ABSTRACT
Significant immunological changes occur throughout pregnancy to tolerize the mother and allow growth of the fetal graft. However, additional local and systemic immunological adaptations also occur, allowing the maternal immune system to continue to protect the dyad against foreign invaders both during pregnancy and after birth through lactation. This fine balance of tolerance and immunity, along with physiological and hormonal changes, contribute to increased susceptibility to particular infections in pregnancy, including more severe COVID-19 disease. Whether these changes also make pregnant women less responsive to vaccination or induce altered immune responses to vaccination remains incompletely understood. To holistically define potential changes in vaccine response during pregnancy and lactation, we deeply profiled the humoral vaccine response in a group of pregnant and lactating women and non-pregnant age-matched controls. Vaccine-specific titers were comparable, albeit slightly lower, between pregnant and lactating women, compared to non-pregnant controls. Among pregnant women, we found higher antibody titers and functions in those vaccinated with the Moderna vaccine. FcR-binding and antibody effector functions were induced with delayed kinetics in both pregnant and lactating women compared to non-pregnant women. Antibody boosting resulted in high FcR-binding titers in breastmilk. These data point to an immune resistance to generate highly inflammatory antibodies during pregnancy and lactation, and a critical need to follow prime/boost timelines in this vulnerable population to ensure full immunity is attained.
Subject(s)
COVID-19ABSTRACT
Background: Sex differences in vulnerability to and severity of SARS-CoV-2 infection have been described in non-pregnant populations. ACE2 and TMPRSS2, host molecules required for viral entry, are regulated by sex steroids and expressed in the placenta. We sought to investigate whether placental ACE2 and TMPRSS2 expression vary by fetal sex and in the presence of maternal SARS-CoV-2 infection. Methods: Placental ACE2 and TMPRSS2 were quantified in 68 pregnant individuals (38 SARS-CoV-2 positive, 30 SARS-CoV-2 negative) delivering at Mass General Brigham from April to June 2020. Maternal SARS-CoV-2 status was determined by nasopharyngeal RT-PCR. Placental SARS-CoV-2 viral load was quantified. RTqPCR was performed to quantify expression of ACE2 and TMPRSS2 relative to the reference gene YWHAZ. Western blots were performed on placental homogenates to quantify protein levels. The impact of fetal sex and SARS-CoV-2 exposure on ACE2 and TMPRSS2 expression was analyzed by 2-way ANOVA. Results: SARS-CoV-2 virus was undetectable in all placentas. Maternal SARS-CoV-2 infection impacted TMPRSS2 placental gene and protein expression in a sexually dimorphic fashion (2-way ANOVA interaction p-value: 0.002). We observed no impact of fetal sex or maternal SARS-CoV-2 status on placental ACE2 gene or protein expression. Placental TMPRSS2 expression was significantly correlated with ACE2 expression in males (Spearman's rho=0.54, p=0.02) but not females (rho=0.23, p=0.34) exposed to maternal SARS-CoV-2. Conclusions: Sex differences in placental TMPRSS2 but not ACE2 were observed in the setting of maternal SARS-CoV-2 infection. These findings may have implications for offspring vulnerability to placental infection and vertical transmission.These findings may have implications for offspring vulnerability to placental infection and vertical transmission.
Subject(s)
COVID-19ABSTRACT
There is a persistent male bias in the prevalence and severity of COVID-19 disease. Underlying mechanisms accounting for this sex difference remain incompletely understood. Interferon responses have been implicated as a modulator of disease in adults, and play a key role in the placental anti-viral response. Moreover, the interferon response has been shown to alter Fc-receptor expression, and therefore may impact placental antibody transfer. Here we examined the intersection of viral-induced placental interferon responses, maternal-fetal antibody transfer, and fetal sex. Placental interferon stimulated genes (ISGs), Fc-receptor expression, and SARS-CoV-2 antibody transfer were interrogated in 68 pregnancies. Sexually dimorphic placental expression of ISGs, interleukin-10, and Fc receptors was observed following maternal SARS-CoV-2 infection, with upregulation in males. Reduced maternal SARS-CoV-2-specific antibody titers and impaired placental antibody transfer were noted in pregnancies with a male fetus. These results demonstrate fetal sex-specific maternal and placental adaptive and innate immune responses to SARS-CoV-2.
Subject(s)
COVID-19ABSTRACT
BackgroundPregnant and lactating women were excluded from initial COVID-19 vaccine trials; thus, data to guide vaccine decision-making are lacking. We sought to evaluate the immunogenicity and reactogenicity of COVID-19 mRNA vaccination in pregnant and lactating women. Methods131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant) were enrolled in a prospective cohort study at two academic medical centers. Titers of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131), umbilical cord sera (N=10), and breastmilk (N=31) at baseline, 2nd vaccine dose, 2-6 weeks post 2nd vaccine, and delivery by Luminex, and confirmed by ELISA. Titers were compared to pregnant women 4-12 weeks from native infection (N=37). Post-vaccination symptoms were assessed. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups. ResultsVaccine-induced immune responses were equivalent in pregnant and lactating vs non-pregnant women. All titers were higher than those induced by SARS-CoV-2 infection during pregnancy. Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. SARS-CoV-2 specific IgG, but not IgA, increased in maternal blood and breastmilk with vaccine boost. No differences were noted in reactogenicity across the groups. ConclusionsCOVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Vaccine-induced immune responses were significantly greater than the response to natural infection. Immune transfer to neonates occurred via placental and breastmilk.