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

Abstract

A genital herpes vaccine is urgently needed to prevent pain and suffering, reduce the incidence of neonatal herpes, and decrease the risk of HIV acquisition and transmission that accompanies genital infection. We evaluated a trivalent HSV-2 subunit antigen vaccine administered with CpG and alum in rhesus macaques and guinea pigs. The vaccine contains glycoproteins C, D and E (gC2, gD2, gE2) to block virus entry by gD2 and immune evasion by gC2 and gE2. In rhesus macaques, the trivalent vaccine induced plasma and mucosa neutralizing antibodies, antibodies that block gC2 and gE2 immune evasion activities, and stimulated CD4 T cell responses. After intravaginal challenge, a self-limited vaginal infection of brief duration was detected by histopathology and immunohistochemistry in naïve, but not in trivalent immunized macaques. Vaccine efficacy was evaluated in female guinea pigs. Animals were mock immunized, or immunized with gD2, the trivalent vaccine or the trivalent vaccine followed by a booster dose of gD2 (trivalent + gD2). The trivalent and trivalent + gD2 groups were 97% and 99% efficacious, respectively in preventing genital lesions and both outperformed gD2 alone. As a marker of transmission risk, vaginal swabs were evaluated daily for HSV-2 DNA and replication competent virus between five and seven weeks after challenge. HSV-2 DNA shedding was reduced in all groups compared with mock. Shedding of replication competent virus occurred on fewer days in the trivalent than gD2 immunized animals while the trivalent + gD2 group had no shedding of replication competent virus. Overall, the trivalent group had genital lesions on < 1% days and shedding of replication competent virus on 0.2% days. The vaccine has outstanding potential for prevention of genital herpes in humans.

Maternal Antiviral Immunoglobulin Accumulates in Neural Tissue of Neonates To Prevent HSV Neurological Disease

“…However, the risk of using live vaccines in pregnancy is likely to be unacceptable at the regulatory level. It might be fruitful, therefore, to reconsider the use of polyvalent subunit, inactivated, or disabled infectious single-cycle (DISC) virus preparations in at-risk women for the protection of their babies from neonatal HSV ( 48 , 49 ).…”

A new era in cytomegalovirus vaccinology: considerations for rational design of next-generation vaccines to prevent congenital cytomegalovirus infection

“… 67 Given that the gD/AS04 subunit vaccine demonstrated no efficacy against HSV-2 in the Phase 3 field study 68 a variety of vaccines employing multiple antigenic targets (gC, gD, gE in combination) have been tested and have met with success in animal models of HSV pathogenesis. 69 – 71 Furthermore, Genocea Biosciences tested the GEN-003 vaccine containing both soluble gD and the ICP4.2 T-cell epitope in phase 2 trials, resulting in a measurable reduction in viral shedding (though comparable to valacyclovir drug therapy). 72 …”

Toll‐like receptors as novel therapeutic targets for herpes simplex virus infection

“…Nevertheless, there have been some positive clinical achievements. For example, in a recent preclinical study, an HSV2 trivalent subunit vaccine containing glycoproteins C, D, and E (gC2, gD2, and gE2) showed immunogenicity in rhesus macaques and displayed more than 97% efficacy in guinea pigs . Also, results from a phase III clinical trial study showed that a recombinant glycoprotein D vaccine, conferred approximately 74% prevention of genital HSV disease in women seronegative for both HSV serotypes …”