Bivalent Boosters for COVID-19: Issues for Pregnancy

Health authorities in various countries have given approval to updated formulations of mRNA vaccine boosters against SARS-CoV2 (the virus that causes COVID-19), but you may have questions about what his means for you, if you are pregnant or planning to become pregnant. Really there are two ways that pregnancy enters the discussion. The first is that pregnancy puts you into a high risk category with respect to COVID-19, although the risk for pregnant women is not thought to be as great as it was early in the pandemic. If you are young with no other health issues, the overall risk is fairly low, but pregnancy does increase the chances that the course of COVID-19 disease would be worse if you are pregnant than it would be if you were not pregnant, all other things being equal. Additionally, the chances of suffering preterm labor and delivery increase if you develop COVID-19. For these reasons, we have emphasized many times here on The Pulse that you should be vaccinated against COVID-19 for your health and also to protect your baby. Furthermore, although venous blood clots are extremely rare in connection with the COVID-19 viral vector vaccines (Johnson and Johnson and AstraZeneca), the risk is not zero and women of reproductive age are at the highest risk. Thus, the mRNA vaccines (Pfizer-BioNTech and Moderna) are the better option for those who still haven not received their initial vaccine doses. Nevertheless, the boosters that we’re discussing today can be given, regardless of which initial vaccine you received for COVID-19.

Just to be absolutely clear, the bivalent formulations, thus far, are for use only as booster jabs. The primary series for Pfizer and Moderna still consists of two shots whose mRNA (genetic material) that carries the recipe for cells to make spike protein of the original Wuhan variant for the immune system to use for target practice. But the new bivalent boosters have mRNA for the Wuhan variant and also an additional strip of mRNA. In bivalent boosters approved in the United Kingdom and Canada, the additional strip of mRNA encodes spike protein of omicron BA.1, the original omicron variant. As of the writing of this post in mid September, 2022, Canada has approved the Moderna version of this formulation, while the UK has approved both the Modern and Pfizer-BioNTech versions. Meanwhile, in the United States, the Food and Drug Administration (FDA) has issued emergency use authorization (EUA) for Moderna and Pfizer-BioNTech bivalent boosters whose second strip of mRNA encodes, not the BA.1 variant spike protein, but the spike protein of the  BA.4 and BA.5 omicron variants (whose spike protein is the same). These are currently circulating omicron variants that have completely replaced BA.1, the original omicron. In issuing the EUA for the bivalent booster, FDA also ended the EUA for the monovalent booster, containing mRNA only for the original Wuhan spike protein. This means that the bivalent boosters are now the only kind of boosters you can receive in the US, meaning the only COVID-19 shots that you can receive as your third, fourth, or fifth dose.

Since most pregnant women are young, however, and since many pregnant women do not have major health issues that put them at high risk for COVID-19, three doses of an mRNA vaccine provide excellent protection against developing severe COVID-19, which is the whole point of vaccination. They do this by building long-term immunity mediated by T lymphocytes and memory B lymphocytes, but there has been a push for additional doses, on account of studies showing that levels of neutralizing antibodies against the viral spike protein drop in the blood over the course of several months. While higher antibody levels do provide you added protection against even mild COVID-19 disease, this added protection is very temporary and there are diminishing returns if one continuously receives booster shots. Antibody levels rise over a period of weeks, but then they drop, and the more boosters that you receive, the less time those levels remain high. This is very different from T lymphocyte immunity, which research shows has not waned after three shots in healthy people, and which seems to be the basis for protection against severe COVID-19.

There are some questions surrounding the FDA’s decision to issue an EUA for the bivalent vaccines so quickly. The UK and Canada have approved the bivalent vaccines targeting the older omicron variant BA.1, because there are data from clinical trials, meaning trials in humans. To be sure, the data are not so impressive and they are based on vaccine doses higher than the doses in the new booster that the FDA approved, the one targeting the BA.4 and BA.5 variants. A couple of months ago, when the data were released, the FDA committee on vaccines and related biological products voted 19-2 in favor of replacing the old boosters, based on a finding that antibody levels in human recipients of the bivalent vaccine (the one encoding BA.1, the original omicron) increased 1.75 times. But there is no evidence that such an increase is clinically significant. To give you perspective, antibody levels are roughly that amount higher in people who receive original Moderna compared with people who receive the original Pfizer, yet those two vaccines protect people roughly equally.

Consequently, one of the two committee members who voted no, Dr. Paul Offit, MD, Director of the Vaccine Education Center and professor of pediatrics at Children’s Hospital of Pennsylvania, was critical of the decision to replace the old, monovalent booster. And he is critical now that the FDA has approved the updated booster, targeting BA.4/BA.5. Offit agrees, as do many experts, that people at risk because of health conditions (like obesity, high blood pressure, etc) or an immunocompromised states (immune system is weak from disease or medications) and those ages 65 and older should receive the new booster. In contrast with the boosters being used in Canada and the UK, targeting BA.1 (the original omicron variant), however, no clinical trial data have been released supporting the use of the booster targeting BA.4/BA.5. As of the writing of this post in mid September, the only data are from mice. Those data show no reason to worry that the new booster is not safe, as do the human data on the bivalent targeting BA.1, but data for efficacy (how well the booster works) consist only of the levels of neutralizing antibodies in the blood. As we discussed above, higher antibody levels do not necessarily mean better clinical outcomes.

On top of that, to be absolutely sure that the bivalent boosters would be safe in the absence of human data, Pfizer/BioNtech and Moderna cut the dosages in half for each of the two mRNA sequences in the shot. With the old Pfizer monovalent booster, the one based only on the Wuhan variant, the dose was 30 micrograms, but in the updated Pfizer booster, you receive 15 micrograms against the Wuhan variant and 15 micrograms against BA.4/BA.5. With the old Moderna booster (which already was half the dose of the Modern primary series vaccine) the dose was 50 micrograms. But in the new Moderna booster, the dose is 25 micrograms against the Wuhan variant and 25 micrograms against BA.4/BA.5. These are in the realm of pediatric doses and while the half doses add up to a full dose in terms of arithmetic, this is not actually how it works in immunology. Studies conducted by Pfizer itself have demonstrated that the antigens (the proteins that the mRNA in the shots cause cells to make for the immune system to use for target practice) compete for attention of the immune system in the lymph nodes where the target practice plays out. In other words, it’s like the person is receiving two vaccines, each at a half dose. Consequently, there is reason to question whether the new boosters will be as effective as the old boosters that are no longer covered by an emergency use authorization in the US.

But the 64,000 dollar question that you may have is what does this mean, if you are pregnant and seeking a booster. First of all, we should point out that for the past year or so, it has been clear that a third shot is indeed very helpful, for everybody. If you have had only the primary series consisting of two shots, and especially not if you are pregnant, it still makes sense to get a booster —a first booster. The mRNA vaccines are not live vaccines, so there is no reason to think that they should present any problem when administered during pregnancy. Now, if you’re in Canada or the UK, the approved bivalent boosters have human testing showing that they are safe and at least as effective as the old boosters. If you’re in the US, the approved booster, targeting BA.4/BA.5 is backed by only a few mouse data and the dosage is cut in half for each sequence, but at the molecular level it’s extremely similar to the other bivalent booster, targeting BA.1, that they did test in humans. Given the serious consequences of COVID-19 illness, especially if you are pregnant, the hypothetical risks of such a booster do not amount to a reason not to get a third shot, if you are pregnant and healthy, or not to get a fourth shot, if you have health conditions that make you high risk.

But what about getting the new bivalent booster as your second booster, your fourth shot, when you are young with no risk factors? This is the point where, based on what’s known in September 2022, it looks as though you’re better off waiting, not because of safety, but because there is no demonstrated benefit. Along with issuing the EUA for the new booster a head of clinical trial results, the FDA did something else concerning. They issued the EUA, allowing for people to receive the new booster as little as two months after the most previous dose. This is in contrast to the five month minimum that was allowed for the monovalent booster. Given all that we have learned through the pandemic to the effect that the vaccines produce better, longer-lasting immunity when the doses are spaced apart more, it’s puzzling why the new booster would be offered so soon after one’s most recent dose. What’s next, continuous vaccine infusion? I’m not worried that there’s a safety issue, but I am concerned that issuing EUAs ahead of clinical trial data —for all people rather than just for high risk people— will erode confidence that people have in health authorities, leading to lower vaccination rates for a range of infectious diseases.

As you proceed through your pregnancy and beyond, keep in mind that it is very important to be vaccinated against COVID-19, among other infectious diseases. But don’t become obsessed with keeping your antibody levels at high concentration to protect you from even mild disease at all times that you’ll be rushing to get a booster every couple of months. There is no reason to think that would be beneficial. While new variants of SARS-CoV2 do keep emerging, the virus actually is not evolving as fast as influenza viruses evolve. As you know, flu vaccines are updated every year, because influenza evolves so quickly, and we may very well get to the point of updating COVID-19 vaccines on a yearly basis. But we don’t know yet if we actually need to do this.

David Warmflash
Dr. David Warmflash is a science communicator and physician with a research background in astrobiology and space medicine. He has completed research fellowships at NASA Johnson Space Center, the University of Pennsylvania, and Brandeis University. Since 2002, he has been collaborating with The Planetary Society on experiments helping us to understand the effects of deep space radiation on life forms, and since 2011 has worked nearly full time in medical writing and science journalism. His focus area includes the emergence of new biotechnologies and their impact on biomedicine, public health, and society.

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