Blocking Herpes Simplex Virus 2 Glycoprotein E Immune Evasion as an Approach To Enhance Efficacy of a Trivalent Subunit Antigen Vaccine for Genital Herpes

Abstract

Herpes simplex virus 2 (HSV-2) subunit antigen vaccines targeting virus entry molecules have failed to prevent genital herpes in human trials. Our approach is to include a virus entry molecule and add antigens that block HSV-2 immune evasion. HSV-2 glycoprotein C (gC2) is an immune evasion molecule that inhibits complement. We previously reported that adding gC2 to gD2 improved vaccine efficacy compared to the efficacy of either antigen alone in mice and guinea pigs. Here we demonstrate that HSV-2 glycoprotein E (gE2) functions as an immune evasion molecule by binding the IgG Fc domain. HSV-2 gE2 is synergistic with gC2 in protecting the virus from antibody and complement neutralization. Antibodies produced by immunization with gE2 blocked gE2-mediated IgG Fc binding and cell-to-cell spread. Mice immunized with gE2 were only partially protected against HSV-2 vaginal challenge in mice; however, when gE2 was added to gC2/gD2 to form a trivalent vaccine, neutralizing antibody titers with and without complement were significantly higher than those produced by gD2 alone. Importantly, the trivalent vaccine protected the dorsal root ganglia (DRG) of 32/33 (97%) mice between days 2 and 7 postchallenge, compared with 27/33 (82%) in the gD2 group. The HSV-2 DNA copy number was significantly lower in mice immunized with the trivalent vaccine than in those immunized with gD2 alone. The extent of DRG protection using the trivalent vaccine was better than what we previously reported for gC2/gD2 immunization. Therefore, gE2 is a candidate antigen for inclusion in a multivalent subunit vaccine that attempts to block HSV-2 immune evasion. IMPORTANCEHerpes simplex virus is the most common cause of genital ulcer disease worldwide. Infection results in emotional distress for infected individuals and their partners, is life threatening for infants exposed to herpes during childbirth, and greatly increases the risk of individuals acquiring and transmitting HIV infection. A vaccine that prevents genital herpes infection will have major public health benefits. Our vaccine approach includes strategies to prevent the virus from evading immune attack. Mice were immunized with a trivalent vaccine containing an antigen that induces antibodies to block virus entry and two antigens that induce antibodies that block immune evasion from antibody and complement. Immunized mice demonstrated no genital disease, and 32/33 (97%) animals had no evidence of infection of dorsal root ganglia, suggesting that the vaccine may prevent the establishment of latency and recurrent infections. T he efficacy of the herpes simplex virus 2 (HSV-2) glycoprotein D (gD2) subunit antigen vaccine for prevention of genital herpes was evaluated in three large human trials (1, 2). In 2002, the first two trials reported that the gD2 vaccine prevented HSV-2 genital disease in HSV-1/HSV-2-seronegative women; however, this result was not reproduced in the 2012 Herpevac trial for women that showed gD2 vaccine efficacy in preventing genital disease caused by HSV-1 but n...

An HSV-2 Trivalent Vaccine Is Immunogenic in Rhesus Macaques and Highly Efficacious in Guinea Pigs

“…We next evaluated whether antibodies induced by the trivalent vaccine block the interaction between gE2 and the IgG Fc domain. Blocking by rhesus nonimmune IgG obtained prior to the first immunization was set at a relative value of 1.0 to distinguish blocking mediated by immune IgG (binds to gE2 at a higher affinity by the F(ab’) 2 than by the Fc domain) and nonimmune IgG (binds to gE2 only by the lower affinity Fc domain) [10, 25]. IgG obtained prior to immunization (pre-immune) and after the fourth immunization of the trivalent vaccine at week 40 was evaluated at concentrations of 0, 50, 100 and 200ng/μl.…”

“…It is possible that antibody-dependent cellular cytotoxicity contributed significantly to vaccine protection as reported for HSV-2 ΔgD2, a gD2 null live virus vaccine [41, 42]. Alternatively, blocking cell-to-cell spread mediated by antibodies to gE2, or enhanced antigen presentation facilitated by blocking the interaction of gC2 with C3b may account for the improved protection by the trivalent vaccine [10, 21]. Additional studies will be required to assess the immune correlates of protection mediated by the trivalent vaccine.…”

“…Genital herpes increases transmission and acquisition of HIV-1 infection by 3- to 4-fold, and poses a risk of 3 per 100,000 live births that infants will develop neonatal herpes during delivery with a mortality of 19% [3–7]. Genital herpes infection is emotionally upsetting for many individuals based on concerns of transmission to their partners [8–10]. A vaccine for genital herpes is urgently needed, yet none is available.…”

“…HSV-1 and HSV-2 glycoprotein E (gE) function as immune evasion molecules by binding the Fc domain of an IgG molecule that is bound by its F(ab’) 2 domain to its target [10, 25]. A vaccine containing gE2 subunit antigen produces antibodies that bind to gE2 and block its immune evasion functions [10].…”

“…A vaccine containing gE2 subunit antigen produces antibodies that bind to gE2 and block its immune evasion functions [10]. HSV-2 gC2 and gE2 perform activities similar to mammalian complement and IgG Fc regulatory proteins, yet share no sequence homology with mammalian receptors, which suggests virtually no risk that immunization will induce autoimmunity [26].…”