Abstract
Subunit vaccines comprised of glycoprotein D (gD-2) failed to prevent HSV-2 highlighting need for novel strategies. To test the hypothesis that deletion of gD-2 unmasks protective antigens, we evaluated the efficacy and safety of an HSV-2 virus deleted in gD-2 and complemented allowing a single round of replication on cells expressing HSV-1 gD (ΔgD(-/+gD-1)). Subcutaneous immunization of C57BL/6 or BALB/c mice with ΔgD(-/+gD1) provided 100% protection against lethal intravaginal or skin challenges and prevented latency. ΔgD(-/+gD1) elicited no disease in SCID mice, whereas 1000-fold lower doses of wild-type virus were lethal. HSV-specific antibodies were detected in serum (titer 1:800,000) following immunization and in vaginal washes after intravaginal challenge. The antibodies elicited cell-mediated cytotoxicity, but little neutralizing activity. Passive transfer of immune serum completely protected wild-type, but not Fcγ-receptor or neonatal Fc-receptor knock-out mice. These studies demonstrate that non-neutralizing Fc-mediated humoral responses confer protection and support advancement of this attenuated vaccine.
Highlights
Herpes simplex viruses (HSV) are major global health problems
We found that a live attenuated virus deleted in HSV serotype 2 (HSV-2) gD protects mice from vaginal, skin, and neuronal disease
We observed no evidence of neurological disease in any model and could not detect virus in dorsal root ganglia (DRG) of vaccinated mice by ex vivo plaque assays or by qPCR with a lower limit of detection of three viral genomes
Summary
Herpes simplex viruses (HSV) are major global health problems. HSV serotype 1 (HSV-1) is associated primarily with oral mucocutaneous disease, sporadic encephalitis, and is a leading cause of corneal blindness worldwide, whereas HSV serotype 2 (HSV-2) is the leading cause of genital ulcerative disease and a major cofactor in fueling the HIV epidemic (Gray et al, 2001; Wald and Link, 2002; Freeman et al, 2006). Gonzalez et al have developed a new potential vaccine that contains live attenuated HSV-2, which completely lacks glycoprotein D and cannot spread from cell-to-cell. When this weakened virus was administered to mice that have a poor immune system, the mice remained healthy. Petro, Gonzalez et al showed that blood serum from immunized mice could be used to completely protect other mice from exposure to wild-type virus These results demonstrate that a live attenuated HSV-2 virus that lacks glycoprotein D (the main component of other failed vaccines) elicits a different type of immune response and is a safe and effective vaccine in mouse models of virus infection. Adoptive transfer experiments showed that protection was mediated by antibodies (Abs) and required both the Fcγ receptor and neonatal Fc receptor (FcRn)
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