A number of vaccines have reached the emergency use authorization (EUA) stage and have been administered to millions of people across the world. However, the clinical trial data on which such approval was based does not include trials on pregnant and lactating women.
A reassuring new preprint in the medRxiv* server reports the immunogenicity and lack of reactogenicity of the coronavirus disease 2019 (COVID-19) vaccine when given to this group of subjects. This will contribute to the sum of knowledge about the implications of vaccination in this high-risk cohort.
COVID-19 in pregnancy
In the USA alone, thousands of pregnant women have been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus that causes COVID-19. The infection may be more serious in pregnancy due to the immunological changes that occur at this time, along with hemodynamic alterations. Thus, pregnancy with COVID-19 is associated with a higher risk of hospitalization, intensive care and death, compared to non-pregnant women.
The first trial in pregnant women began in February 2021. The hesitancy to include this group stems from the novelty of the earliest approved vaccines, which are based on a messenger ribonucleic acid (mRNA) platform encoding the SARS-CoV-2 spike antigen.
The questions raised in this study include the efficiency of antibody production against the vaccine antigens in pregnancy and lactation and the transfer of such antibodies across the placenta and in breast milk to the neonates. Vaccine-associated side effects in pregnancy were also evaluated, particularly fever, which is a known teratogen.
The study thus compared vaccinated pregnant and lactating mothers with non-pregnant controls and with naturally infected pregnant women.
The study included 131 women, including 84 pregnant, 31 lactating and 16 non-pregnant women. All were in the reproductive age group. Of the pregnant subjects, 13 were delivered during the study period, and cord blood samples were obtained from 10 of them.
Since most of the women were healthcare workers at the two study centers, they were mostly white non-Hispanic women in their mid-30s. Another comparison group included 37 banked sera from women with natural SARS-CoV-2 infection in pregnancy.
The vaccinated women received either the Pfizer/BioNTech or Moderna mRNA vaccines. The mean term of pregnancy at the time of the first vaccine dose was 23 weeks. About 13% were vaccinated in the first trimester, 46% in the second and 40% in the third.
The most common reactogenic effects included soreness at the site of injection, tiredness and headache. After the second dose, in particular, fever with chills was also common, being reported in a third of pregnant women compared to 50% of non-pregnant women after the booster dose.
However, the cumulative symptom score was low after the first dose and comparable in pregnant, lactating and non-pregnant women after the second dose.
Response to maternal vaccine
The researchers found that antibodies to the spike, the receptor-binding domain (RBD), and the S2 subunit of the spike, showed a rise with respect to all isotypes – IgM, IgG and IgA, after the first vaccine dose. Antibodies to the spike increased faster than anti-RBD antibodies after both doses of the vaccine, but both reached the same final titer.
The antibody IgG titers showed a further rise after the second dose of the vaccine in both pregnant and lactating groups. IgM and IgA titers also rose strongly after the first dose, and did not show a marked rise after the booster dose, in any group.
The Moderna vaccine was associated with higher IgA responses to the spike and the RBD compared to the Pfizer vaccine, perhaps because the former allows a longer interval between doses.
With both vaccines, the dominant antibody isotype in serum was igG in all groups. However, the antibody levels were higher following vaccination than in natural infection in pregnancy, emphasizing the strong humoral immunity produced by the mRNA vaccines.
Breast milk antibodies
The study also shows that breastmilk showed a rise in IgG, IgA and IgM after both the first and second doses of the vaccine. As with serum, the levels of IgM and IgA remained stable after the booster dose, but IgG levels went up.
Anti-RBD IgG1 showed a surge over the whole period, but not after the first dose only. IgA and IgM to the RBD showed no rise in breast milk after the first or second dose. Thus, the booster dose appears to enhance the transfer of IgG into breast milk.
Transplacental antibody transfer
The researchers also demonstrated that spike- and RBD-specific IgG was present in the umbilical cord blood samples collected from 10 of the newborns of vaccinated mothers. The lowest antibody titer came from a mother who delivered after her first dose, which she had received 17 days earlier.
In this patient, anti-spike but not anti-RBD IgG1 antibodies were efficiently transferred into the cord blood proportional to the time since the booster dose. This indicates the importance of the time from vaccination in determining how fast a given IgG is transferred to cord blood after the pregnant woman is vaccinated.
The study also shows that the composite reactogenicity score after both vaccine doses was proportional to the maternal antibody titers in maternal serum and breast milk. The titers also correlated well to the anti-spike and anti-RBD IgG1 and IgG3 titers in serum, to the anti-spike IgG1 in serum and breastmilk, and to IgG3 and IgA in breast milk.
No association was noted between the serum antibody titers and chronic morbidities in pregnancy.
What are the implications?
The study shows the robust and comparable IgG response to the presence of the vaccine antigen, markedly higher compared to that elicited by a natural infection in pregnancy. The booster dose further increased serum IgG levels, allowing its transfer to the newborn via both breast milk and placenta.
The lack of a similar boost for IgM is attributed to the class switching to IgG. However, the IgA titers failed to show a rise, perhaps because of the intramuscular route. The Moderna vaccine induced a higher IgA titer, perhaps because the longer dose interval allowed more powerful boosting of the immune response.
IgG transfer to breast milk increased after the booster dose, but not the IgA, thus ensuring the newborn receives high IgG levels in breast milk. With natural infections, however, the IgA response dominates in breast milk. This is probably due to the difference in the route of exposure, since natural immunity is the result of mucosally-acquired infection.
More research will show which of these is more efficient in protecting the newborn via breast milk. The timing of maternal vaccination to optimize neonatal protection is also an issue to be determined.
Meanwhile, the safety of vaccination during pregnancy is a reassuring finding, echoing the findings of the US Center for Disease (CDC), based on data acquired by the V-safe app. However, the high fever occurrence is a concerning finding, as it is associated with congenital anomalies in the first trimester.
Thus, mRNA vaccination results in robust vaccine-induced immunity during pregnancy that may provide critical protection to this vulnerable and unique population of mother:infant dyads.”
Future research on the potential risk to the fetus will complement these findings to develop evidence-based guidelines on COVID-19 vaccination, especially using different platforms, in pregnancy.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.