ABSTRACT
The SARS-CoV-2 virus activates maternal and placental immune responses, which in the setting of other infections occurring during pregnancy are known to impact fetal brain development. The effects of maternal immune activation on neurodevelopment are mediated at least in part by fetal brain microglia. However, microglia are inaccessible for direct analysis, and there are no validated non-invasive surrogate models to evaluate in utero microglial priming and function. We have previously demonstrated shared transcriptional programs between microglia and Hofbauer cells (HBCs, or fetal placental macrophages) in mouse models. Here, we assessed the impact of maternal SARS-CoV-2 on HBCs isolated from term placentas using single-cell RNA-sequencing. We demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells, with altered morphology and impaired synaptic pruning behavior compared to HBC models from negative controls. These findings suggest that HBCs isolated at birth can be used to create personalized cellular models of offspring microglial programming.
ABSTRACT
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.