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Anthony Nesburn, Arif A Khan, Ruchi Srivastava, Steven Wechsler, Lbachir BenMohamed; Therapeutic Immunization with Herpes Simplex Virus Type 1 Glycoprotein D Derived “Asymptomatic” Human CD8+ T-cell Epitopes Protects Against Recurrent Ocular Herpetic in Latently Infected HLA Transgenic Rabbits: Correlation with low Frequency of Exhausted PD-1+TIM-3+CD8+ T Cells. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1855.
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© ARVO (1962-2015); The Authors (2016-present)
Most blinding ocular herpetic disease is due to reactivation of herpes simplex virus type 1 (HSV-1) from latency rather than to primary acute infection. No herpes simplex vaccine is currently available for use in humans. Past therapeutic vaccine clinical trials that used whole HSV glycoprotein D (gD) have failed to prevent herpetic disease.
In this study, we used the HLA-A*02:01 transgenic (HLA Tg) rabbit model of ocular herpes to assess the therapeutic efficacy of HSV-1 gD epitopes that are mainly recognized by CD8+ T cells from “naturally” protected HLA-A*02:01 positive, HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease). Three ASYMP CD8+ T cell epitopes (gD53-61, gD70-78 and gD278-286) were linked with a promiscuous CD4+ T-cell epitope (gD49-82) to create 3 separate pairs of CD4-CD8 peptides, which were then each covalently coupled to an Ne-palmitoyl-lysine moiety, a toll like receptor 2 (TLR-2) ligand. This resulted in the construction of 3 CD4-CD8 lipopeptide vaccines. Latently infected HLA-Tg rabbits were immunized with a mixture of these 3 ASYMP lipopeptide vaccines, delivered as eye drops in sterile PBS.
The therapeutic vaccine significantly reduced HSV-1 shedding detected in tears and reduced recurrent ocular herpetic disease. The protection was associated with: (i) a boost in the number and function of HLA-restricted HSV-1 gD-specific CD8+ T cells in draining lymph nodes (DLN), cornea, conjunctiva, and trigeminal ganglia (TG); and (ii) a decreased number of exhausted HSV-1 gD-specific PD-1+TIM-3+CD8+ T-cells.
The results underscore the potential of an ASYMPTOMATIC CD8+ T cell epitope-based therapeutic vaccine strategy against recurrent ocular herpetic disease.
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