The Boosters Are All Right

No human data? No problem. We're used to flying blind in this pandemic.

Photo by Fusion Medical Animation on Unsplash

Yes, that is supposed to be a reference to The Who, from back when more people listened to them than that other entity sharing those same six letters. (I admit that I lack the self-esteem before the world to spell “Alright” as The Who did.) I mean it, though; I think the new boosters probably are all right. Despite a lack of solid evidence — and that’s putting it charitably — the bivalent Covid-19 booster just approved by the FDA has now been recommended by the CDC for all adults more than 2 months out from their last infection or booster. Do I like the science? No. But I’ll recommend this booster, because as physicians we have to make choices with limited information.

While I don’t agree with the scope of the CDC recommendation at all, I worry that the “BUT THIS WAS ONLY TESTED ON 8 MICE!!!🤦🤦🤦” Twitter crowd might poison the appeal of what is probably a perfectly acceptable vaccine for those who stand to benefit from it.

First, though, let’s review the concerns.

#1: BUT THIS WAS ONLY TESTED ON 8 MICE!!!🤦🤦🤦

Fair enough. The original plan for an updated Omicron vaccine involved adding features of the Omicron BA.1 spike to the original Wuhan strain (hence, “bivalent”); this was tested by Moderna and Pfizer on actual human beings, and is the booster type just approved in Canada and the UK. While clinical data is still forthcoming, the bivalent original/BA.1 bivalent vaccine was a bit less than twice as effective at creating antibodies to the currently circulating BA.4 and BA.5 strains than the original booster shot in both Pfizer and Moderna— an underwhelming improvement by most accounts. Pfizer made use of the most famous 8 mice in medicine by testing its actual current bivalent vaccine, mixing equal parts of the original strain with BA.4/5; there they saw almost 3X the improvement relative to the original vaccine booster. Again, though: 8 mice. That’s it for safety and efficacy testing of the actual bivalent BA.4/5 vaccine that was just approved. Pfizer and Moderna have human trials underway.

#2: The human studies on Pfizer and Moderna’s BA.1 bivalent vaccine were too small to pick up even modestly rare adverse events.

Moderna’s 1273.214 booster study only involved 437 participants; Pfizer’s, 1,234. If we’re concerned that something about a reformulated vaccine with components of the Omicron spike might lead to a different rate of adverse events, that’s just not enough. Maybe a trial with a few ten thousand men under 30 could inform us if the rate of myocarditis was substantially different than estimates for the original vaccine formulation. I think it’s hard to make a case for why a spike protein that causes less severe disease would lead to a higher rate of severe adverse events when incorporated into a vaccine. Still, the lack of any effort to find out can be faulted.

#3: We don’t know if these boosters add any protection against severe disease to the huge number of people who were infected by Omicron.

The appeal of the bivalent vaccine with components of the actual circulating virus is to update our immune response to include some of the unique aspects of the Omicron spike protein. What about the maybe half of Americans who have had an Omicron infection in the past 6 months — is it possible they have won’t have additional benefit in preventing severe disease with an Omicron-including booster? Yes, it is, and the small studies currently underway are terribly underpowered to answer this question, given the low rates of hospitalization currently due to a less virulent strain and the broad swath of immunity provided by vaccines and the recent waves of infection.

#4: The CDC is encouraging people to get this bivalent vaccine 2 months after their last booster (or infection) despite a lack of scientific consensus.

One can make a strong case that the CDC simply made this number up. I side with Canada here, which recommended spacing the booster out 6 months rather than 2 months from last Covid booster or infection to allow maturation of the immune response. I also suspect a booster’s safety profile improves with greater spacing based on observational evidence around myocarditis risk. Many have also observed that the White House messaging is a weird mix of “do it now, even if you just had Omicron in June!” with “now we can settle down and start getting our Covid shots just once a year.” It doesn’t really make sense, scientifically, or from a sci-comm perspective.

So — why is this new bivalent vaccine “alright”?

Well, we really don’t have reason to suspect it won’t be all right, and that’s going to have to be good enough for a while — at least until that clinical trial data begins to come in. We might have to get used to this, too. Every year we trot out a new flu shot based on our best calculations of what types of flu are circulating in the southern hemisphere and are most likely to make it north for our winter, without burning the time needed for human trials. Given the speed of change in SARS-CoV-2 variants, proper trials might preclude the use of ever catching up to the viral strain in actual circulation.

In any case, we don’t have a choice in the matter anymore; the old vaccine booster is being phased out in favor of the new options (the original strain will still be used for those unvaccinated hold-outs in the U.S. who decide to pursue the primary vaccine series; yes, all four of them). The only question that matters now is: can we recommend this bivalent booster?

To that end, I think the body of data is adequate.

Compared to the original booster (30mcg for Pfizer, 50mcg for Moderna), this one features 15mcg and 25mcg of the Wuhan strain and 15mcg and 25mcg of the BA.4/5 components, respectively. It’s reasonable to hypothesize that the milder Omicron component might prove less able to provoke an immune response than a booster with a full 30 or 50mcg of the original strain, but that was not seen in the antibody testing in humans with the BA.1 bivalent booster or those 8 mice with the BA.4/5 bivalent shot; both showed a modest improvement in neutralizing antibodies across variants compared to an original strain booster. No one has looked to see how well these responses hold up after 3 or 6 months, but we already know that antibody levels fall off a cliff within 3 months of an original strain booster, and it’s frankly hard to imagine this shot will be even less durable when it comes to preventing infection. As to boosting people who have already had Omicron, both mice and men showed a similar response to the bivalent shots as the original booster.

I don’t expect the clinical data, when it finally emerges, will blow us away with a lasting high degree of protection against even mild infection. However, I would be quite surprised if it is demonstrably worse than our current booster.

The same argument can be made in terms of safety. Given the falling rates of intensive care admissions for Covid patients suggesting that end-organ damage has become rather rare in the Omicron era, I don’t think there is a plausible reason to think that swapping out half of the original strain for BA.4/5 proteins would lead to more adverse events. Science is not always plausible, of course, and a ghastly surprise might pop up in post-marketing data. I just find that unlikely.

That said, what we are left with is uncertainty, which is part and parcel of the practice of medicine. For every example in which we have reliable evidence with a clear-cut decision to be made — say, giving a patient with a kidney infection and septic shock IV antibiotics and fluids — there are ten more in which the available guidelines are based on flimsy, flawed, or pharma-funded data which might not apply well to the patient across the desk — like which blood pressure med to start for a newly diagnosed hypertensive patient, or when to order imaging for a patient with severe back pain. Therein lies at least the intellectual aspect of the “art of medicine”: sorting through reams of imperfect guidelines and studies and matching them to the needs of an actual patient requiring a plan.

In this case, the need to freelance ahead of better data is not a new feature of this pandemic. Whether spacing out vaccine doses, suggesting caution to adolescent boys due to myocarditis risks, or shifting guidance around Paxlovid rebound, many physicians (and entire nations) moved ahead of CDC recommendations as the evidence mounted that other practices were superior. Eventually, the CDC came around. Here, it’s the CDC which has moved ahead of the evidence, but I expect the data will eventually prove them right.

This booster is probably a fine, even superior, choice, despite the “8 mice” noise. Should a healthy 20-year-old, thrice-vaccinated, male college student be required, or even advised, to get it? Of course not; risks probably outweigh benefits, and the lack of reliable data is unacceptable with so little risk of severe disease. Will I recommend it to elderly, medically complex, immune compromised, or medically frail patients? Of course, but with at least a 6 month pause between their most recent booster or Covid-19 infection, except in the most high risk situations.

Most patients, though, fall in between these extremes. The very large group of low or medium risk people, with substantial immunity already from multiple vaccines and/or infections, have a more challenging decision to make.

I am not a fan of the CDC’s and White House’s one-size-fits-all messaging:

Annual autumnal Covid shots, given that recent waves have not followed an influenza-like seasonal pattern so much as being driven by new variants, might never make sense. Shots at the first signs of a new wave might. The high risk might benefit from a booster every 3-6 months, especially before times of high exposure; the low risk might never need a booster, unless avoiding an infection for a brief period of high infection risk is worthwhile for them. Given the slight window of protection from infection and transmission provided by the current vaccines (nasal or nebulized Covid immunizations could change this, but we still wait for the data there, too), I don’t follow the White House encouraging everyone to get boosted to protect their grandma — unless we’re really going to recommend this every 3 months.

True, I am frustrated that the FDA did not ask for a higher standard of evidence for these bivalent boosters. I don’t buy their argument that it was unnecessary to re-convene their advisory committee, VRBAC. I find almost every aspect of the CDC’s broad recommendation for universal adult (and teenage, for Pfizer) boosters with this new shot to be unsettling. I’m not happy with how this all went down, and wish I could believe that we might do a better job the next go-round.

The process was a failure. The product, though, is probably all right.