[We are experimenting with Twitter threads.]

We’re always reading about how the pandemic has created a new emphasis on preprints, so it stands to reason that non-reviewed preposts would now have a place in blogs. Maybe then I’ll “publish” some of the half-baked posts languishing on draft in errorstatistics.com. I’ll update or replace this prepost after reviewing.

The Booster wars

Like most wars, the recent “booster wars” have (unintended) casualties. I refer, of course, to the disagreement about whether third shots of Covid vaccines are called for because of the evidence of waning protection after 6 or so months, coupled with the more virulent delta variant. Last week’s skirmish, resulting in the FDA advisory committee voting 16 to 2 against approving a third shot of Pfizer’s vaccine (to anyone over 16) seemed to be more of a backlash by some members in FDA’s Office of Vaccines against being sidelined by the White House when they announced last month already that a booster shot was forthcoming for all. (Two members, including the director of the Office of Vaccines is leaving, presumably as a result, at least that’s how it was described in the press). The FDA advisory committee claimed there was not enough evidence of benefit to recommend boosters for all, given the unknown risks such as myocarditis (although the data Pfizer presented include just 1 case, I believe). 

I watched the last 3 hours of the day’s session on Friday September 17. (It was oddly reassuring that the FDA had at least as many technical glitches with zoom as the rest of us; but not reassuring to see the seeming cavalier attitude of some members). Right after voting the booster plan down the panel immediately turned around and approved the booster for anyone over 65 or who was in a severe risk group. Then, 15 minutes later, they broadened that to include anyone “at high risk of occupational exposure”—at any level of exposure—to Covid,  such as healthcare workers, teachers and many others.

Do our health experts realize how detrimental their infighting is to the rest of us? Couldn’t they have come to somewhat of an agreement—at least as to how to explain their opposed standpoints—before making rival pronouncements and issuing dueling preprints? For at least one whole month now, we’ve been witnessing squabbling agencies. It came as a surprise to hear Biden/Fauci announce in mid-August that boosters were necessary, it was only a matter of time. “Even among government scientists, the idea has been met with skepticism and anger” we read in the NYT. Fauci said last month it would probably be 8 months, no make that 6 months (after the last vaccine).[1] “Fauci said: he was ‘certain‘ that Americans would need booster shots of the COVID-19 vaccine” possibly at 5 months! Today he even strengthened that view, asserting “the third shots should be viewed as a part of the COVID-19 vaccine regimen, just like the first and second shots,… I think that three shots will be the actual correct regimen”. 

Does that mean he’s prepared now, despite the analysis of the FDA panel, to have the booster mandated wherever the others currently are? Apparently.

We’d all love to see the plan

So what would the plan be then? Boosters every 6 months? Israel is preparing for a 4th dose already. What about the development of boosters for Delta and other variants? Is that in the works in the U.S.? And if boosters are to be recommended on the basis of declining levels of neutralizing antibodies (correlated, it is thought, with breakthrough cases), why not recommend people test their levels? I did go out and get my levels tested a couple of weeks ago but it was anything but routine. Friday’s FDA panel voted to wait until more evidence is in. If our numbers are high, then, is it advisable to wait, even if we fall into the FDA’s (vague) permissible category? The answers we are getting are simplistic, defensive, and, to my knowledge, don’t address this and other fairly obvious conundrums for an anxious public.

The main basis for the rejection by the FDA panel was described in aLancet article appearing right before: they find the available evidence pointing to the need for boosters to be weak, based on observational studies, they claim, of just a few weeks:

“Randomised trials are relatively easy to interpret reliably, but there are substantial challenges in estimating vaccine efficacy from observational studies undertaken in the context of rapid vaccine roll-out.

Although the benefits of primary COVID-19 vaccination clearly outweigh the risks, there could be risks if boosters are widely introduced too soon, or too frequently, especially with vaccines that can have immune-mediated side-effects (such as myocarditis, which is more common after the second dose of some mRNA vaccines, or Guillain-Barre syndrome, which has been associated with adenovirus-vectored COVID-19 vaccines). If unnecessary boosting causes significant adverse reactions, there could be implications for vaccine acceptance that go beyond COVID-19 vaccines. Thus, widespread boosting should be undertaken only if there is clear evidence that it is appropriate.”[2]

This seems a sensible precautionary stance, unfortunately obscured by the feeling it reflected agency power dynamics.[3] Maybe the U.S. would have more of its own data, if the CDC had not stopped recording breakthrough infections in May, 2021 (except for those who are hospitalized or die). Anyway, Fauci does not address the panel’s concerns about limited data. But, given those concerns, it does make one wonder why the same panel turned around and recommended approval of the booster for various occupations, rather than recommending waiting for more data. The FDA’s misgivings will doubtless also give grounds for unvaccinees to point out that even the FDA is worried about safety of the approved vaccines. After all, a third dose, 6 months after the second, does not seem substantially riskier, especially given the lack of caveats when telling those who have had Covid to get fully vaccinated in addition. Actually, it now appears that getting vaxxed after having Covid provides “superhuman” Covid immunity.

Will our immunity (from vaccinations) evolve, or be obstructed?

In a study published online last month, [Paul] Bieniasz and his colleagues found antibodies in these individuals that can strongly neutralize the six variants of concern tested, including delta and beta, as well as several other viruses related to SARS-CoV-2, including one in bats, two in pangolins and the one that caused the first coronavirus pandemic, SARS-CoV-1. (see link)

In fact, these antibodies were even able to deactivate a virus engineered, on purpose, to be highly resistant to neutralization. This virus contained 20 mutations that are known to prevent SARS-CoV-2 antibodies from binding to it. Antibodies from people who were only vaccinated or who only had prior coronavirus infections were essentially useless against this mutant virus. But antibodies in people with the “hybrid immunity” could neutralize it.

Understandably, many are excited about the possibility that a booster shot will create, in vaccinated people, the kind of “super-human” immunity response seen in those who followed Covid infections with vaccines (i.e., those with hybrid immunity). Then Covid, it is thought, would become like the common cold. Even though it was only 14 people, that they all showed this is impressive. (There isn’t information on the reverse order, vaccine, then infection.) Throughout the pandemic, I have found that Paul Bieniasz, who led this study, is doing some of the most interesting and path-breaking work.

But there are worries by other researchers that repeated infection with one strain can actually reduce the development of immunity to novel strains—although you don’t typically hear about this.

In the case of Covid, some scientists are concerned that the immune system’s reaction to the vaccines being deployed now could leave an indelible imprint, and that next-generation products, updated in response to emerging variants of the SARS-CoV-2, won’t confer as much protection. (Stat News)

Immunologists call this ‘original antigenic sin’, and it is apparently a key obstacle to creating immunity to flu variants—although, again, we don’t hear about it in the yearly prodding to get flu shots.

The concern is that even when a booster variant comes along, our immune systems, having repeatedly encountered the early Covid variant, will largely trigger neutralizing antibodies to it rather than the novel variant. As such, I’ve heard some doctors advise people to try to go as long as they can with the primary shots. To know how long to wait, we’d need to know our (approximate) neutralizing antibody levels. As of now, if you do manage to get a quantitative test (no dichotomania), you have to go through non-standard channels to find an interpretation of numbers. Not even doctors seem to know. The public is capable of understanding that, at present, there is no clear “correlate of protection” as they call it, (between neutralizing antibodies and infection); that’s not a reason to obscure or bury the information, especially as policy decisions that affect them rely on precisely these numbers. We should also be conducting studies to test what those numbers mean in terms of infection, disease and transmission (V. Prasad)

Here are some very useful discussions:

It may be argued that future booster variants are going to be so loaded up that they will force our immune systems to pay attention (to the new variant)–but are we sure? And do we want to get to that point? Of course, like many of you,  I’m just a member of the non-expert lay population whose life is affected by Covid policy decisions that are made without my input. (I don’t know what P. Bieniasz thinks of this, but he’s convincing on the need for boosters.)

A simple first step

We’re bound to hear, any day now—perhaps even before I put up this prepost—of the FDA’s ruling on Pfizer, based on Friday’s FDA panel. Presumably they will concur with the panel, and a similar approval seems likely for Moderna in a few weeks (although I hear Moderna wants the booster to be a half dose of the original[4]). But these narrow rulings will not address the broad and legitimate questions people have, and without answers to those questions, people cannot wisely decide whether to take up any opportunity to get a booster. This just increases the feeling that agencies and politicians have their agendas, and we have to fend for ourselves. As a simple first step, how about calling all of the point people on Covid vaccines together—being particularly sure to include representatives of rival positions—to address these specific questions, and reveal the uncertainties that are the engine behind their policies, although they are generally hidden under wraps. Not one of these hour long glitzy “roundtables”, but an extended (and perhaps ongoing) forum, where answers are challenged by others and by data.

Lest people start to have hesitations with this new policy, why not give the public the information they need to critically navigate the pandemic for themselves? It’s fairly clear that our agencies aren’t doing it for us.

What do you think? Please write with your thoughts and corrections. I’d be interested to hear as well, what questions you’d like the vaccine and virology experts to answer. 

[1] In Mid-august, CDC director Walensky, agreeing with Fauci, gave these reasons for boosting: “First, vaccine-induced protection against SARS-CoV-2 infection begins to decrease over time. Second, vaccine effectiveness against severe disease, hospitalization and death remains relatively high. And third, vaccine effectiveness is generally decreased against the delta variant.” (Washington Post)

[2] An additional shot has already been approved for anyone considered immunocompromised. Several other countries are either contemplating or already giving boosters.

[3] Perhaps the disagreement is between the weight to be given infections vs severe disease. Or perhaps it’s about which is worse: that announcing boosters would increase vaccine hesitancy, or that declining anti-virus potency of vaccines will increase transmission. They also felt it would be more beneficial to increase global vaccination, but the committee announced at the start, that such considerations would not be considered relevant.

[4] So are half-doses being manufactured, or will people who want Moderna boosters have to wait until they’re produced?