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PFIZER VACCINE MEGATHREADThe FDA's VRBPAC voted 17-4-1 on 12/10/20 to approve the emergency use authorization (EUA) for Pfizer/BioNTech's SARS-CoV-2 vaccine candidate (BNT162b2). The EUA was officially issued on 12/11/20 and the vaccine will begin distribution this week.
This thread will contain:
-General impressions
-Background information
-Safety information
-Conclusions
I'll also be doing threads later on stuff that's too technical for the main thread for those interested. Sources will be numbered and boxed [like so]
-General impressions
-Background information
-Safety information
-Conclusions
I'll also be doing threads later on stuff that's too technical for the main thread for those interested. Sources will be numbered and boxed [like so]
GENERAL IMPRESSIONSBased on the data within the FDA briefing document [1] and the subsequent NEJM paper [2], the Pfizer vaccine appears to be safe and effective at preventing symptomatic cases of COVID-19.
I would take this vaccine if it was offered to me.
BACKGROUND INFORMATIONThe primary goal of any vaccine is to generate an immune response in which an individual produces neutralizing antibodies against a virus and later memory B cells, which will produce that antibody again if the person is re-exposed [3]
For an antibody to be neutralizing, it has to bind to a part of the virus that is critical to its functioning. The target of the Pfizer vaccine is the SARS-CoV-2 spike protein, which the virus uses to bind to the ACE2 receptor present on some human cells and enter them [4].
![For an antibody to be neutralizing, it has to bind to a part of the virus that is critical to its functioning. The target of the Pfizer vaccine is the SARS-CoV-2 spike protein, which the virus uses to bind to the ACE2 receptor present on some human cells and enter them [4].](https://pbs.twimg.com/media/EpKEf0XXcAIdsND.jpg "For an antibody to be neutralizing, it has to bind to a part of the virus that is critical to its functioning. The target of the Pfizer vaccine is the SARS-CoV-2 spike protein, which the virus uses to bind to the ACE2 receptor present on some human cells and enter them [4].")
An antibody that binds to the right location on the S1 subunits of the virus' spike protein will physically prevent the virus from binding to ACE2 and entering human cells. Vaccines also attempt to elicit T-cell responses, but that biology is too complex for this thread.
The Pfizer vaccine is an mRNA vaccine, meaning that instead of injecting people with viral particles or proteins from the virus, it contains a molecule that instructs the vaccine recipient's cells to generate a viral protein which will then elicit an immune response.
Pfizer's vaccine contains mRNA that encodes the full-length spike protein discussed above, contained within lipid nanoparticles to help the mRNA enter the cell. Because RNA is a very "fragile" molecule, the vaccine must be stored frozen at -80C and used within 6 hours of thawing.
I won't go into detail about the Phase I/II data for this vaccine, but it showed that the 30ug dose of the vaccine led to the production of neutralizing antibodies of similar quantity and quality compared to the response generated by an actual coronavirus infection [6].
![I won't go into detail about the Phase I/II data for this vaccine, but it showed that the 30ug dose of the vaccine led to the production of neutralizing antibodies of similar quantity and quality compared to the response generated by an actual coronavirus infection [6].](https://pbs.twimg.com/media/EpKL7WCXEAEDNVN.jpg "I won't go into detail about the Phase I/II data for this vaccine, but it showed that the 30ug dose of the vaccine led to the production of neutralizing antibodies of similar quantity and quality compared to the response generated by an actual coronavirus infection [6].")
The phase I/II study did not observe any life-threatening side effects at any dose, and one severe side effect (chills) in the 30ug dose [6].
![The phase I/II study did not observe any life-threatening side effects at any dose, and one severe side effect (chills) in the 30ug dose [6].](https://pbs.twimg.com/media/EpKNVbuXMAMUShX.jpg "The phase I/II study did not observe any life-threatening side effects at any dose, and one severe side effect (chills) in the 30ug dose [6].")
EFFICACY INFORMATIONWith that out of the way, we can start with our first question - does it work?
The short answer to this question is yes. Out of ~18,000 participants in each group, the placebo group had 162 cases of COVID-19, and the vaccine group had 8, representing a 95% reduction (the number that made the headlines) [1].
![The short answer to this question is yes. Out of ~18,000 participants in each group, the placebo group had 162 cases of COVID-19, and the vaccine group had 8, representing a 95% reduction (the number that made the headlines) [1].](https://pbs.twimg.com/media/EpKPxlmXMAAXb82.png "The short answer to this question is yes. Out of ~18,000 participants in each group, the placebo group had 162 cases of COVID-19, and the vaccine group had 8, representing a 95% reduction (the number that made the headlines) [1].")
The figure showing the cumulative cases in each group is pretty impressive - the curves are aligned until around day 10, and begin to separate when the subjects were likely starting to really pump out antibodies following dose 1 [1].
![The figure showing the cumulative cases in each group is pretty impressive - the curves are aligned until around day 10, and begin to separate when the subjects were likely starting to really pump out antibodies following dose 1 [1].](https://pbs.twimg.com/media/EpKQxQfXEAAuh0h.jpg "The figure showing the cumulative cases in each group is pretty impressive - the curves are aligned until around day 10, and begin to separate when the subjects were likely starting to really pump out antibodies following dose 1 [1].")
None of the subgroups (age, race, comorbidities) showed a large difference in efficacy [1]. I've seen some discussion of the lack of Black and Native American participants, but I can't think of any plausible reason the vaccine would be less effective in those populations.
There wasn't enough data to determine statistically if the vaccine prevented severe COVID-19 cases, but the overall results, numbers in the table, and qualitative description of the cases leads me to believe that it probably does.
This trial does not show that the vaccine prevents COVID-19 infection or transmission. The low rates of reinfection following COVID infection and the high efficacy of the vaccine makes it seem likely that it prevents transmission, but we have no direct evidence of this.
l think this is a well-designed* trial, but I would like to discuss one possible source bias I've seen discussed: since the vaccine produces more side effects than placebo, the trial was likely somewhat unblinded since patients could guess what group they were in.
I don't think this is a major issue, mostly because I'd think that it would cut against the vaccine - people who believed they were in the vaccine group would be more likely to do more risky behaviors than those who thought they were still susceptible to COVID.
*The lack of serial COVID testing in trial participants is a major weakness, and I'll get back to this in the conclusion
SAFETY INFORMATIONNow that we know that the vaccine can prevent symptomatic cases of COVID-19, we can get to the questions that seems to be worrying a lot of people - is the vaccine safe?
(The bulk of the safety data is from 7-8 weeks post dose 1)
The short answer to this is also yes, at least for most people. The most common side effects were those that are associated with an immune response, such as pain at the injection site, fatigue, etc.
The vaccine does not appear to have caused any deaths or to have caused anyone to drop out of the study.
The vaccine group had a slightly higher rate of serious adverse events than placebo (0.6% vs. 0.5%), but the difference seems to be driven by a small number of unrelated illnesses.
Out of the ~20,000 people in the vaccine group, three of had serious adverse events that study investigators believed to be caused by the vaccine - a shoulder injury, an arrhythmia, and a lymphadenopathy. The FDA does not believe that the arrhythmia was caused by the vaccine.
(Pfizer doesn't think the lymphadenopathy is either but I will never trust the bamboozlers)
(will post the rest momentarily, twitter won't let me do more than 25 tweets at once)
(will post the rest momentarily, twitter won't let me do more than 25 tweets at once)
One important note is that there is NO SAFETY DATA FOR PREGNANT WOMEN. Pregnant women were screened out of the study, so we have no data whatsoever on the effects the vaccine may have on them or their babies.
To wrap this section up, the vaccine seems safe for the population it was recommended for (except pregnant women). It will hurt and you might feel like shit for a couple days following each dose (especially dose 2), but the chance that you'll be seriously harmed is extremely low.
CONCLUSIONSAs I said before, I think this vaccine is safe and effective, and I will take it when offered to me through the hospital I work at.
I think that the trial was well-designed, and I don't have any bones to pick with how it was conducted. It seemed to have been well-run and relatively transparent.
I did not like how the VRBPAC committee members were so chummy with the Pfizer employees during the committee meeting - they received very few tough questions and even the members that voted against the EUA were extremely tame. The public input process was also somewhat farcical
That being said, I've spent a lot of time reading papers and listening to talks in which the authors/presenters were trying to bamboozle, and it did NOT seem like that was what was happening here. I think that all appropriate data was presented and framed reasonably.
My one major problem with the trial was lack of serial testing. Although only a cluster RCT could really nail the question of transmission, showing a reduction in PCR-positive COVID cases would have given me a lot more confidence that this vaccine can actually end the pandemic.
As for who should get it, I think it's reasonable for healthcare workers, other essential workers, and older/otherwise at-risk people. I'll be getting it since I work in-person at a hospital.
If you're young, healthy, and stay home all day, I think it would be reasonable to wait until the vaccine gets full approval in the spring and we have data from the full phase III trial.
I don't expect anything will change with the full results, but since the BLA process will be occurring around the same time we start vaccinating the general public, I think that if you're offered it before then it would be worth it to wait a few weeks just to be sure.
There you go folks, some data and some opinions about the pfizer trial. Sources used are listed below. Go forth and read for yourselves
[1] https://www.fda.gov/media/144245/download
[2] https://www.nejm.org/doi/full/10.1056/NEJMoa2034577
[3] Janeway’s Immunobiology 9th ed. pgs. 731-732
[4] https://www.nature.com/articles/s41401-020-0485-4
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597572/
[6] https://www.nature.com/articles/s41586-020-2639-4
[2] https://www.nejm.org/doi/full/10.1056/NEJMoa2034577
[3] Janeway’s Immunobiology 9th ed. pgs. 731-732
[4] https://www.nature.com/articles/s41401-020-0485-4
[5] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597572/
[6] https://www.nature.com/articles/s41586-020-2639-4
