A trivalent gC2/gD2/gE2 vaccine for herpes simplex virus generates antibody responses that block immune evasion domains on gC2 better than natural infection.

•Our goal is to produce antibodies to immune evasion domains through immunization.•Antibodies produced by HSV infection bind gC2 yet do not block gC2 binding to C3b.•Antibodies produced by immunization bind gC2 and prevent C3b from binding.•Immunizing infected animals produces gC2 antibodies that prevent C3b from binding.•Vaccines make the weakly immunogenic immune evasion domains of gC2 more immunogenic.