(108) Unique maternal immunoproteomic signatures by trimester and in response to de novo mRNA vaccination

Use of COVID-19 mRNA vaccines in pregnant individuals presents a unique opportunity to define baseline trimester-specific immunoproteomic signatures, and to examine how de novo vaccines might perturb these signatures across trimesters (TMs).


Study Design:

The maternal proteome was profiled across TMs at baseline and in response to COVID-19 vaccination (vax) in 466 samples from 296 pregnant individuals, including 104 from 1st, 198 from 2nd, and 164 from 3^rd TM, using an aptamer-based proteomics assay. Maternal plasma samples were collected prevax/baseline (V0, N=182), 3-4 weeks after 1^stmRNA vax (V1, N=120) and 2-6 weeks after 2^nd mRNA vax (V2, N=164). Effects of TM, maternal age, BMI, and infant sex on protein expression were evaluated by a local inverse Simpson’s Index. Partial least squares discriminant analyses with regularization determined proteins best defining the TMs prevax. Generalized additive modeling (GAM) evaluated TM-specific responses to vaccination, and pathways analysis (IPA) inferred biological implications of differentially-expressed proteins by TM.


Results:

44 proteins distinguished baseline samples across TMs (Fig 1A/B). Variable of importance analysis identified top proteins that distinguished TMs prevax (Fig 1C). IPA analyses demonstrated that the 1^st TM was defined by mitogenesis, chemotaxis, and apoptotic signaling; 2^nd by pathways of NK- and T-cell survival and differentiation; and 3^rd by pro-inflammatory cytokine signaling, immunogenic cell death signaling, and nervous system development. GAM modeling demonstrated TM-specific responses to vaccination after both 1^st and 2^nd dose of mRNA vax (Fig 1D), including dysregulation of proteins involved in interferon, WNT and apoptosis signaling, and cell-cell adhesion.


Conclusion:

In normal pregnancy, trimesters were defined by a specific immunoproteomic signature. De novo mRNA vaccination altered expression of proteins in a trimester-specific manner. Enhanced understanding of how vaccines and other exposures alter the immune proteome by trimester may provide new opportunities to optimize maternal and neonatal health.