On Tuesday, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 19-2 to approve the use later this year of Covid-19 vaccines based on an Omicron variant sequence. One of us (P.A.O.) was among those voting “no.” It is possible these vaccines will be two-component designs that also include the current version. Will Americans soon be better protected against Covid-19?
The Covid-19 vaccines currently authorized for use in the U.S. are all based on the sequence of the original SARS-CoV-2 virus, which was obtained early in 2020. The virus has evolved over the past 30 months, creating variants that are either more infectious, or harder to counter by vaccination, or both. In late December 2021, the Omicron variant (BA.1) emerged, becoming the most dominant strain in the U.S. BA.1 has now been almost completely replaced by other Omicron-based variants. The BA.4 and BA.5 viruses currently account for 50% of all circulating strains. Earlier variants, like Alpha and Delta, have essentially vanished.
While vaccines made from the original SARS-CoV-2 strain provided strong protection against SARS-CoV-2 circulating in 2020 and 2021, the Omicron variants have been more problematic. They are highly resistant to neutralizing antibodies, which the human immune system uses to prevent infection. As a result, the Omicron viruses find it easier to break through this protective barrier, causing what are mostly mild infections. That’s true whether the neutralizing antibodies were elicited by vaccination or by earlier infection with Alpha or Delta variants. Fortunately, most people have enough neutralizing antibodies to strongly protect them against severe disease and death — that key task requires immune memory cells and lower neutralizing antibody levels than are needed to completely fend off the virus.
Once it became clear that the Omicron variants resisted neutralizing antibodies, thereby increasing the frequencies of mostly mild infections, vaccine companies began rapidly redesigning their Covid-19 vaccines. The revised vaccines were all based on the initial Omicron BA.1 sequence, which was an appropriate step to take. By now, most Americans already have antibodies against SARS-CoV-2’s spike protein because they were vaccinated or infected or both. As a result, the most frequent use of an Omicron-containing vaccine will be as a booster dose for certain high-risk groups.
What is known about Omicron-based vaccines? BA.1 versions have been tested as boosters in experimental animals and also in small-scale human trials. The goals of the studies were to measure the levels of neutralizing antibodies produced, compared to using the original vaccine as a booster under similar conditions.
The animal data have been around for several months. They are quite similar to what’s recently emerged from various human trials. Two to four weeks after the booster shots, neutralizing antibody levels against Omicron BA.1 were about twofold higher with the Omicron-based vaccine than with the original vaccine. Moderna recently released some information on a two-component Omicron plus original booster vaccine. The Omicron (BA.1) neutralizing antibody levels induced were higher than when the original vaccine was used by itself but, again, by less than two-fold. In contrast, Pfizer showed data at the VRBPAC meeting indicating that its two-component vaccine actually performed less well than an Omicron-only booster. Even allowing for the nature of very early data, the story on two-component vaccines is far from clear.
What do an approximately twofold higher level of neutralizing antibodies mean in practice? Is an Omicron-based booster sufficiently superior to the standard one to justify a switch?
That kind of twofold difference is, for example, similar to the modestly greater peak in neutralizing antibodies triggered by the first two doses of the Moderna vaccine compared with the Pfizer vaccine. Those two vaccines provided almost identical protection against mild and severe Covid-19, although the benefits of the Pfizer vaccine waned a bit quicker over time.
We would all gain from having more insights into the performance of the Omicron-based Covid-19 vaccines. The full datasets from all the variant booster trials should now be analyzed using the best available models to provide an informed judgement about whether — and to what extent — the slightly superior neutralizing antibody response to Omicron-based boosters translates into significantly greater protection against BA.4/BA.5-mediated infections and severe or fatal disease.
Moderna and Pfizer executives have claimed that the Omicron vaccines will be protective for longer. That may be true, but how long is longer? A few weeks? A month or two? Again, detailed modeling of the data might provide important information. It’s important to be sure that changing the booster vaccine to include the Omicron sequence offers enough of an advantage to justify the cost and complexity associated with making the switch.
The reason why the Omicron and earlier variant boosters are little or no better than a standard booster is rooted in immunology. The immune system responds to the first sight of the viral spike protein by making neutralizing antibodies and by starting to lay down memory cells that are an archive of what it is seeing. Those memory cells improve over a multi-month period and are then triggered into action when the immune system reencounters the spike protein, either as an infection or in a booster vaccination. The resulting neutralizing antibody response doesn’t appear to depend very much on whether the boost was with the original sequence, the Beta sequence, the Delta sequence, or the Omicron sequence — all are about equally as good at reawakening immune memory cells. The Omicron vaccines also seem to elicit some neutralizing antibodies that are unique to that variant and that make a minor contribution to the overall response. It’s possible that component could improve over time or after additional boosts, but we have no data to evaluate.
Because no one can predict how SARS-CoV-2 will further evolve, there’s no way to tell whether one or more Omicron-based boosts over the next year would be beneficial against what may emerge. What is known is that the increasingly prevalent BA.4 and BA.5 variants are even more resistant to neutralizing antibodies, typically by three- or four-fold, than the now-vanished BA.1 variant on which the Omicron vaccines are based. The trend toward greater resistance of neutralizing antibodies may well worsen.
Some experts have suggested that a booster should be based not on the BA.1 sequence but on BA.4/BA.5 sequences. To do that in a relevant time frame would mean foregoing clinical trials to obtain immunogenicity data. A reasonable assumption is that a booster based on BA.4/BA.5 would be better tailored to those now dominant strains. Nonetheless, the increase in neutralizing antibodies over the standard vaccine boost may still be only modest — probably on par with what’s being seen with the BA.1 boosters.
If an Omicron-based booster provides little advantage over the vaccine stocks that already exist, is it worth the switch? Making and rolling out an entirely new supply of Covid-19 vaccines on a nationwide basis is no trivial matter, particularly when Congress seems reluctant to provide the funds. Would the country be better off using the available resources to accelerate the creation of next-generation vaccines that can produce neutralizing antibodies in amounts high enough to deal with most variants? Or vaccines that can be delivered into the nose, a route that may provide stronger protection against infection? Strategic decisions of this nature require a deep dive into the immunology of how vaccines work; and the use of sophisticated models on neutralizing antibody actions.
Vaccines remain of critical importance at this stage of the pandemic. We strongly urge that everyone who needs a vaccine dose gets one, particularly never-vaccinated people who have been fooled by distortions about vaccine safety. But it’s important to understand what vaccines can and cannot now do, and what any composition switch really means for protection against Covid-19.
Perhaps researchers will learn that particularly vulnerable people, like those who are older or sicker, might benefit sufficiently to justify the use of an Omicron-based booster, but the wider population would not. Decisions could be tailored to specific sub-populations.
Whatever the decision, Americans will need to receive accurate information about how the new boosters perform against mild infections and virus transmission. It isn’t likely that an Omicron-based booster will be a magic bullet, although it might be perceived that way. It is essential to avoid offering people a false sense of security. Those who recently received an Omicron booster should not think they are now bulletproof against SARS-CoV-2 and increase their infection risk by altering their behavior. There are signs that behavioral changes may already be visible in infection statistics from the Centers for Disease Control and Prevention.
A multibillion-dollar decision to launch a vaccine based wholly or in part on the BA.1, BA.4, or BA.5 sequence that would affect more than 100 million people need not be unduly rushed. A decision of this magnitude should be based on as much expertise and analysis as is reasonably practical. Our joint concern is that this may not be what happens in the coming days, when the FDA will likely accept the majority advice given by its advisory committee without fully weighing what the exact composition of the new vaccine should be, and assessing whether it confers significant advantages over the current vaccine. Using an additional week or two to obtain more input seems a prudent step to take.
John P. Moore is a professor of microbiology and immunology at Weill Cornell Medicine in New York City. Paul A. Offit is a pediatrician, professor of pediatrics, and director of the Vaccine Education Center at the Children’s Hospital of Philadelphia, and a member of the FDA’s Vaccines and Related Biological Products Advisory Committee.
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