from the FDA. My guess, and it's only that, is pregnancy will not be an absolute contraindication to vaccination and women will be directed to discuss individually with their physician to weigh benefits versus potential risks. In terms of racial and ethnic distribution, the study group included a little under 10% Black or African Americans (about 4000 total) and a little over 25% Hispanic/Latinx participants.
The final special group, the one this audience cares most about, is children. The bulk of the study participants were adults 18 years and older, with a small number of 16- and 17-year olds. Pfizer has begun enrolling younger subjects down to age 12 years, a total of 2000, but no data on that yet. If no problems in that population, they will move to the 5-11 year-old age group, perhaps around April 2021, but they may need to determine if vaccine dose should be different in this younger population. I was surprised that there was some hesitancy from VRBPAC voting members about recommending use of the vaccine for the 16-17 year age group but ultimately the panel voted to recommend authorizing the vaccine for ages 16 and older, with 17 votes in favor, 4 against, and 1 abstention.
Two other important caveats from the FDA meeting: first, extensive post-authorization tracking is planned and already in place. This is called pharmacovigilance and will use both existing and newer vaccine tracking measures. I am very reassured about the quality of this pharmacovigilance plan, and this is where we begin to get some idea of how long immunity from the vaccine will persist. Second is the tricky ethical issue of what to do about the placebo recipients from this trial. Should they all be offered vaccines, which would make some of the long-term follow-up more difficult to assess? It would be great to invite all the trial participants to participate in a "blind crossover" trial, where prior vaccine recipients receive 2 doses of placebo and prior placebo recipients get 2 doses of the vaccine, everyone still remaining blinded but now everyone has the benefit from the vaccine. However, the logistic difficulties of performing what is essentially a new clinical trial for 40,000+ people is significant.
Next steps for this vaccine include what we hope will be a statement the evening of December 11 from FDA regarding recommendation for emergency use authorization. ACIP/CDC meetings are scheduled the afternoons of December 11 and 13, culminating in a vote to decide on whether the data warrant a recommendation for going forward assuming FDA recommends authorization. Then, on December 17, FDA VRBPAC will meet to discuss the Moderna vaccine data, with meeting materials to be posted soon on the web link earlier in this post.
In closing, I need to answer the many questions I've received from friends and colleagues: if offered, will I choose to receive this vaccine? My answer is unquestionably yes. Although we don't have long-term follow up of recipients, most significant side effects from vaccines appear in the first 6 weeks after immunization, and we have lots of information about that time period. Of course we don't know about any extremely rare side effects, but we never have that information about new drugs or vaccines until they are in widespread use. I'm perhaps a bit biased ahead of time in favor of vaccination: my age and occupation puts me in a high-risk group, I'm very familiar with the FDA review process and know several of the reviewers (no, I don't have any inside information about what they are doing with this or any other vaccine), and it turns out one of the senior vice presidents at Pfizer who presented most of the clinical data is an old friend of mine. I don't think any of these potential biases is coloring my decision, however.
Stay tuned for more updates!