A genital tract peptide epitope vaccine targeting TLR-2 efficiently induces local and systemic CD8+ T cells and protects against herpes simplex virus type 2 challenge

Abstract

The next generation of needle-free mucosal vaccines is being rationally designed according to rules that govern the way in which the epitopes are recognized by and stimulate the genital mucosal immune system. We hypothesized that synthetic peptide epitopes extended with an agonist of Toll-like receptor 2 (TLR-2), that are abundantly expressed by dendritic and epithelial cells of the vaginal mucosa, would lead to induction of protective immunity against genital herpes. To test this hypothesis, we intravaginally (IVAG) immunized wild-type B6, TLR-2 (TLR2 −/−) or myeloid differentiation factor 88 deficient (MyD88 −/−) mice with a herpes simplex virus type 2 (HSV-2) CD8 + T-cell peptide epitope extended by a palmitic acid moiety (a TLR-2 agonist). IVAG delivery of the lipopeptide generated HSV-2-specific memory CD8 + cytotoxic T cells both locally in the genital tract draining lymph nodes and systemically in the spleen. Moreover, lipopeptide-immunized TLR2 −/− and MyD88 −/− mice developed significantly less HSV-specific CD8 + T-cell response, earlier death, faster disease progression, and higher vaginal HSV-2 titers compared to lipopeptide-immunized wild-type B6 mice. IVAG immunization with self-adjuvanting lipid-tailed peptides appears to be a novel mucosal vaccine approach, which has attractive practical and immunological features.

CXCL10/CXCR3-Dependent Mobilization of Herpes Simplex Virus-Specific CD8 + T EM and CD8 + T RM Cells within Infected Tissues Allows Efficient Protection against Recurrent Herpesvirus Infection and Disease

“…Work from our laboratory and others has shown that the CD8 ϩ T cells are critical for protection against recurrent ocular herpesvirus infection and disease (23,24,39). However, the relative contribution of each of the CD8 ϩ T cell subpopulations in protection against recurrent herpes has not been reported.…”

“…To the best of our knowledge, this is the first report that demonstrates a crucial role for both the CD8 ϩ T EM and CD8 ϩ T RM cell subpopulations, but not the CD8 ϩ T CM subpopulation, in protection against recurrent herpesvirus infection and disease. Thus, based on these new findings, a worthy goal of a herpes immunotherapeutic vaccine should be to develop a vaccine strategy that would generate and maintain a sufficient number of antiviral memory CD8 ϩ T EM and CD8 ϩ T RM cells within peripheral tissues, such as latently infected TG, the root of virus reactivation that leads to virus shedding and recurrent ocular herpetic disease (23)(24)(25)(26). However, this goal remains unattainable because the TG appear to be a "closed immunological compartment" to accepting homing of conventional circulating memory CD8 ϩ T cell subpopulations such as the CD8 ϩ T EM cells that could be migrating into latently infected TG from the neighboring draining lymph nodes through the circulation system (14,43).…”

“…Data for each assay were compared by analysis of variance (ANOVA) and unpaired t test using Graph Pad Prism 5 software (San Diego, CA). Differences between the groups were identified using unpaired t test, multiple comparison Mann-Whitney test and two-tail analyses, as we previously described (23). Data are expressed as means Ϯ standard deviations (SD).…”

Comparison of the Host Immune Response to Herpes Simplex Virus 1 (HSV-1) and HSV-2 at Two Different Mucosal Sites

“…Whereas it was previously suggested that oral and genital infections were primarily associated with HSV-1 and HSV-2, respectively, an increase in the incidence of genital HSV-1 infection has been seen over the past 20 years (4,9,16,18,29). As a result of the clinical significance of the pathogens in terms of prevalence and morbidity, a number of investigative teams have developed vaccines to HSV-1 or HSV-2, some of which have been evaluated against HSV-1 and/or HSV-2 (2,5,11,15,20,22,26,32,33,41). While sequence conservation is widely appreciated for HSV-1-and HSV-2-related genes, side-by-side comparisons of the immune responses to these pathogens in the eye or genital tract have not been extensively studied.…”

Topical Herpes Simplex Virus 2 (HSV-2) Vaccination with Human Papillomavirus Vectors Expressing gB/gD Ectodomains Induces Genital-Tissue-Resident Memory CD8+T Cells and Reduces Genital Disease and Viral Shedding after HSV-2 Challenge

“…A variety of HSV-2 vaccine approaches have shown protective efficacy in animal models, including live attenuated, nonreplicating viral vector, subunit, or DNA vaccines (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). Recombinant soluble HSV-2 glycoprotein D (gD) combined with an aluminum salt and monophosphoryl lipid A adjuvant (alum-MPL) has been the most promising recent vaccine to undergo extensive clinical evaluation.…”