title: Targeting the genital tract mucosa with a lipopeptide/recombinant adenovirus prime/boost vaccine induces potent and long-lasting CD8+ T cell immunity against herpes: importance of MyD88.
abstract: Targeting of the mucosal immune system of the genital tract with subunit vaccines has failed to induce potent and durable local CD8(+) T cell immunity, which is crucial for protection against many sexually transmitted viral pathogens, including HSV type 2 (HSV-2), which causes genital herpes. In this study, we aimed to investigate the potential of a novel lipopeptide/adenovirus type 5 (Lipo/rAdv5) prime/boost mucosal vaccine for induction of CD8(+) T cell immunity to protect the female genital tract from herpes. The lipopeptide vaccine and the rAdv5 vaccine express the immunodominant HSV-2 CD8(+) T cell epitope (gB(498-505)), and both were delivered intravaginally in the progesterone-induced B6 mouse model of genital herpes. Compared with mice immunized with the homologous lipopeptide/lipopeptide (Lipo/Lipo) vaccine, the Lipo/rAdv5 prime/boost immunized mice 1) developed potent and sustained HSV-specific CD8(+) T cells, detected in both the genital tract draining nodes and in the vaginal mucosa; 2) had significantly lower virus titers; 3) had decreased overt signs of genital herpes disease; and 4) did not succumb to lethal infection (p < 0.005) after intravaginal HSV-2 challenge. Polyfunctional CD8(+) T cells, producing IFN-γ, TNF-α, and IL-2 and exhibiting cytotoxic activity, were associated with protection (p < 0.005). The protective CD8(+) T cell response was significantly compromised in the absence of the adapter MyD88 (p = 0.0001). Taken together, these findings indicate that targeting of the vaginal mucosa with a Lipo/rAdv5 prime/boost vaccine elicits a potent, MyD88-dependent, and long-lasting mucosal CD8(+) T cell protective immunity against sexually transmitted herpes infection and disease.
authors.affiliation: Laboratory of Cellular and Molecular Immunology, Gavin Herbert Eye Institute, School of Medicine, University of California Irvine, Irvine, CA 92697, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.forename: Xavier
authors.initials: X
authors.lastname: Dervillez
authors.forename: Aziz Alami
authors.initials: AA
authors.lastname: Chentoufi
authors.forename: Tina
authors.initials: T
authors.lastname: Badakhshan
authors.forename: Ilham
authors.initials: I
authors.lastname: Bettahi
authors.forename: Lbachir
authors.initials: L
authors.lastname: Benmohamed
mesh_terms: D062705:Adenovirus Vaccines / Q000008:administration & dosage* / Q000276:immunology; D000282:Administration, Intravaginal; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D005260:Female; D005836:Genitalia, Female / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D007111:Immunity, Cellular; D007117:Immunization, Secondary / Q000379:methods; D055666:Lipopeptides / Q000008:administration & dosage* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009092:Mucous Membrane / Q000276:immunology / Q000378:metabolism / Q000821:virology; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology*; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
chemical_list: D062705:Adenovirus Vaccines; D055666:Lipopeptides; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic