OOn Tuesday, the FDA’s Vaccines and Related Biologicals Advisory Committee (VRBPAC) voted 19 to 2 to approve the use later this year of Covid-19 vaccines based on a variant Omicron sequence. One of us (PAO) was among those who voted “no”. It is possible that these vaccines are two-component designs that also include the current version. Will Americans soon be better protected against Covid-19?
The Covid-19 vaccines currently licensed in the United States are all based on the sequence of the original SARS-CoV-2 virus, which was obtained in early 2020. The virus has evolved over the past 30 months, creating variants that are either more contagious, or more difficult to counter with vaccination, or both. In late December 2021, the Omicron variant (BA.1) emerged, becoming the most dominant strain in the United States. BA.1 has now been almost completely superseded by other Omicron-based variants. The BA.4 and BA.5 viruses currently represent 50% of all circulating strains. Earlier variants, like Alpha and Delta, have all but disappeared.
While vaccines made from the original SARS-CoV-2 strain offered strong protection against circulating SARS-CoV-2 in 2020 and 2021, 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, Omicron viruses have an easier time breaking through this protective barrier, causing mostly mild infections. This is true whether the neutralizing antibodies were elicited by vaccination or by previous infection with Alpha or Delta variants. Fortunately, most people have enough neutralizing antibodies to strongly protect them against serious illness and death – this key task requires immune memory cells and lower levels of neutralizing antibodies than are needed to fully ward off the virus.
Once it became clear that Omicron variants were resistant to neutralizing antibodies, thereby increasing the frequency of mostly mild infections, vaccine companies began rapidly redesigning their Covid-19 vaccines. The revised vaccines were all based on the original Omicron BA.1 sequence, which was an appropriate step to take. By now, most Americans already have antibodies against the SARS-CoV-2 spike protein because they were vaccinated or infected or both. Therefore, the most frequent use of a vaccine containing Omicron will be a booster dose for certain high-risk groups.
What do we know about Omicron-based vaccines? BA.1 versions have been tested as boosters in experimental animals and also in small-scale human trials. The aims 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 has existed for several months. They are quite similar to what has recently emerged from various human trials. Two to four weeks after the booster shots, neutralizing antibody levels against Omicron BA.1 were about twice as high with the Omicron-based vaccine as with the original vaccine. Moderna recently released information on a two-component Omicron plus an original booster vaccine. The levels of Omicron (BA.1) neutralizing antibodies induced were higher than when the original vaccine was used alone but, again, less than double. In contrast, Pfizer presented data at the VRBPAC meeting indicating that its two-component vaccine actually worked worse than an Omicron-only booster. Even taking into account the nature of very early data, the story of two-component vaccines is far from clear.
What does an approximately twice higher level of neutralizing antibodies mean in practice? Is an Omicron-based booster sufficiently superior to the standard to justify a change?
This type of double difference is, for example, similar to the slightly higher peak of neutralizing antibodies triggered by the first two doses of the Moderna vaccine compared to the Pfizer vaccine. These two vaccines provided almost identical protection against mild and severe Covid-19, although the benefits of the Pfizer vaccine waned somewhat more rapidly over time.
We would all benefit from more information on the performance of Omicron-based Covid-19 vaccines. The full datasets of all variant booster assays must now be analyzed using the best available models to provide an informed judgment as to whether – and to what extent – the slightly greater response of neutralizing antibodies to boosters at Omicron base results in significantly superior protection against BA. 4/BA.5-mediated infections and serious or fatal illnesses.
Moderna and Pfizer executives claimed Omicron vaccines would protect longer. That may be true, but how long is longer? A few weeks? A month or two? Again, detailed data modeling could provide important insights. It is important to ensure that changing the booster vaccine to include the Omicron sequence provides enough benefit to justify the cost and complexity associated with the change.
The reason why Omicron boosters and earlier variants 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 beginning to establish memory cells that are an archive of what it sees. These memory cells improve over a period of months and are then triggered when the immune system encounters the spike protein again, either as an infection or in a booster vaccination. The resulting neutralizing antibody response doesn’t seem to depend much on whether the boost was with the original sequence, the Beta sequence, the Delta sequence, or the Omicron sequence – all are about equally effective in waking up the cells immune memory. Omicron vaccines also appear to elicit neutralizing antibodies which are unique to this variant and which make a minor contribution to the overall response. It is possible that this component improves over time or after additional boosts, but we have no data to evaluate.
Because no one can predict how SARS-CoV-2 will evolve, there is no way to tell if 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, usually three or four times, than the now extinct BA.1 variant on which Omicron vaccines are based. The trend towards greater neutralizing antibody resistance may well be getting worse.
Some experts have suggested that a recall should not be based on the BA.1 sequence but on the BA.4/BA.5 sequences. To do so in a relevant timeframe would be to forgo clinical trials to obtain immunogenicity data. A reasonable hypothesis is that a booster based on BA.4/BA.5 would be better suited to these now dominant strains. Nevertheless, the increase in neutralizing antibodies relative to the standard vaccine booster may still be only modest – likely on par with what is seen with BA.1 boosters.
If an Omicron-based booster offers little benefit over existing vaccine stocks, is it worth the switch? Manufacturing and rolling out an all-new supply of Covid-19 vaccines nationwide is no small feat, especially when Congress seems reluctant to provide the funds. Would the country be better off using available resources to accelerate the creation of next-generation vaccines capable of producing neutralizing antibodies in quantities high enough to cope with most variants? Or vaccines that can be administered through the nose, a route that may offer better 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 the neutralizing actions of antibodies.
Vaccines remain critically important at this stage of the pandemic. We urge that everyone who needs a dose of vaccine gets one, especially never-vaccinated people who have been duped by distortions about vaccine safety. But it’s important to understand what vaccines can and can’t do now, and what any change in composition really means for protection against Covid-19.
Researchers may learn that particularly vulnerable people, such as those who are older or sicker, may benefit enough to warrant the use of an Omicron-based booster, but not the general population. Decisions could be tailored to specific subpopulations.
Whatever the decision, Americans will need to be provided with accurate information about the performance of new boosters against mild infections and transmission of the virus. An Omicron-based booster is unlikely to be a silver bullet, although it could be perceived that way. It is essential to avoid giving people a false sense of security. Those who have recently received an Omicron booster should not think that they are now bulletproof against SARS-CoV-2 and are increasing their risk of infection by changing their behavior. There are signs that behavioral changes may already be visible in infection statistics from the Centers for Disease Control and Prevention.
A multi-billion dollar decision to launch a vaccine based in whole or in part on the BA.1, BA.4 or BA.5 sequence that would affect more than 100 million people should not be unduly hasty. A decision of this magnitude should be based on as much expertise and analysis as reasonably possible. Our common concern is that this may not be what happens in the next few days, when the FDA will likely accept the majority opinion given by its advisory committee without fully weighing what the exact composition of the new vaccine should be, and assess whether it confers significant advantages over the current vaccine. Using an extra week or two to get more information seems like a prudent step to take.
John P. Moore is a professor of microbiology and immunology at Weill Cornell Medicine in New York. Paul A. Offit is a pediatrician, professor of pediatrics and director of the Vaccine Education Center at Children’s Hospital of Philadelphia, and a member of the FDA’s Vaccines and Related Biologics Advisory Committee.
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