Antibody effector functions are required for broad and potent protection of neonates from herpes simplex virus infection.

The failure of multiple herpes simplex virus (HSV) vaccine candidates that induce neutralizing antibody responses raises the hypothesis that other activities, such as Fc domain-dependent effector functions, may be critical for protection. While neonatal HSV (nHSV) infection result in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, suggesting the potential efficacy of antibody-based therapeutics to protect neonates. We therefore investigated the mechanisms of monoclonal antibody (mAb)-mediated protection in a mouse model of nHSV infection. Both neutralization and effector functions contributed to robust protection against nHSV-1. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types that is consistent with vaccine trial results. Together, these results emphasize that effector functions are crucial for optimal mAb-mediated protection, informing effective Ab and vaccine design, and demonstrating the potential of polyfunctional Abs as potent therapeutics for nHSV infections.