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The Big Booster Question We Should Be Focused On
— What will a new generation of variant-targeting and infection-preventing vaccines look like?
by John P. Moore, PhD, and E. John Wherry, PhD
America's COVID-19 vaccine booster policy remains confusing. We are regularly asked by members of the public, friends, and (even!) highly aware professional colleagues what they should do: "Given my (details of vaccine/medical) history, should I get a booster now or do you think I should wait a few months for a "better" one. Or can I get both?" Questions like these are also being thrown at our circle of vaccine/immunology/virology friends. None of us have a definitive answer. We are simply not in a cookie-cutter world right now.
The FDA recently recommended that vaccine companies make new versions based on sequences from the now dominant Omicron-lineage viruses, specifically the BA.4/5 variants. However, as we will discuss, there are substantial questions about just how much better a BA.4/5 vaccine would be.
An urgent question is now this: Should Americans wait until an Omicron-based vaccine becomes available -- perhaps as soon as September or October? Or should they be boosted much sooner with the currently available standard vaccine? There's a strong case for not waiting, at least for people who are at risk of poor outcomes after infection, or whose psychological welfare is affected by fears of infection. But if people are boosted soon with the standard vaccine, could they then be re-boosted only a few months (or even a few weeks) later when the BA.4/5 boosters are around? This scenario is being suggested by some pundits and on social media, but we think it's not the best way to use boosters. The spacing between doses is important for maximum benefit. Waiting at least 4 months would be a prudent course to take, and 6 months might be best. One reason for delaying is that the elevated antibody levels soon after a vaccine dose can impair the response to another one. An infection also acts like a vaccine booster, and the same immunology dynamics apply. Having a booster dose too soon after the last one or after an infection isn't "dangerous" but may not add much to our immune responses. As of yesterday, the FDA has reportedly decided that Americans under 50 should wait to receive second boosters until the Omicron-targeting vaccines are available this fall.
Let's examine the state of vaccine protection today to inform a discussion of the right direction for booster policy to head next.
First, even two doses of an mRNA vaccine still provide solid protection against severe disease and death in otherwise healthy individuals. However, an average of more than 350 Americans still die each day from COVID-19. Many are unvaccinated and most others fall into the now well-known high-risk groups (age and pre-existing conditions). Primary vaccination and/or boosting would save many of these lives, and yet vaccine uptake, especially for boosters, remains disappointingly low.
Where the vaccines are no longer working well is protecting against milder "at-home" infections with the Omicron-variants, a situation that is worsening as those viruses (currently BA.4 and BA.5) become more resistant to infection-preventing neutralizing antibodies (NAbs). While these infections are often not severe, the experience can sometimes be highly unpleasant. There is also a fiscal cost when people have to take time off work due to their symptoms and a small but real risk of developing long-COVID symptoms that can have serious long-term consequences. Ideally, we would want to see strong protection against all infections. Unfortunately, this is no longer possible, at least not with the vaccines around now or those that will be available later this year. We say this based on what we know of how the immune system responds to vaccines (or previous infections), and of how Omicron sequence-based vaccines are performing in animal studies and human trials.
When we are first vaccinated (or infected), our immune system responds by producing antibodies that recognize the virus spike-protein we are exposed to. Antibodies protect against future infection and, together with some help from T cells, they also prevent severe disease and death. A key goal of vaccination, and an important consequence of some infections, is the establishment of immunological memory in the form of persisting antibodies as well as memory B cells and T cells. If properly induced and maintained, these memory components have the ability to recognize the virus/vaccine components if seen again in the future, respond quickly, and prevent infection and/or disease. For most vaccines (and many virus infections), it is antibodies that prevent symptomatic -- and even mild -- infection by blocking viruses from entering the body. This part of our immune response is why a hepatitis B vaccine or childhood infection gives us life-long protection. We don't see that kind of sustained benefit for the COVID-19 vaccines, but nonetheless, immunological memory -- in the form of memory B and T cells -- is generated, and it improves over time.
A key point here is that our memory B cells and T cells were created after exposure to virus sequences that are now long gone. The standard vaccines are based on the ancestral, Wuhan virus that was around in early 2020. Infections during 2020 and 2021 were almost always with that virus or ones reasonably close to it (Alpha and Delta). The emergence and increasing divergence of Omicron viruses from late 2021 onwards complicates matters because the key viral Spike proteins are now much more mutated. Most Omicron infections this year have occurred in people who were vaccinated and/or previously infected (since they are now the majority of the population) -- their initial immune memory is based largely on what they first saw.
When exposed to a virus Spike-protein from the Omicron lineage, our immune memory cells are activated and start to produce NAbs. However, those newly made NAbs arise from memory B cells first generated to the long gone ancestral virus. Only some of them are active against Omicron-lineage variants, but what fraction remains a key question. This phenomenon applies to Omicron infections and also the Omicron-based booster vaccines. In other words, those sequence-tweaked vaccines mostly re-awaken our memories of seeing a form of the virus that isn't now circulating. These events have consequences.
Animal and human studies have consistently shown that an Omicron booster is only marginally (less than twofold) better than the ancestral (i.e., current standard) version at triggering the production of NAbs against Omicron-lineage viruses. Indeed, for NAbs against the presently dominant Omicron-BA.4/5 variants, the benefit of the Moderna Omicron two-component (BA.1 plus ancestral) booster over the ancestral version was almost non-existent.
On one hand, this does mean that even a boost with a standard vaccine increases our levels of antibodies against Omicron-lineage viruses. But it also means that an Omicron booster is only marginally better than the standard one at triggering these NAb increases. It's hard to say whether the slightly higher NAb levels would provide much, if any, additional protection against infections compared to what the standard booster can do. For sure, people at risk for severe infection outcomes should not wait months for an Omicron booster that may be little better than the one that's available now. And it would be a mistake for anyone to increase their exposure to the virus in the belief that an Omicron booster gave them super-strong protection.
We can't boost our way out of this pandemic with the present generation of vaccines. They have worked really well, saving hundreds of thousands of lives in this country alone and tens of millions globally, but they have their limitations when it comes to preventing mild infections by Omicron lineage viruses. Tweaking their composition isn't the long-term answer.
We need to focus on better vaccines. The basic research has now been accomplished on many promising candidates, including some that better trigger antibody responses in the nose and others that stimulate much higher NAb levels that can cope with virus variants. However, these new vaccines are only slowly moving through the clinical trial and approval process. The American vaccine science and regulatory infrastructures have seemingly reverted to pre-pandemic timelines in which vaccines take much longer (many years) to bring to market. It is not even clear how a next-generation vaccine would be authorized here. Placebo-controlled phase III trials like we saw in 2020 are no longer practical, as potential volunteers are now already vaccinated and/or infected. Alternative procedures are required, but what are they going to be? The Biden administration needs to revisit how the promising new vaccines can be produced, tested, and approved, in order to speed their implementation and regain control over the pandemic.
Until better vaccine options emerge, we have to work with the ones available now or in a few months. In summary: Anyone who would benefit from an additional boost should act as soon as one is authorized for their age- and health-risk group. If that's the current standard vaccine, take it, and don't wait for an Omicron-based one. When those BA.4/5-based vaccines are rolled out, wait a sensible time (multiple months) before having another boost. And do not regard them as some form of a "magic bullet" that will dramatically reduce your risk of infection -- they probably won't do that.
John P. Moore, PhD, is a professor of microbiology and immunology at Weill Cornell Medicine in New York City. E. John Wherry, PhD, is professor and chair of the Department of Systems Pharmacology and Translational Therapeutics at the University of Pennsylvania Medical School.
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