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Tag: BioNTech

Pfizer/BioNTech, Dose 2 + 6-Month Follow-Up Results

Another press release by Pfizer, this one with results from their main phase 3 trial (46,307 participants). They have followed up participants for 6 months post shot-2. The press release has some slices of data, which will certainly be released in more detail at the time of their application for full FDA approval — and presumably when they submit a journal article.

Here are the two things that caught my eye:

On the left we see more confirmation of what we knew: the superb efficacy of the Pfizer/BioNTech COVID-19 vaccine. There is now so much data that the uncertainty on the efficacy is tiny. The peak posterior probability estimate in the plot is 91%. The result is basically consistent with the previous results. It’s worth remembering that the original targets for vaccine efficacies when the development effort began in early 2020 was “anything over 50%.” The fact that this generation of vaccines is ringing the bell in the 70-90% range is really an astonishing feat.

Now to the right-hand panel. The trial has a South Africa arm (well, at 800 participants, more like a “finger”). Of these, 9 placebo-group participants became infected, and zero vaccine group-participants. Of the 9 placebo-group participants, 6 were confirmed to have been infected by the B.1.351 lineage. If you have 6 placebo infections, and zero vaccine infections, you get the plot on the right hand side. This is what the flacks who work for Pfizer’s PR department have to say about this:

In South Africa, where the B.1.351 lineage is prevalent and 800 participants were enrolled, nine cases of COVID-19 were observed, all in the placebo group, indicating vaccine efficacy of 100% (95% CI, [53.5, 100.0]). In an exploratory analysis, the nine strains were sequenced and six of the nine were confirmed to be of the B.1.351 lineage. These data support previous results from immunogenicity studies demonstrating that BNT162b2 induced a robust neutralizing antibody response to the B1.351 variant, and although lower than to the wild-type strain, it does not appear to affect the high observed efficacy against this variant.i

OK, now look at that plot. Does that say “100% efficacy against B.1.351” to you? Because to me it says “we got bupkus for evidence, since we had too few people in South Africa participating in this study.” The 90% credible region starts at 50% efficacy!

You should also be aware that the stuff about “robust neutralizing antibody response” is based on this paper, which however showed that in-vitro neutralization of B.1.351 required far more concentrated vaccine-induced antibodies than were required for other variants — I cannot understand how the how one could possibly characterize that result as “robust”. In any event, its a wet lab result, not a clinical trial. We still don’t have any quality evidence about the performance of the mRNA vaccines against the B.1.351 variant. And that has me very worried.

Pfizer/BioNTech and Adolescents

Pfizer has a press release today concerning its phase 3 trial of its BNT162b2 COVID-19 vaccine in U.S. adolescents, ages 12-15. There’s only one topline number from the trial in the press release — 18 cases in the placebo group, 0 in the vaccine group. The result is the following plot:

Efficacy of Pfizer/BioNTech COVID-19 vaccine in U.S. adolescents, ages 12-15. For an explanation of the features in this plot, see this post.

This is a very impressive result — with 90% probability the efficacy in adolescents is higher than 85.5%. It should probably not be regarded as a very surprising result: the immune systems of adolescents are generally better-functioning and more responsive than those of adults, so it would be more surprising if the efficacy were lower than the result found for older individuals. The more relevant part of the study is probably the fact that the vaccine is safe to use even at age 12, which is good news.

A few comments:

(1) The press release does not state the time period over which the study was conducted, so it isn’t possible to assess from this information the extent to which protectiveness extends to variants currently in circulation in the US.

(2) This was a small study — about 2,200 individuals (as opposed to 45,000 in the principal study). For this reason, the efficacy results are less constrained (the curves are broader) for adolescents than for older individuals.

(3) As usual, the fact that there were zero COVID-19 cases in the vaccine group in this small study is misleadingly described as representing “100%” efficacy in the press release, a claim picked up by science news reporters who should know better. From the above plot, a plausible value of the efficacy is certainly in the high 90s, but nothing is 100%. When the vaccine is administered to millions of adolescents (as opposed to the 2200 in this study) there will certainly be a few vaccinated adolescents who contract COVID-19. This will not be a vaccine failure, just an illustration of how small probabilities work.

Pfizer will apply to the FDA for an Emergency Use Authorization “as quickly as possible”. When they submit their information packet — which invariably contains a wealth of information, exceeding even what is later published in refereed journal articles — I’ll mine it for another post.

Pfizer-BioNTech BNT162b2 Vaccine

These plots result from the analysis of the Phase 3 trial data of Pfizer-BioNTech’s joint 2-dose mRNA-based vaccine, reported in this article.

Pfizer-BioNTech’s overall vaccine efficacy seems entirely comparable to Moderna’s. Interestingly, Pfizer-BioNTech’s “severe” protective efficacy seems rather disappointing, compared to Moderna’s. Note that this result does not show that Pfizer’s vaccine has lower efficacy against the severe disease than Moderna’s — only that Pfizer collected much worse evidence about severe disease efficacy than Moderna did. Pfizer only had 9 severe cases in its placebo group, as opposed to Moderna’s 30. This indicates that Pfizer was less diligent in recruiting trial participants with co-morbidities associated with the severe disease. In fact, the efficacy against severe disease could be the same as Moderna’s (why wouldn’t it be? the vaccines are very similar…), but Pfizer didn’t design their Phase 3 study in such a way to establish this.

Update, 17 February 2021: In a letter to NEJM, D. Skowronski and G. De Serres drill down into the Pfizer data released to the FDA, extracting cases occurring between the first and second shot. They found something remarkable about the cases 14 days or more after shot 1, but before shot 2:

Efficacy inferred from cases in the Pfizer phase 3 clinical trial, occurring before shot 2 but more than 14 days after shot 1.

It turns out that this vaccine’s most likely efficacy after a single shot is 92%, not that different from the top-line efficacy number, and the 90% credible region is bounded below at 78%. The authors actually cite a 95% confidence interval (this is technically different from the credible regions reported on this site) as bounded below at 69%, a bit more conservative, but not inconsistent with the Bayesian result.

This is remarkable, but not that surprising. If you look at the now-famous Figure 13 of the Pfizer submission’s briefing document to the FDA, you can clearly see that by day 14 substantial protective efficacy has taken hold. There are better ways to analyze the uptake of efficacy than cutting the data in this way, but only if the Pfizer team were to release the full data for Figure 13. As it stands, Skowronski and De Serres have made an important discovery on the basis of a clever hack of the released data.

Their letter asserts that this evidence justifies delaying the second dose, so as to make early vaccinations available to more people. It’s a serious argument. I don’t feel qualified to assess its strength, although it does seem worth pointing out that this kind of data cannot speak to whether the protective efficacy of a 1-dose schedule declines faster than that from a 2-dose schedule, since all this data is from a short period after the first dose. In a pandemic-driven vaccination scarcity crisis, it may be worth taking the risk, or it may not. At a minimum I would say that the FDA has good general reasons not to support deviations from the only schedule that has been tested in an actual clinical trial. Exceptions should be extremely rare, and justified by extreme circumstances.

Update, 18 February 2021: Aaron Esser-Kahn (University of Chicago) shared the following with me, which I think is helpful to thinking about vaccine schedule changes:

I do think these arguments about 2nd dose delay are very complicated and not always appreciated by those not familiar with the complexity of the immune response . On first pass its very exciting that it protects, but what can’t be known without further experiment are the following (1) how long does it protect for? (2) Do the antibodies and cellular responses decrease rapidly? (3) What does the antibody and cellular selection look like? While I completely agree that a 3 week boost is arbitrary (having arbitrarily made this decision many times myself, I know it’s arbitrary), there are important considerations about the window in which B-Cell and T-cell selection are happening. Too long and you will get different cells and antibodies out. This could have longer term effects. So its always a questions of the devil you know vs. the one you don’t. One major risk you run is generating sub-optimal responses that allow viral selection in vaccinated individuals with weaker responses.