SARS-CoV-2 breakthrough infection during pregnancy preferentially elicits IgG4 response and enhanced placental-transfer

Background: Emerging SARS-CoV-2 variants and waning humoral immunity have led to increased occurrences of breakthrough infection. Pregnant individuals and neonates are particularly vulnerable to adverse outcomes associated with COVID-19. Objective: We aimed to evaluate the maternal anti-SARS-CoV-2 IgG response and the placental transfer of antibodies to the fetus following breakthrough infection, infection in unvaccinated participants, and vaccination in the absence of infection during pregnancy. Methods: Pregnant patients (n = 165) were enrolled at Oregon Health & Science University and assigned to three cohorts based on infection and vaccination status. Receptor-binding domain (RBD) and nucleocapsid protein (NP) specific IgG endpoint titers (EPT) and optical density (OD) values were determined via ELISA longitudinally in maternal blood and breastmilk, and at delivery in paired maternal, umbilical cord, and newborn blood. Results: Breakthrough infection in vaccinated participants induced a higher maternal RBD-specific IgG response compared to infection or vaccination alone in maternal plasma and breastmilk. As reported with repeated vaccination, breakthrough infection skewed RBD-specific IgG responses toward an IgG4 response. IgG1 and IgG3 were the dominant NP-specific subclasses for both breakthrough infection and unvaccinated/infection groups. The breakthrough infection cohort had the highest newborn-to-maternal ratio of RBD-specific IgG with a strong correlation between maternal and newborn delivery titers. Conclusion: Breakthrough infection during pregnancy prolongs pre-existing humoral immunity and facilitates the transplacental transfer of antibodies to the neonate, reflecting an antibody priming effect induced by prior vaccination rather than infection alone. These results warrant continued administration of updated SARS-CoV-2 vaccination during pregnancy to reduce disease severity and provide greater protection to newborns.