Abstract
Multiple failed herpes simplex virus (HSV) vaccine candidates induce robust neutralizing antibody (Ab) responses in clinical trials, raising the hypothesis that Fc-domain-dependent effector functions may be critical for protection. While neonatal HSV (nHSV) infection results in mortality and lifelong neurological morbidity in humans, it is uncommon among neonates with a seropositive birthing parent, supporting the hypothesis that Ab-based therapeutics could protect neonates from HSV. We therefore investigated the mechanisms of monoclonal Ab (mAb)-mediated protection in a mouse model of nHSV infection. For a panel of glycoprotein D (gD)-specific mAbs, neutralization and effector functions contributed to nHSV-1 protection. In contrast, effector functions alone were sufficient to protect against nHSV-2, exposing a functional dichotomy between virus types consistent with vaccine trial results. Effector functions are therefore crucial for protection by these gD-specific mAbs, informing effective Ab and vaccine design and demonstrating the potential of polyfunctional Abs as therapeutics for nHSV infections.