On January 26, 2023, the US Food and Drug Administration’s (FDA) Vaccines and Related Biological Products Advisory Committee met to discuss current issues related to immunization against SARS-CoV2, the virus that causes COVID-19. Prominent among discussions was the topic of mRNA vaccine boosters. On August 31, 2022, the FDA issued emergency use authorization (EUA) for new booster shots of Pfizer-BioNTech and Moderna. In doing so, the FDA ended EUA for previous boosters made by those same companies, boosters whose compositions matched that of the vaccine doses that are still given in the primary series (the first two doses). Since women of childbearing age in the western world are now getting mostly mRNA vaccines for their primary series doses and for boosters, it’s worthwhile to explore the recent committee meeting in terms of its relevance to pregnancy.
Let’s first review the rationale for Pfizer-BioNTech and Moderna being at the top of the list of vaccine options for pregnant women when it comes to protection against SARS-CoV2. In early 2021, it became clear that immunization with the COVID-19 viral vector vaccines of Janssen (Johnson and Johnson) and AstraZeneca COVID-19 could, in very rare cases, provoke the formation of blood clots. In particular, researchers identified a small number of cases consumptive coagulopathies, meaning that platelets (cell fragments that form clots) are stimulated to clot to such a degree that platelet supplies are consumed. This leads to thrombocytopenia, a deficiency of platelets, making the person vulnerable to hemorrhage, ironically while she is suffering from blood clots. One particularly dangerous type of blood clot forming in this setting is called cerebral venous sinus thrombosis (CVST). This rare type of blood clot in the sinuses that drain venous blood from the brain. A safety signal emerged related to a handful of CVST cases in premenopausal women who had received the Janssen vaccine recently. This was on top of rare clotting conditions also emerging in connection with the AstraZeneca vaccine, which, like the Janssen, is a viral vector vaccine. This led to recommendations that young and middle-aged women be vaccinated with an mRNA vaccine rather than with a viral vector vaccine. Later on, researchers also found that the Janssen vaccine was not as effective as the mRNA vaccines. As a consequence of all of this, for women of reproductive age in particular, mRNA vaccines have been the main option.
When they first hit the market in early 2021, both mRNA vaccines —the one from Pfizer-BioNTech and the one from Moderna— provided mRNA that instructs cells to manufacture a piece of spike protein corresponding to the spike protein of the so-called ancestral variant, sometimes called the Wuhan variants, of SARS-CoV2. This is what people still receive in the two shots of the primary series. For those receiving booster shots, however, the shots today contain the ancestral sequence and also another mRNA sequence corresponding to the omicron BA.4 and BA.5 variants. The dosage of each sequence of mRNA in the new boosters is half the dosage of the one sequence of the old boosters. Thus far, these bivalent boosters have not proven themselves to be superior to the monovalent boosters that they replaced.
Based on what scientists know about immunology, a reasonable explanation for this is that the newer sequence is not doing much, if anything, to the immune system of the booster recipients. They are responding, only to the half dose of the ancestral sequence because they have special cells, called memory B lymphocytes that react particularly to spike protein made from this sequence, because that’s what the previous vaccine doses provoked and because the two sequences are going to the same lymph nodes as they are injected together. This is helping with immunity, simply because the old shot was good enough for provoking immunity. Immunologically, the spike protein did not change so much in the evolution from the ancestral variant to BA.4/5, variants which, by the way, have since been replaced by other variants.
While the Committee discussed many topics, the members only voted on one issue. This was a unanimous vote (all 21 members) saying that the primary sequence and the boosters should be harmonized. Whether or not they dosage is the same, they should have the same composition rather than the current situation in which the primary series is for ancestral spike protein while the boosters are for ancestral and omicron BA.4/5. While it was not subject to a vote, various members of the committee said that the primary series should be bivalent, consisting of a sequence for currently circulating variants plus the ancestral sequence. Not all of the committee members agreed with this and I must point out that, immunologically, it does not make any sense to include a sequence for a variant that no longer exists. Doing so would not benefit people who receive the vaccine for the first time and, for those who already have received doses monovalent for the ancestral variant, including the ancestral sequence alongside an updated sequence would dampen or prevent the response to that new sequence.
As for pregnancy in the context of the recent Committee meeting, the issue is that, across the United States, for those who already have received three shots of a COVID-19 vaccine, the only vaccine available for another boost (as of the writing of this post, late January 2023) is the bivalent ancestral/BA.4/5 boosters of Pfizer-BioNTech and Moderna. If you want a boost to get a temporary rise in levels of IgG antibodies to immunize your fetus, you are stuck getting what effectively is a pediatric dose of the ancestral sequence, plus a sequence BA.4.5 variants that won’t do as much. Meanwhile, however, there are potential developments on the horizon. Protein subunit vaccines may eventually get approval for use as a fourth shot and further in the future we may see COVID-19 vaccines targeting something other than the spike protein, namely SARS-CoV2’s nucleocapsid protein.
