title: A heat shock protein based polyvalent vaccine targeting HSV-2: CD4(+) and CD8(+) cellular immunity and protective efficacy.
abstract: Efforts to develop a subunit vaccine against genital herpes have been hampered by lack of knowledge of the protective antigens of HSV-2, the causative agent of the disease. Vaccines based either on selected antigens or attenuated live virus approaches have not demonstrated meaningful clinical activity. We present here results of a therapeutic vaccine candidate, HerpV (formerly called AG-707), consisting of 32 HSV-2 peptides derived from 22 HSV-2 proteins, complexed non-covalently to the HSP70 chaperone and formulated with QS-21 saponin adjuvant. HerpV is observed to be immunogenic, generating CD4(+) and CD8(+) T cell responses in three mouse strains including HLA-A2 transgenic mice. Optimal T cell stimulation was dependent on the synergistic adjuvant properties of QS-21 with hsp70. The vaccine provided significant protection from viral challenge in a mouse prophylaxis model and showed signals of activity in a guinea pig therapeutic model of existing infection. Peripheral blood mononuclear cells from human HSV-2(+) subjects also showed reactivity in vitro to a subset of individual peptides and to the pool of all 32 peptides. Recombinant human Hsc70 complexed with the 32 peptides also stimulated the expansion of CD8(+) T cells from HSV-2(+) subjects in vitro. These studies demonstrate that HerpV is a promising immunotherapy candidate for genital herpes, and provide a foundation for evaluating HerpV in human HSV-2(+) subjects with the intent of eliciting CD4(+) and CD8(+) T cell responses to a broad array of viral antigens.
authors.affiliation: Agenus Inc., Lexington, MA, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Mo
authors.forename: Cristina
authors.initials: C
authors.lastname: Musselli
authors.forename: Hong
authors.initials: H
authors.lastname: Chen
authors.forename: John
authors.initials: J
authors.lastname: Pappas
authors.forename: Kenneth
authors.initials: K
authors.lastname: Leclair
authors.forename: Aston
authors.initials: A
authors.lastname: Liu
authors.forename: Roman M
authors.initials: RM
authors.lastname: Chicz
authors.forename: Alemseged
authors.initials: A
authors.lastname: Truneh
authors.forename: Stephen
authors.initials: S
authors.lastname: Monks
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Levey
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Srivastava
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004195:Disease Models, Animal; D006168:Guinea Pigs; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D022301:Herpes Simplex Virus Vaccines / Q000008:administration & dosage / Q000009:adverse effects* / Q000235:genetics / Q000276:immunology*; D018258:Herpesvirus 2, Human / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012503:Saponins / Q000008:administration & dosage; D022223:Vaccines, Subunit / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000276:immunology; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D015789:HLA-A2 Antigen; D050883:HSC70 Heat-Shock Proteins; C494371:HSPA8 protein, human; D022301:Herpes Simplex Virus Vaccines; D012503:Saponins; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D014764:Viral Proteins