In part 1 of this series, we explored passive immunity more deeply than we have done in the past. We did this, so that we could now take a deep dive into the issue of a fourth dose of vaccine against SARS-CoV2 (the virus that causes COVID-19). We’re talking fourth dose, because this is what you probably would be getting, if you choose to get boosted with an updated bivalent booster (although for many people it’s fifth dose), this is where the issue gets very complicated for those who are otherwise healthy. Many people at this point also have had a mildly symptomatic, or an asymptomatic, infection with SARS-CoV2. I had a mildly symptomatic infection back in May 2022, which I picked up, of all places, at the annual scientific meeting of the Aerospace Medical Association. And guess what? That’s a dose. It boosts your immune system as a vaccine booster boosts your system, except that it boosts it with more than just the viral spike protein. The includes all the antigens of the virus, so the nucleocapsid protein too, meaning the protein that forms the main bulk of the virus particle. I wasn’t happy to get that infection, but the silver lining is that having received three doses of mRNA vaccine, all giving the immune system target practice against a component of the spike protein of the ancestral (Wuhan) variant of the virus, at least I know that the immunity was broadened.
Why is broadened immunity desirable? The reason is that the virus is evolving and, so far, we don’t know if it will evolve a way to evade the vaccines the way that it has evaded many of the mAb therapies. In promoting the bivalent vaccine, the rationale has been that it should broaden your immunity by supplying your immune system target practice, both against spike protein of the ancestral variant and against spike protein the omicron BA.4 and BA.5 variants. These are the variants that were circulating the most when the updated booster was authorized on September 1, so there was a logical basis for formulating the new booster to fight those. There was no logic, however, to including the ancestral variant spike, however, since that was gone by that time, just as the BA.4/5 variants also now seem to be in the rear-view mirror.
If the formulation of the booster does not match the variants that are circulating and could infect you, or your fetus, what does it actually do when you receive it? Based on research conducted last year and published in the prestigious New England Journal of Medicine, it appears that either the ancestral spike protein, or the spike protein of the first omicron variant (BA.1), can generate immunity against any of the variants. It also appears that monovalent vaccines —vaccines containing mRNA encoding just one type of spike protein— work better than bivalent vaccines. The potential problem with including the ancestral sequence in the new boosters is that we have all received these two or three times —some people four or five times. So, our immune systems are primed to respond better to antigen created from that sequence, then to variants of that antigen. This is called imprinting and it’s probably the reason why the immune response to the new boosters has been disappointing. You get the bivalent injected into your left shoulder, both versions of the antigen protein are displayed on the membranes of antigen presenting cells in the same germinal centers of the same lymph nodes in your left armpit, so the old antigen outcompetes the new, “updated” one. It’s for this reason that some experts think that the ancestral component of the vaccines should be dropped and in the process, they may as well update the other component with one or more sequences of current variants.
While it is relatively easy for me —as a male, middle aged, no disease risk factors, with three doses of the ancestral sequence, plus one mild symptomatic infection— to hold off and avoid imprinting more on the ancestral antigen while waiting for a better booster, a booster that would broaden the immune response, you do not have that luxury, if you are a woman who recently has become pregnant. You have two issues. One is that pregnancy makes you more likely to suffer a severe case of COVID-19 if you do become infected. Another is a need to provide passive immunity to your fetus.
In terms of your own health, if you have no health conditions, such as heart disease, diabetes, obesity, or you’re taking immunosuppressive medications (such as for rheumatological diseases), if you already have received three vaccine doses, is there any benefit to receiving another one? The answer is that it probably doesn’t add to the T cell immunity and the protection against severe COVID-19 that you already have. But it does boost your levels of neutralizing antibodies for a short time and those antibodies give you extra protection against the virus, making it less likely you’ll get even mild COVID-19. Within a few weeks of receiving the booster, those antibody levels peak and they are mostly IgG, so they pass through the placenta to your fetus. The caveat is that each additional boost you receive gives you a shorter period of extra protection.
In other words, there are diminishing returns with each boost. That, plus the imprinting possibility, weights against having everybody simply get boosted every few months. Just as there are reasons why tetanus boosters are given just every ten years (after the childhood primary series), it may turn out that we don’t need so many doses against SARS-CoV2. For all the comparisons that have been made with seasonal influenza, for which we are vaccinated once per year, there’s no reason yet to think this will be the case for SARS-CoV2. There’s also no reason to think it will be like measles-mumps-rubella-varicella, or polio, where you get a certain amount of shots during childhood and then you are set for life.
We just don’t know yet, and since we don’t know, it seems logical that, if you are inclined to get boosted to protect your baby, it would make sense to time things appropriately. If you are pregnant now, get your booster at the optimal time, meaning a month or so prior to delivery. Don’t cut things too short since there’s always a possibility that you’ll deliver early. You want to have the antibody levels peak in those final days before giving birth. This also means that, if you are not pregnant and you are planning to become pregnant, if you already have had three vaccine doses, or if you have had two doses plus a natural infection, it probably makes sense now to hold off on that booster until you become pregnant and then get the booster in the third trimester.
