Quantitative mechanistic model reveals key determinants of placental IgG transfer and informs prenatal immunization strategies

Abstract

Transplacental antibody transfer is crucially important in shaping neonatal immunity. Recently, prenatal maternal immunization has been employed to boost pathogen-specific immunoglobulin G (IgG) transfer to the fetus. Multiple factors have been implicated in antibody transfer, but how these key dynamic regulators work together to elicit the observed selectivity is pertinent to engineering vaccines for mothers to optimally immunize their newborns. Here, we present the first quantitative mechanistic model to uncover the determinants of placental antibody transfer and inform personalized immunization approaches. We identified placental FcγRIIb primarily expressed by endothelial cells as a limiting factor in this receptor-mediated transfer, which plays a key role in promoting preferential transport of subclasses IgG1, IgG3, and IgG4, but not IgG2. Integrated computational modeling and in vitro experiments reveal that IgG subclass abundance, Fc receptor (FcR) binding affinity, and FcR abundance in syncytiotrophoblasts and endothelial cells contribute to inter-subclass competition and potentially inter- and intra-patient antibody transfer heterogeneity. We utilize this model as an in silico immunization testbed, unveiling an opportunity for precision prenatal immunization approaches that account for a patient's anticipated gestational length, vaccine-induced IgG subclass, and placental FcR expression. By combining a computational model of maternal vaccination with this placental transfer model, we identified the optimal gestational age range for vaccination that maximizes the titer of antibody in the newborn. This optimum vaccination time varies with gestational age, placental properties, and vaccine-specific dynamics. This computational approach provides new perspectives on the dynamics of maternal-fetal antibody transfer in humans and potential avenues to optimize prenatal vaccinations that promote neonatal immunity.