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Tag: Johnson & Johnson

A Dissent on the Meaning of the J&J Trial Results

The FDA’s approval of Emergency Use Authorization of the Johnson & Johnson COVID-19 vaccine is being greeted ecstatically and uncritically by public officials and media. In my opinion, this is an indication that hardly anyone has actually looked at the data supplied by the company to the EUA committee, or read the briefing document in detail.

I wrote up a quick but careful analysis last week, which you may review here.

For present purposes, I’ll note only in passing the statistical illiteracy of journalistic celebrations of “85 percent efficacy against severe forms of COVID-19 and 100 percent efficacy against hospitalization and death” (NYT), figures that ignore both the considerable uncertainties in efficacy estimates and the carefully cherry-picked data that produces such numbers by nimble selections of geographical subregions of the trial, and by passing back and forth between results for 14 days and 28 days post-vaccine, whichever produces the better-seeming (though not actually better) result.

The point that I wish would draw notice is that the South African arm of the trial suggests that a variant crisis is imminent. The J&J vaccine is marginally effective at stopping transmission of the B.1.351 variant that is 95% prevalent in South Africa, and it’s efficacy against the severe disease could actually be as low as 50%. Here are the two relevant plots from that arm of the trial:

The right-hand figure offers some reassurance about “severe” disease (although if you think it means 80% you should not work as a science reporter). The left-hand figure, however, is extremely worrying. It says that the vaccine does nothing to restrain the spread of the virus, since all those “moderate” COVID-19 cases are shedding virus, and so are a nearly equal number of asymptomatic cases.

Here are some consequences:

B.1.135 Is The West’s Future Native Variant

It took less than 3 months for the original SARS-CoV-2 virus to travel from Wuhan to the U.S. and become an uncontrolled epidemic. It’s probably safe to assume that the freely-propagating B.1.135 variant, unrestrained by vaccination, will soon have high prevalence in the US and in Europe as well. It has mutated its way to a fitness advantage, so it will likely take over the SARS-CoV-2 genome within in a few months, probably by June at the latest.

It’s Not Just J&J’s Problem

I have no beef against J&J, and don’t mean to single the company out for criticism. There is plenty of evidence now that this is not just a J&J vaccine issue. We already know that the Novavax clinical trial had a South Africa arm that found the same thing. And South Africa has halted it’s rollout of the AstraZeneca vaccine, asserting that it “…offers minimal protection against mild and moderate cases”, as a consequence of the variant’s prevalence.

We don’t know how B.1.135 affects the efficacy of the Pfizer and Moderna vaccines, or that of the Sputnik V vaccine for that matter, since their clinical trials saw essentially zero prevalence of that variant. One may hope that since those vaccines appear to induce a more robust immune response, they may yield broader immunity against variants. But without new trials, all we can do is wait and find out.

Transmission Matters

Much of the media celebration appears to center on the ability of the J&J vaccine to prevent “severe” disease. As we saw above, even this ability is reduced in light of the advent of B.1.135. But ignoring the ineffectiveness of the vaccine at preventing transmission is madness. The probability of a mutation that increases transmissibility (or disease severity, for that matter) is proportional to the infection rate — the more cases per day, the higher the chances of a more dangerous mutation. The reason that we’re seeing proliferation of variants now, to an extent not noticeable during the March or August waves, is that the Winter wave case count eclipsed that of the other two — there have been many more mutation opportunities since October 2020 than there were before.

A vaccine is a tool for epidemic control, not a treatment or a cure. Focusing on prevention of the worst disease outcomes while ignoring transmission prevention totally misses the point. It’s tantamount to celebrating relief now, while ignoring the worse trouble to come.

A Silver Lining

The one reason that I can see not to panic now is that the next-generation vaccines that have come into being in the past year — mRNA and adenovirus vector — are reportedly very straightforward to re-target at new variants, and updated versions can be quickly produced at industrial scales, at least after current supply-chain bottlenecks are sorted out. What this means is that while everyone who gets a J&J, AZ, or Novavax vaccine now will be needing a booster by summer (and this may also be true for the Pfizer, Moderna, and Sputnik vaccines as well), at least there is reason to believe that such boosters will be widely available. For this reason, the public-health messaging on the J&J vaccine is correct: if you are offered a shot of the J&J vaccine, you should accept it. Just make sure you get a booster as soon as it is available.

The epidemic control strategy has to be to get total infection rates down (to slow the rise of newer, more dangerous variants), while rapidly developing, producing, distributing, and jabbing updated boosters to stamp out existing variants. And doing this everywhere, including in third-world nations that can’t afford to fund their own rapid-response anti-variant campaigns, because any large reservoir of transmitted virus is a potential source of newer, even more dangerous variants.

Moreover, the summer-booster messaging needs to start now. We all know how delicate public support for mass vaccination campaigns is, and how easily it can be poisoned by militantly ignorant, scientifically illiterate disinformation spread by the anti-vaxxer crowd. Those people will have a field day with rising-again infection rates among vaccinated individuals that are to be expected this summer and fall, unless there’s a comprehensive public health messaging program about variants and boosters. The sooner the better.

And reporters need to get smarter about reporting “victories” like this one, that carry seeds of future problems. When the victory turns out to be not as complete as first reported, and possibly even reversible, the consequences for public support of mass vaccination campaigns are unlikely to be good.

Johnson & Johnson/Janssen Ad26.COV2.S Vaccine

The FDA Emergency Use Authorization (EUA) committe that will decide whether to approve the J&J/Janssen vaccine meets Friday, 26 February 2021, and as promised, the FDA has released the briefing document submitted by the company two days in advance. There’s a great deal of information in such documents, often more than appears in the corresponding journal article, when it is published..

The phase 3 clinical trial was conducted in three countries: the US, Brazil, and South Africa. This is interesting because of the different incidences of SARS-CoV-2 variants prevalent in those locations at the time of the trial: differences are informative about protective efficacy against different variants. In addition, the data cut that seems most relevant is distinguishing the overall “Moderate+Severe COVID-19” endpoint from the “Severe COVID-19” endpoint (as usual, one has to read the document in detail to understand the precise definitions of terms such as “Moderate” and “Severe”). So, let’s take a look.

Here’s the top-line efficacy, for “Moderate+Severe” endpoints, across all three countries, infections beginning 14 days post-vaccination.

Overall Efficacy of the J&J/Janssen vaccine. For an explanation of the features of this plot, see this post.

The overall efficacy looks pretty good: 67%, with pretty tight bounds. One should be cautious of invidious comparisons with the crazy-high efficacies of the Moderna and Pfizer/BioNTech vaccines: For an individual, 67% means a 2/3 reduction in the probability of contracting COVID-19 in any interaction with an infectious person. For a vaccinated population, this kind of efficacy means that the virus is in serious trouble: it means that if you could vaccinate everyone with this efficacy, you could get to herd immunity almost immediately (assuming an R0 of 3-ish).

So far so good. Let’s dig into the subgroup analyses. First, here’s protectiveness against “Moderate+Severe” COVID-19 across countries:

The news here is about variants, and it’s mixed. The efficacy is highest (74% peak value) in the USA, where the circulating variant is principally the Wuhan-H1 variant D614G (“classic” SARS-CoV-2), which was found in 96.4% of sequenced cases in the study.

In Brazil, where the study found a mix of P1 lineage (69.4%) and D614G (30.6%) the peak efficacy is a bit lower than in the USA (66%), but the wider curve (due to smaller numbers in the subgroup) shows that it’s quite possible that the efficacy in Brazil is the same as in the USA.

The bad news is from South Africa, where the B.1.351 variant constituted 94.5% of sequenced cases. Here the efficacy is clearly reduced (52% peak). The curve is wider, again due to lower subgroup numbers, so the actual efficacy could be a bit higher, but note that there’s more “pink” to the left of the peak than to the right. The area is proportional to probability, so unfortunately the smart bet would be that the actual efficacy is lower than 52%, rather than higher.

Now let’s take a look at protection against “Severe COVID-19”.

Here there’s some better news. The curves are all wider, because again the subset-of-a-subset numbers are lower, but there are some clearly improved trends. The efficacies are all systematically higher for the “Severe” disease sets than for “Moderate+Severe” sets. That is, in all countries, including South Africa, it appears that chances of contracting the severe form of the disease are appreciably lower for the vaccinated population. One should worry about the uncertainties due to low case numbers here, but again it is reassuring that in all cases the efficacy peaks move to higher values when only severe disease is counted.

It looks to me like a mixed-news situation. Protection against disease is clear except against the B.1.351 South African variant, and even here there seems at least to be reasonable protection against severe disease. On the other hand, protection against transmission (which is not technically evaluated in this study) is likely not great against B.1.351, since the vaccinated population will still have plenty of symptomatic virus-shedders, to say nothing of the asymptomatic cases.

To be fair to J&J, the Moderna and Pfizer/BioNTech vaccine trials did not confront variant subsets, so it is not possible to know with this kind of precision how badly affected their efficacies will be by the advent of B.1.351. Moreover, reportedly all the vaccine manufacturers believe that they can tweak their vaccines to target variants quickly, and the FDA has announced a speeded-up approval process for such re-tuned vaccines (similar to the annual flu vaccine approval process, which is highly streamlined).

My conclusion is that it is important to ship and jab as many doses as possible now, because one key factor in getting the epidemic under control is to stop the proliferation of variants, which appear in proportion to case numbers — the reason we’re suddenly beset by variants now, instead of in March, or August, is that case numbers during the winter wave eclipsed the cases in previous waves by a large factor. If we can get the cases down to the point that variants take much longer to develop, the vaccine-tuning process can control even the most transmissible variants. It’s a process, but there’s a good outcome at the end, I’m pretty sure.

Johnson & Johnson/Janssen Ad26.COV2.S Vaccine (Preliminary, From Press Release)

The “data” for these plots is obtained from a Johnson & Johnson corporate press release issued on 29 January 2021. The release is actually not that informative — among other things, it doesn’t state explicitly the number of vaccine-group and placebo-group infections in the clinical trial, or for any of its subgroups. We have to wait either for a briefing document submitted to an FDA EUA committe, or a published journal article.

Update (5 Feb. 2021): The FDA has announced that the EUA committee will meet on 26 February 2021, and that background materials will be made available to the public “no later than two business days prior to the meeting”. So it should be possible to update this post with real data on or about 24 February.

Update (25 Feb. 2021): The EUA briefing is now available, so this post is not the best place to read about this vaccine. See this post instead.

On the other hand, it is possible to guess one pair of numbers from the press release, even if they are not stated explicitly. The release states that 468 symptomatic cases of COVID-19 were observed overall, and that the overall efficacy inferred from this is 66%. From this, with a very little algebra, we can surmise that the number of vaccine cases was 119 and the number of placebo cases was 349, assuming the placebo and vaccine groups were the same size.

We therefore tentatively have this analysis:

Johnson & Johnson/Janssen efficacy analysis using data guessed from information in the J&J press release. For an explanation of the features of this plot, see this post.

The peak is at 66% (by construction, since this is how I guessed the data). The vaccine looks quite effective — not as spectacular as some of the other vaccine topline results, but certainly enough to be effective in a vaccination campaign. The trial was conducted over North and South America, as well as in South Africa, so it is quite likely that this analysis mingles different efficacies due to the emergence of different variants in different regions — compare the results reported by Novavax for their vaccine.