US COVID-19 vaccine booster policy remains confusing. We are regularly asked by members of the public, friends and (even!) very conscious professional colleagues what to do: “Given my (details of vaccine/medical) history, should I get a booster now or do you think I’m waiting? a few months on a “better one. Or can I get both?” These kinds of questions are also asked in our circle of friends in the field of vaccines/immunology/virology. None of us have a definitive answer. We’re just not in a world of cookie cutters right now.
The FDA recently recommended that vaccine companies create new versions based on sequences of the now dominant Omicron viruses, specifically the BA.4/5 variants. However, as we’ll discuss, there are substantial questions about how much better a BA.4/5 vaccine would be.
A pressing question now is this: Should Americans wait for an Omicron-based vaccine to become available — perhaps as early as September or October? Or should they be boosted much sooner with the now available standard vaccine? There are strong arguments against waiting, at least for people who are at risk for poor outcomes after infection, or whose psychological well-being is affected by fear of infection. But if people get a quick boost with the standard vaccine, can they not be boosted again until a few months (or even a few weeks) later when the BA.4/5 boosters are around? This scenario is suggested by some experts and on social media, but we don’t think it’s the best way to use boosters. The distance between doses is important for maximum benefit. It would be wise to wait at least 4 months, and 6 months may be best. One reason for the delay is that the elevated antibody levels shortly after a vaccine dose may reduce the response to another dose. An infection also acts as a vaccine booster and the same immunological dynamics apply. Getting a booster dose too soon after the last one or after an infection isn’t “dangerous,” but it may not add much to our immune response. As of yesterday, the FDA has reportedly ruled that Americans under 50 should wait to receive second boosters until the Omicron-targeted vaccines are available this fall.
Let’s take a look at the current state of vaccine protection to spark a discussion about the right direction for follow-up policy.
First, even two doses of an mRNA vaccine still provide solid protection against serious illness and death in otherwise healthy individuals. However, on average, more than 350 Americans still die from COVID-19 every day. Many are unvaccinated and most of the others fall into the now known risk groups (age and pre-existing conditions). Primary vaccination and/or boosting would save many of these lives, yet vaccination coverage, especially for boosters, remains disappointingly low.
Where the vaccines no longer work well is protection against milder “home” infections with the Omicron variants, a situation that worsens as those viruses (currently BA.4 and BA.5) become more resistant to infection-preventing neutralization antibodies (NAbs). ). While these infections are often not serious, the experience can sometimes be very unpleasant. There are also tax costs when people have to take time off work due to their symptoms and a small but real risk of developing long-term COVID symptoms that can have serious long-term consequences. Ideally, we would like to see strong protection against all infections. Unfortunately, this is no longer possible, at least not with the vaccines that are out there now or that will be available later this year. We say this based on what we know about how the immune system responds to vaccines (or previous infections), and how Omicron sequence-based vaccines perform in animal 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 infections and, along with some help from T cells, they also prevent serious illness and death. An important goal of vaccination, and an important consequence of some infections, is the establishment of an immunological memory in the form of persistent antibodies, as well as memory B cells and T cells. When properly induced and maintained, these memory components can recognize the virus/vaccine components when seen again in the future, respond quickly and prevent infection and/or disease. For most vaccines (and many viral infections), they are antibodies that prevent symptomatic — and even mild — infection by preventing viruses from entering the body. This part of our immune response is why a hepatitis B vaccine or a childhood infection gives us lifelong protection. We don’t see that kind of sustained benefit for the COVID-19 vaccines, but nevertheless, immunological memory — in the form of memory B and T cells — is generated and it improves over time.
An important 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 there in early 2020. In 2020 and 2021, infections were almost always with that virus or fairly close to it (Alpha and Delta). The emergence and increasing divergence of Omicron viruses from late 2021 complicates matters as the major viral Spike proteins are now much more mutated. Most Omicron infections this year have occurred in people who had been vaccinated and/or previously infected (as they now make up the majority of the population) – their initial immune memory is largely based on what they saw for the first time.
When we are exposed to a virus Spike protein of the Omicron line, our immune memory cells are activated and begin to produce NAbs. However, those newly made NAbs arise from memory B cells that were first generated to the long-gone ancestral virus. Few of them are active against Omicron lineage variants, but which fraction remains an important question. This phenomenon applies to Omicron infections as well as the Omicron-based booster vaccines. In other words, those modified sequence vaccines usually trigger our memories of seeing a form of the virus that isn’t circulating now. These events have consequences.
Animal and human studies have consistently shown that an Omicron booster is only marginally (less than twice) better than the ancestral (i.e., the current standard) version at triggering the production of NAbs against Omicron viruses. Indeed, for NAbs against the currently dominant Omicron-BA.4/5 variants, the advantage of the Moderna Omicron two-component (BA.1 plus ancestral) booster over the ancestral version was almost non-existent.
On the one hand, this means that even a boost with a standard vaccine increases our levels of antibodies to Omicron viruses. But it also means that an Omicron booster is only marginally better than the stock at triggering these NAb increases. It’s hard to say whether the slightly higher levels of NAb would provide much or no additional protection against infection compared to what the standard booster can do. Certainly, people at risk of serious infection outcomes should not wait months for an Omicron booster that may not be much better than the one available now. And it would be a mistake for anyone to increase their exposure to the virus on the assumption that an Omicron booster would provide them with super-strong protection.
We cannot boost our way out of this pandemic with the current generation of vaccines. They have worked very well, saving hundreds of thousands of lives in this country alone and tens of millions worldwide, but they have their limitations when it comes to preventing mild infections from Omicron viruses. Changing their composition is not the long-term answer.
We need to focus on better vaccines. The basic research has now been conducted on many promising candidates, including some that elicit better antibody responses in the nose and others that stimulate much higher levels of NAb resistant to virus variants. However, these new vaccines are only slowly going through the clinical trial and approval process. American vaccine science and regulatory infrastructures have seemingly reverted to pre-pandemic timelines where vaccines take much longer (many years) to market. It’s not even clear how a next-generation vaccine would be allowed here. Placebo-controlled phase III trials as we saw them in 2020 are no longer practical, as potential volunteers are already vaccinated and/or infected. Alternative procedures are needed, but what will they become? The Biden administration needs to rethink how the promising new vaccines can be produced, tested and approved to accelerate their implementation and bring the pandemic back under control.
Until better vaccine options emerge, we have to work with the ones that are available now or in a few months. In summary, anyone who would benefit from an extra boost should act as soon as one is approved for their age and health risk group. If that’s the current standard vaccine, take it and don’t wait for an Omicron-based vaccine. When those BA.4/5 based vaccines roll out, wait a reasonable amount of time (several months) before getting another boost. And don’t think of them as some kind of “magic bullet” that will drastically reduce your risk of infection — they probably won’t.
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 division of systems pharmacology and translational therapy at the University of Pennsylvania Medical School.
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