Maternal proteome profiling reveals dynamic gestational age-specific responses to de novo vaccination

Pregnancy is characterized by dynamic immunological adaptations which are essential for maintaining both maternal and fetal health. The first-time use of coronavirus disease 2019 (COVID-19) vaccines in pregnant individuals presented an opportunity to discover pregnancy-specific immunoproteomic signatures across gestation. In this study, we profiled abundance levels of 1,451 unique proteins at baseline and in response to de novo COVID-19 vaccination in 466 samples from 278 pregnant individuals. Self-organizing map analysis identified 11 clusters of proteins based on similar longitudinal trajectories, with each cluster associated with distinct biological processes. Further functional characterization of protein expression levels across gestation revealed inflection points at 18-20 and 30-32 weeks of gestation, providing insight into expression dynamics of proteins associated with regulation of immune tolerance. Generalized additive modeling inferred gestational age-specific responses to the first and second dose of the vaccine; these highlight enrichment in proteins associated with cellular motility and canonical immune signaling after first and third trimester vaccination, but relative suppression of proteins associated with immune and inflammatory signal transduction pathways after second trimester vaccination consistent with diminished antibody responses when pregnant individuals are vaccinated exclusively in the second trimester. These findings advance our understanding of trimester-specific immune responses to vaccines, providing opportunities to enhance maternal and neonatal health.