Recombinant Vesicular Stomatitis Virus Vectors Expressing Herpes Simplex Virus Type 2 gD Elicit Robust CD4⁺Th1 Immune Responses and Are Protective in Mouse and Guinea Pig Models of Vaginal Challenge

Abstract

Recombinant vesicular stomatitis virus (rVSV) vectors offer an attractive approach for the induction of robust cellular and humoral immune responses directed against human pathogen target antigens. We evaluated rVSV vectors expressing full-length glycoprotein D (gD) from herpes simplex virus type 2 (HSV-2) in mice and guinea pigs for immunogenicity and protective efficacy against genital challenge with wild-type HSV-2. Robust Th1-polarized anti-gD immune responses were demonstrated in the murine model as measured by induction of gD-specific cytotoxic T lymphocytes and increased gamma interferon expression. The isotype makeup of the serum anti-gD immunoglobulin G (IgG) response was consistent with the presence of a Th1-CD4 ؉ anti-gD response, characterized by a high IgG2a/IgG1 IgG subclass ratio. Functional anti-HSV-2 neutralizing serum antibody responses were readily demonstrated in both guinea pigs and mice that had been immunized with rVSV-gD vaccines. Furthermore, guinea pigs and mice were prophylactically protected from genital challenge with high doses of wild-type HSV-2. In addition, guinea pigs were highly protected against the establishment of latent infection as evidenced by low or absent HSV-2 genome copies in dorsal root ganglia after virus challenge. In summary, rVSV-gD vectors were successfully used to elicit potent anti-gD Th1-like cellular and humoral immune responses that were protective against HSV-2 disease in guinea pigs and mice.Herpes simplex virus type 2 (HSV-2) infections remain a serious public health problem worldwide. HSV-2 genital lesions are not only painful and disfiguring but also facilitate the transmission of human immunodeficiency virus (HIV) (7). The seroprevalence in the United States has increased by 30% between 1976 and 1994, and roughly one of every five people over the age of 12 in the United States is infected with HSV-2 (15). Individuals latently infected with HSV-2 remain infected for life and can exhibit asymptomatic viral shedding. It is therefore believed that, without intervention, such as the development of prophylactic and/or therapeutic HSV-2 vaccines, HSV-2 prevalence will continue to rise in the future.Small experimental animal vaginal challenge models in mice and guinea pigs have been used for preclinical evaluation of a number of HSV-2 vaccine strategies, including subunit vaccines (gB and/or gD with or without interleukin-12 [IL-12]), plasmid HSV DNA vaccines (gD and/or gB with or without cytokine DNA (IL-2, IL-4, IL-10, IL-12, IL-15, or IL-18), attenuated HSV-2 vaccines (TKϪ, BlacZ, dl5-29, RAV 9395, ICP10⌬PK, or AD472), and virus-vectored HSV-2 vaccines (adenovirus, varicella-zoster virus, or vaccinia virus) (1,9,12,17,21,22, 34, 39, 40,45,60,62,66). Various degrees of success have been achieved in these preclinical studies, but limited success has carried over to the clinical setting, where the experience with HSV-2 subunit vaccines has had mixed results (10). Nonetheless, an adjuvanted gD subunit approach has achieved some success in early clinical trials...

Rapid Pathogenesis Induced by a Vesicular Stomatitis Virus Matrix Protein Mutant: Viral Pathogenesis Is Linked to Induction of Tumor Necrosis Factor Alpha

“…It should be noted that there is no induction of weight loss by rwtVSV given intranasally to rhesus macaques (21) or guinea pigs (12). Weight loss is therefore clearly a speciesspecific phenomenon and even differs among mouse strains.…”

Pan-HSV-2 IgG Antibody in Vaccinated Mice and Guinea Pigs Correlates with Protection against Herpes Simplex Virus 2

“…Previous attempts to identify correlates of immunity to HSV-2 have focused on immune responses to the immunogens under study; namely, gB and/or gD [1]–[7], [13], [75]. These approaches do not consider HSV-2's full complement of antigens.…”

Requirement for CD4 T Cell Help in Maintenance of Memory CD8 T Cell Responses Is Epitope Dependent

“…3 expressing appropriate foreign Ags have been used to generate effective experimental vaccines protecting against infection or disease caused by multiple viral pathogens including an SIV-HIV hybrid causing AIDS in rhesus macaques (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11). The VSV-based HIV vaccine developed in our laboratory has protected macaques from AIDS for up to 5 years postchallenge, but it does not generate sterilizing immunity (10).…”