In August, the FDA authorized updated COVID-19 vaccine boosters containing an equal mix of the ancestral vaccine and a component tailored against the Omicron BA.4/5 subvariants. It rejected the idea of yet another booster of the original vaccine -- which the U.S. has in abundant supply -- or authorizing a monovalent Omicron-only booster. In our view, this decision was not clear cut and may have been the wrong one.
European countries made different choices based on similar information, opting instead for a bivalent vaccine containing an equal mix of the ancestral vaccine and one designed against the Omicron BA.1 subvariant. Meanwhile, the World Health Organization's Strategic Advisory Group of Experts on Immunization (SAGE) committee recently noted that "...currently available data are not sufficient to support the issuance of any preferential recommendation for bivalent variant-containing vaccine boosters over ancestral-virus-only boosters....The bulk of the benefit is from the provision of a booster dose, irrespective of whether it is a monovalent or bivalent vaccine."
Why are there such different perspectives? Let's look at what the immunology tells us.
When a dose of a BA.4/5-specific vaccine booster is given, most of the resulting increase in antibody production is derived from memory B-cells primed by the ancestral vaccine. Only a small fraction of the antibodies recognize new binding sites unique to BA.4/5. Furthermore, because the bivalent boosters are a 50-50 blend of the ancestral and BA.4/5 vaccines, only a half-dose of Omicron-specific vaccine is being administered. These points are why we and colleagues have argued that the updated boosters may be at best minimally better at eliciting neutralizing antibodies against BA.4/5 compared to the original vaccines. Two preprints released this week show that this is indeed the case. And at least one study provides clinical data showing that the updated COVID-19 booster probably won't protect any better against Omicron infections than the original vaccine. It's important that people recognize these limitations and do not increase their exposure to the virus after being boosted.
A reasonable counter-argument was that we do need to keep up with the times and develop vaccines to better protect against the Omicron subvariants. Yet, administering a monovalent, and hence a full dose, of a BA.4/5 vaccine may have better achieved this goal. The available data suggest that monovalent Omicron vaccines elicit a stronger antibody response to Omicron subvariants than do bivalent formulations.
In moving ahead with the bivalent formula, the FDA may have wanted to hedge its bets against the possible re-emergence of a pre-Omicron or Delta-like variant this winter, a scenario that, while unlikely, is not impossible. At the same time, the U.S. was well prepared for that outcome, because we have enormous supplies of the ancestral COVID-19 vaccines, until they expire. These vaccines can now only be used for initial vaccinations, not boosters, at a time when very few Americans are lining up to get their initial COVID-19 vaccine series.
The FDA and CDC didn't assess an approach that could have considered vaccination against the Omicron variants as if they were entirely new viruses. We know that two full doses of the ancestral vaccines were needed to induce strong antibody responses. The same immunology considerations could have been applied to eliciting antibodies against the sites that are unique to the Omicron variants -- here, the science suggests two full-doses of an Omicron-specific monovalent vaccine would be much more effective than the single half-dose that's in the bivalent booster. This might have been a good option for vulnerable populations in need of the strongest practically achievable protection.
In rolling out boosters, the FDA and the CDC should also apply the lessons learned in properly spacing vaccine doses, as this is important for optimal benefit. The CDC advises that a booster can be given "within 2 months" of infection or vaccination. However, a 4- to 6-month interval would be substantially better if the goal is to maximize antibody production. Boosting too soon after the previous dose (or infection) likely won't work as well as waiting a few more months. One reason is the presence of pre-existing antibodies in the blood, which can form complexes with the spike proteins produced by the vaccine and thus impair how the immune system responds to the vaccine. The levels of those anti-spike antibodies are high for a month or two after vaccination or infection, but fall steadily over the next few months. Furthermore, boosting too soon abrogates B-cell responses to vaccination.
As we've heard over and over again, vaccines on shelves don't prevent COVID-19 -- vaccinations in arms do. One obvious factor driving poor booster uptake is that many aren't even aware that updated bivalent boosters exist. A recent Kaiser Family Foundation (KFF) survey shows that over half of adults in the U.S. have heard only "a little" (31%) or "nothing at all" (20%) about them. Another potential factor in the low uptake of the bivalent boosters could be the FDA's decision to authorize it without having human safety data in hand, only mouse studies. As scientists and healthcare professionals with vaccine experience, we have no concerns about the safety of the bivalent vaccine. It's still the same vaccine, just with a tweak. To us, it's akin to having a car resprayed in a different color. We would not require a full safety evaluation before driving it. However, the public is very fickle about mRNA vaccine safety because of the vicious lies circulated by vaccine skeptics. Authorizing a new vaccine based on only mouse data was asking for trouble. A significant fraction of the public (18%) is now in "wait and see mode," perhaps a reflection of a lack of trust in the safety of the bivalent boosters. This outcome was all too predictable. The FDA and CDC should have seen it coming. At the very least, the messaging could have been better. Furthermore, the FDA de-authorization for the standard booster eliminated an option for people who trusted that one but may be antsy about the safety of new bivalent versions.
The people at greatest risk for severe and fatal outcomes are those who haven't yet gotten vaccinated against COVID-19. According to KFF polling, this group has proven very resistant to change, although some are now slowly coming around. Unfortunately, the FDA did not authorize the bivalent vaccines for use as a primary series or to boost a previously infected but never vaccinated person. An updated primary series based on the bivalent vaccine might provide better protection as well. The bivalent vaccine would essentially initiate two different primary series responses -- one against ancestral viruses and one against Omicron subvariants.
There remain many uncertainties about how best to design and implement COVID-19 vaccines in the face of what seems to be an ever-evolving virus. The pandemic, in one form or another, will be with us for many years yet. To respond as effectively as possible, we must continue to study different vaccine designs in carefully designed clinical trials. We must fully factor in the outstanding improvements to the knowledge of viral immunology that have emerged in the past 2 years. Forewarned is forearmed.
John P. Moore, PhD, is a professor of microbiology and immunology at Weill Cornell Medicine in New York City. Céline Gounder, MD, ScM, is an internist, infectious disease specialist, and epidemiologist; a senior fellow and editor-at-large for public health at the Kaiser Family Foundation and Kaiser Health News
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