Linking Humoral Immunity to Protective Herpes Simplex Viral Vaccines: Is Sterilizing Immunity Achievable?
Petro, Christopher Daniel
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Human herpes simplex viruses (HSV) type 1 and type 2 are a continued global burden with worldwide HSV-2 prevalence >500 million. Furthermore, epidemiological studies consistently demonstrate that HSV-2 is associated with an increased risk of acquiring and transmitting HIV-1. Currently, there is no effective cure or vaccine against HSV infection.;Past HSV vaccines focused on subunit formulations designed to elicit neutralizing antibodies targeting the envelope glycoprotein D (gD). While these vaccines elicited high levels of neutralizing antibodies in animals and humans, they failed to protect against HSV-2 infections in clinical trials. This lack of correlation between neutralizing Abs and HSV protection led to the hypothesis that a vaccine that elicits multi-functional antibodies engaging Fcgamma-receptors may provide greater protection than neutralization alone, serving as an immune-correlate. To test this hypothesis we 1) genetically engineered HSV virions as a live single-cycle viral vaccine deleted in gD and assessed this vaccine to generate Fc effector antibodies and efficacy against murine HSV infections, and 2) characterizing the functionality of local HSV antibodies from a cohort of HSV and HSV/HIV infected individuals that can control outbreaks (asymptomatic) vs individuals that cannot (symptomatic).;We first engineered an HSV-2 virus deleted for gD (DeltagD -2). Subcutaneous immunization of mice with DeltagD-2 provided 100% protection against lethal challenges of clinical HSV-1 and HSV-2 isolates as well as prevented the establishment of latency. Notably, mice immunized with HSV-2 DeltagD-2 elicited high HSV-specific antibodies that were weakly neutralizing but possessed antibody-dependent-cellular cytotoxicity and phagocytosis functions. Passive transfer of Deltag D-2 immune serum completely protected wild-type, but not Fcgamma-receptor knock-out mice. Secondly, when measuring mucosal HSV specific antibodies from clinically asymptomatic vs symptomatic individuals, we observed a marked difference in neutralization in asymptomatic individuals compared to symptomatic individuals. When isotyped, asymptomatic individuals had elevated IgG3 HSV specific antibodies which are consistent with antibodies that can engage Fcgamma-receptors.;These studies challenge the dogma that neutralizing antibodies are crucial for HSV containment. We show that non-neutralizing Fc effector activating antibodies can be used as a surrogate marker for immunity as seen in mice via vaccination and in clinical samples.