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Tag: Novavax

Novavax Announces Results From Another NVX-CoV2373 Phase 3 Trial

Graziani, Carlo J. 0 Comments

Novavax issued a press release today with final results of a second phase 3 trial — a separate one from the one that the company conducted in the UK, which I discussed in this post. It appears to be a larger study (about 30,000 participants, twice the 15,000 of the UK study) and randomized 2:1 vaccine-to-placebo to increase the efficacy signal. I’m not certain of the reason for the study duplication, but there are some undoubted benefits that have resulted from it: having been conducted later in the epidemic than the trials of earlier vaccines, this study saw more “Variants of Interest” (VOI) and “Variants of Concern” (VOC) as defined by the CDC, and was able to target them specifically in assessing efficacy. The result is surprisingly good news.

Here are the results:

Efficacy of Novavax NVX-CoV2373 COVID-19 vaccine in US/Mexico Phase 3 trial. Left panel: overall efficacy. Right panel: Efficacy against Variants of Interest (VoI) and Variants of Concern (VoC) as defined by the CDC. For an explanation of the features in these plots, see this post.

The first point is that this vaccine is in the same sort of efficacy category as the Pfizer/BioNTech and Moderna vaccines — perhaps a few percent lower, but still this is spectacular performance, with a peak at 89% (Novavax claims 90.4%, I’m not sure what the source of the small discrepancy is, but it’s probably not important). Given that this is a vaccine that stores at 2-8 degrees C, we now have another important tool for large-scale global vaccination programs, and none too soon.

The second point is performance against variants. Compare the right panel to the left: This is not what I expected, at all. There is no significant decrease in the efficacy of the vaccine against variants. Which could mean broad protection against mutated strains of SARS-CoV-2. Of course, the press release does not specify which variants are implicated, and the lumping together of several mutations may mask some bad news that will only be discernible later.

Recall that a Variant of Concern is defined as one “…for which there is evidence of an increase in transmissibility, more severe disease, significant reduction in neutralization by antibodies generated during previous infection or vaccination, reduced effectiveness of treatments or vaccines, or diagnostic detection failures.” The B.1.1.7 (“UK”) variant is a higher-transmissibility VoC, but it seems to be effectively blocked by the present crop of vaccines. On the other hand, the B.1.351 (“South Africa”) variant is a reduced-vaccine-effectiveness VoC, since it seems to have some trick that reduces vaccine-induced immunity, to a poorly-known extent that depends on the type of vaccine — in fact, Novavax’ own Phase 2b South Africa trial took a major hit from this variant. Obviously, lumping these two VoCs together in a single study would not be a useful thing to do, since might conceal some serious trouble to be expected later on. If, for example, the mix of VoCs in the US and Mexico is currently not rich in B1.351, but the proportion of that variant grows in the next few months, it is possible that we could see the efficacy of this vaccine decline.

On balance, however, I would say the story here is guardedly positive. As usual, more information is needed than is supplied in a press release.

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Novavax NVX-CoV2373 Vaccine: Trials Complete, Partial Data Released

Graziani, Carlo J. 0 Comments

Novavax issued another press release today, with some partial information concerning the now-completed trials, a Phase 3 trial in the UK, and Phase 2b trial in South Africa. The data is a continuation of the data analyzed in this post, and tells a similar story, although with more abundant numbers (and hence less uncertainty). There is some actual data in the press release, but there are also some efficacy estimates not backed by released data, which I can therefore not evaluate here. As usual, when the Emergency Use Authorization request gets to the FDA, a briefing document will be made public with complete trial information. I will issue another update when that happens.

Meantime, here’s what the released data for UK trial looks like:

Results from the Novavax Phase 3 UK trial. Left panel: Overall efficacy. Right panel: Efficacy against “severe” disease. For an explanation of the features in these plots, see this post.

This looks pretty good. Not that different from the preliminary results, but the constraints on efficacy are tighter, since the numbers are higher. The overall result in the left panel is extremely good (most likely value 90%), despite high prevalence of the B.1.1.7 variant. That’s the variant that is more transmissible, and possibly responsible for more severe disease with worse clinical outcomes, but which is also known not to be a so-called “escape variant” — that is, it is not less susceptible to immunity due to previous infection by “classic” SARS-CoV-2, or due to existing vaccines. So it’s not surprising that the Novavax vaccine stops it.

The “severe” disease result is shown on the right. This is what, unfortunately, is described in the press release and reported in naive media outlets as “100%” protection. From the plot it should be clear why this is an inappropriate description of the result — when you have 5 severe cases in the placebo group and 0 in the vaccine group, that’s good news, but nowhere near establishing “100% protection” — based on this data, the 90% credible region says that the protection could be as low as 40%! This kind of thing is the why it is useful to reason in terms of quantified uncertainties, as displayed in these plots, rather than with naive and deceptive point estimates. What we can say based on this data is that there is some moderately weak evidence of efficacy greater than about 40% against severe disease. If Novavax had designed their study as well as Moderna did, including many individuals at risk for severe disease, then they might have collected better evidence (as Moderna did).

Now, here’s the South African trial data analysis:

Results from the Novavax Phase 2b South Africa trial. Left panel: Overall efficacy. Right panel: Efficacy against “severe” disease.

In the overall results on the left we see again the troubling effect of the South African “escape variant”, B.1.351, which has already demonstrated its ability to evade immunity produced by the Johnson & Johnson and AstraZeneca vaccines, and for which there is in vitro evidence of decreased immunogenesis by the Pfizer/BioNTech and Moderna vaccines. This result is no worse than the J&J South Africa result, but it’s not any better either. Despite the spin in the press release, it suggests that efficacy to the B.1.351 variant is likely lower than the 50% threshold limit established by the FDA for usefulness. And if the vaccines are this poor at stopping disease, they are almost certainly nearly ineffective at stopping the spread of the virus, since it is being propagated by all all the carriers who get mild or moderate forms of the disease, to say nothing of all the asymptomatic carriers.

This reinforces the point that I made in this post: The B.1.351 variant very likely largely escapes immunity from all existing vaccines. Since (1) we can expect most of the Northern hemisphere to be vaccinated by early summer, so that other variants will be under control, and (2) we know that it only takes a few months for SARS-CoV-2 to travel all over the globe (witness this time it took for the epidemic to spread from Wuhan to the rest of the world in the first place), we can expect that most COVID-19 in the Northern hemisphere will be caused by B.1.351 by sometime this year. Booster vaccines that address B.1.351 are already being prepared — Moderna’s is already in Phase 2, and there’s no doubt that the other manufacturers aren’t far behind. So, we should all get shots as soon as they are available, because they are effective at stopping the spread of classic SARS-CoV-2 and most of its variants. But we should all be prepared to get booster shots this year, as soon as the B.1.351-specific vaccines are available.

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Novavax NVX-CoV2373 Vaccine

Graziani, Carlo J. 2 Comments

These plots result from the data reported in a Novavax corporate press release issued on 28 January 2021. I’ll update them if more detailed and/or authoritative information becomes available.

Novavax reported results from two clinical trials: a Phase 3 trial performed in the UK, and a Phase 2b trial performed in South Africa. The press release does not state the dose schedule, but from information at clinicaltrials.gov here and here it appears to be a 2-dose schedule, with doses 21 days apart. The South African trial was performed under conditions of high prevalence of a new variant of the SARS-CoV-2 variant. Here are the plots:

Right: Phase 3 study performed in the UK. Left: Phase 2b study performed in South Africa, with high prevalence of a new SARS-CoV-2 variant. For an explanation of the features of these plots, see this post.

In the UK, against SARS-CoV-2 “classic”, the efficacy is as impressive as the other principal vaccines (e.g. Moderna, Pfizer/BioNTech, AstraZeneca, Sputnik V). The peak at 89% is certainly very encouraging news.

The South African trial results are worrisome, however. The numbers are still small (this is a Phase 2 trial), but the peak efficacy against the South African variant is below 50%. It is not clear to me why the press release claims that 15 vaccine cases and 29 placebo cases results in an effectiveness estimate of “60%”, unless they chose a larger size for the vaccine group than for the placebo group — the press release doesn’t contain the necessary detail. I’ll be revisiting this one when the company submits a briefing document to the FDA EUA committee, or when they publish a journal article.

In any event, it seems clear that (a) the efficacy against the South African variant is considerably lower than against the “classic” SARS-CoV-2, and (b) the study numbers are not yet large enough to ascertain how much lower — the 90% credible region goes from 69% (only a little lower than the UK estimate) to 15% (basically useless). It seems clear that this vaccine — and probably all the other ones — will have to be updated soon to fight new variants.

Updated 5 February 2021: Dan, in the comments, points out that the 60% efficacy claimed in the press release corresponds to efficacy in HIV-negative participants. I should learn to read the nuances in press releases more carefully…

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