For simplicity, the schematic represents bulk IgG transport, whereas the model includes separate equations for each IgG subclass. this placental transfer model using the tetanus, diphtheria, and acellular pertussis (Tdap) vaccine as a case study. Model simulations unveiled precision prenatal immunization opportunities that account for a patients anticipated gestational length, placental size, and FcR expression by modulating vaccine timing, dosage, and adjuvant. This computational approach provides new perspectives on the dynamics of maternal-fetal antibody transfer in MDS1-EVI1 humans and potential avenues to optimize prenatal vaccinations that promote neonatal immunity. Introduction Neonates are vulnerable to infections due to their tolerogenic immune phenotype; for the same reason, neonatal vaccinations have been met with limited success to date (1). To provide passive immunity while the neonatal immune system adapts to the environment and in mouse placenta (14,22,23). Though informative, the experimental methods underlying these findings do not capture the dynamic nature or time scale of placental antibody transport. To disentangle the involvement of non-canonical FcRs in IgG sieving, innovative methods that recapitulate the longitudinal dynamics of this fundamental process are needed. Placental antibody transfer can be leveraged by maternal prenatal vaccines which boost pathogen-specific IgG transport to the neonate (24). Identifying improved immunization strategies to maximize neonatal antibody titers is Exicorilant nontrivial. Placental growth and Exicorilant development dynamically regulating IgG transport coupled with known maternal immune adaptations during pregnancy together define a unique immunization design space which poses a challenge to empirical vaccine optimization by clinical trials alone (25). Predictive kinetic-dynamic modeling can be employed to rationally design vaccines that maximize IgG transfer to the neonate. The ability to Exicorilant make predictions of vaccine-induced antibody transfer would enable pre-clinical dosing strategy studies, expediting translation of novel therapeutics from bench to bedside. In the United States, expecting mothers are routinely vaccinated against tetanus, diphtheria, and acellular pertussis (Tdap) during the early third trimester (26), but emerging evidence suggests that this recommendation may not optimally protect the entire population. First, it has been shown that maternal Tdap immunization earlier in gestation results in higher pertussis toxin (PT)- and filamentous hemagglutinin (FHA)-specific IgG in infants regardless of gestational length (26C28). Second, current vaccination efforts are designed to elicit high antibody transfer to term neonates, yet third trimester immunization may not allot sufficient time for the mother to mount a humoral immune response and subsequently transfer antibodies to preterm neonates (28). Collectively, this evidence supports the potential for personalized vaccine approaches that account for factors such as maternal baseline IgG titer, immunization history, placental function, and risk of preterm delivery Exicorilant to maximize pathogen-specific IgG transfer to the neonate, especially among premature neonates. To uncover the molecular regulators of placental antibody transport and to inform the development of personalized immunization approaches, we developed the first computational model of human placental IgG transfer. In a case study on Tdap immunization, we use this model as an testbed for prenatal vaccine design and identify potential strategies to improve transfer of vaccine-induced antibodies, both at a patient-specific and population level. Ultimately, this model-driven Exicorilant investigation sheds light on the dynamic regulation of maternal-fetal IgG transfer and provides a foundation to develop precision vaccine approaches which promote neonatal immunity. Results Mechanistic model recapitulates IgG subclass-specific placental transfer To elucidate mechanisms of IgG transfer and selective sieving, we devised a dynamic model of IgG transplacental transfer. The model consists of ordinary differential equations (ODEs) describing IgG mass transport through the distinct layers comprising the maternal-fetal interface: STB FcRn-mediated transcytosis, diffusion through intervillous stroma, and EC FcRn- and FcRIIb-mediated transcytosis (Fig 1A) (see Appendix S1 for model equations). FcRn is widely implicated in placental.