Antibodies targeting HSV glycoprotein B require effector functions to protect neonatal mice

Glycoprotein B (gB) serves as the viral fusion protein for herpes simplex virus (HSV), mediating fusion between viral and host membranes resulting in infection. As such, gB represents a critical target for the host immune system with high potential relevance for vaccine design. Here, we investigated the mechanisms of protection for a panel of gB-specific monoclonal antibodies (mAbs) in a mouse model of neonatal HSV (nHSV) infection. Depending on dose, viral neutralization contributed, but Fc effector functions were critical for mAb-mediated protection against nHSV mortality. Moreover, adeno-associated virus-mediated <i>in vivo</i> expression of a gB-specific mAb in mice provided transgenerational protection against HSV-1 and HSV-2 mortality. These findings demonstrate that antibodies targeting gB can serve as potent therapeutics and that they require diverse functional profiles to afford optimal protection, informing vaccine design.IMPORTANCEAntibodies represent promising drugs for the prevention and treatment of viral infections, especially when efficacious vaccines are unavailable. Determining the dominant mechanisms of Ab-mediated protection is a critical step in the design and optimization of potential antibody therapies. In this study of antibody-mediated protection of neonatal mice from herpes simplex virus, efficacy and mechanism of action of antibodies that recognize viral glycoprotein B (gB) were dependent on dose, effector functions, and viral neutralization capacity. Overall, while viral neutralization likely contributes to monoclonal antibody-mediated protection, the ability for gB-specific antibodies to mediate Fc domain-dependent effector functions was unexpectedly crucial.