Mechanistic insights into the kinetics of Fc receptor-mediated placental antibody transfer to optimize maternal vaccine strategies - ABSTRACT Infants are vulnerable to infection due to their tolerogenic immune phenotype and limited adaptive immune memory, which has limited the success of newborn vaccines. Trans-placental transfer of immunoglobulin G (IgG) from mother to fetus provides crucial protection in the first weeks of life. As such, maternal immunization has been implemented as a public health strategy to protect infants against serious infections early in life. The neonatal Fc receptor (FcRn) plays a well- defined role by binding to IgG and transporting it across the placental syncytiotrophoblast to the stroma, which is followed by transport across the fetal capillary endothelium to the fetus, but emerging evidence suggests low-affinity Fc gamma receptors FcγRIIb and FcγRIIIa might co- regulate IgG transfer with FcRn. However, their role is less established and is often debated. As the placenta develops with pregnancy progression, IgG transfer efficiency dynamically evolves and fetal IgG concentrations at full-term pregnancy surpass maternal levels. Despite partial success of maternal vaccines in reducing the occurance of some neonatal infections, current vaccines do not provide comparable protection across pregnancies with varying gestational length, placental and maternal immune features. Progress in this field has been limited by stark inter-species differences in placental transfer confounding insights from rodent models, which is exacerbated by the important regulatory challenges of studies involving pregnant women. A mathematical mechanistic model of transplacental antibody transfer presents a novel alternative, which takes individual maternal and placental information and predicts antibody levels in the newborn. Our long-term goal is to realize the promise of personalized vaccines for mothers to maximally immunize newborns. To achieve this goal, in this application, we will (i) identify the key Fc receptors (FcR) and the mechanisms by which they mediate transfer through placental cellular layers, (ii) determine antibody Fc features that best synergize with these FcR kinetics such as IgG subclass and Fc N-glycosylation, and (iii) develop and validate a mechanistic model of IgG transfer that combines these insights toward an in silico vaccine testbed. Our in-silico testing platform will pave the way for rational design of vaccines, which is capable of saving tremendous effort and budget for vaccine clinical trials by avoiding predictable low-efficacy strategies.
