ABSTRACT The fetal/neonatal period represents a unique period of vulnerability to viral infections. While Herpesviruses such as herpes simplex virus (HSV) are highly prevalent and typically non life-threatening infections among healthy adults, they are among the most consequential viral infections of early life. HSV infection during parturition or the early postnatal period results in disseminated disease or encephalitis in up to 50% of infected newbowns. Without treatment, mortality is high and an estimated 70% of surviving infants with central nervous system (CNS) involvement suffer long-term neurodevelopmental sequelae despite aggressive treatment with acyclovir. Fortunately, newborns in our pathogen-rich world inherit some of the protection provided by the maternal immune system in the form of transferred antibodies (Ab). For HSV, maternal Ab seropositivity, resulting in placental transfer of Ab capable of directly neutralizing virus and eliciting the diverse effector functions of the innate immune system, is associated with dramatically decreased risk of nHSV. There is no currently approved HSV vaccine whereby maternal Abs could be induced among seronegative mothers. As an alternative, our previous work has demonstrated that maternal Ab readily accesses neural tissues of the fetus and is sufficient to prevent nHSV. Preliminary data now demonstrate a novel mouse model system whereby we can model not only mortality and viral burden, but also behavioral pathologies that are frequent and lifelong in humans following nHSV. The central hypothesis of this proposal is that the development of effective vaccines and therapeutic antibodies for nHSV infections will benefit from careful in vivo and in vitro evaluation of antibody mechanism(s) of action. Presently, there is a critical gap in knowledge of the mechanisms whereby Ab-based interventions provide benefit in the context of nHSV infection, and how these interventions might be optimized in order to best prevent this devastating disease. Our objective is to define and refine the means by which monoclonal antibodies (mAbs) can be used to prevent or reduce nHSV morbidity and mortality. We hypothesize that while Ab effector functions contribute to direct neutralization activity, they are modulated by the viral Fc Receptor (vFcR), glycoprotein E (gE/gI complex). Guided by strong preliminary data, the project goals will be achieved though completion of two Specific Aims: 1) Define the mechanism(s) of action of mAbs that prevent nHSV, and 2) Define the role of the viral Fc receptor (gE/gI) in influencing antiviral mAb activity.