Baby's First Antibody: An Integrative Systems Approach to Define Regulatory Mechanisms of Placental Antibody Transfer Across Spatial and Temporal Scales

Infants are vulnerable to infections due to a limited ability to mount a humoral immune response and their tolerogenic immune phenotype, which has impeded the success of newborn vaccination. Transplacental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life, and maternal immunization has recently been implemented as a public health strategy to protect newborns against serious infections. Despite their early success, current maternal vaccines do not provide comparable protection across pregnancies with varying gestational length, placental, and maternal immune features, nor do they account for the dynamic interplay between the maternal immune response and placental transfer. Moreover, progress toward the rational design of maternal vaccines has been hindered by inadequacies of existing experimental models and safety challenges related to investigating longitudinal dynamics of IgG transfer in pregnant humans.
This dissertation investigates the key regulators of placental antibody transfer across spatial and temporal scales using integrative experimental, mechanistic, and data-driven modeling approaches. We developed the first mechanistic model of placental IgG transfer in humans to probe novel regulators of transfer efficiency and selectivity, revealing a key role for FcγRIIb expressed by placental endothelial cells as a regulator of subclass-specific IgG transfer. The model also predicted that the optimal Tdap administration window to maximize pertussis-specific antibody transfer to the fetus falls during the second trimester, earlier than the current public health guidelines in the U.S. but similar to the recommendations in Europe. To better define the complementary roles of FcRn and FcγRs in IgG transfer, we conducted a multiplex immunohistochemistry (mIHC) study of placental tissue from two human cohorts spanning first to third trimester. We uncovered consistent cell type-specific patterns of Fc receptor expression, colocalization, and their expression trajectories across pregnancy in both cohorts, pointing toward a window around 20 weeks gestational age when the global frequency of Fc receptor expression is highest and IgG transfer likely reaches its peak efficiency. Finally, we validated our model-driven hypothesis that FcγRIIb drives endothelial cell IgG transcytosis in vitro. Through a complementary mechanistic model of our experimental system, we identified two possible mechanisms of FcγRIIb-mediated transcytosis and distinct kinetic bottlenecks of each.
Ultimately, this work provides novel insights into the dynamic regulation of placental IgG transfer throughout gestation and supports the hypothesis that placental FcγRs co-regulate transfer together with FcRn. These findings hold broad implications for the optimization of prenatal vaccine timing and formulation to maximize immune protection for both mothers and newborns.