A tissue-targeted prime/pull/keep therapeutic herpes simplex virus vaccine protects against recurrent ocular herpes infection and disease in HLA-A*0201 transgenic rabbits.

UNLABELLED: Herpes simplex virus type 1 (HSV-1) continues to be one of the most prevalent viral infections globally, with approximately 3.72 billion individuals affected worldwide. A clinical herpes vaccine is still lacking. In the present study, a novel prime/pull/keep vaccine was tested in a human leukocyte antigen transgenic rabbit model of ocular herpes (HLA-A*0201 Tg rabbit). Ten asymptomatic (ASYMP) CD8+ T-cell peptide epitopes and 3 CD4+ T-cell epitopes were selected from the HSV-1 glycoproteins D and B (gD and gB), viral tegument proteins (VP11/12 and VP13/14), and the DNA replication-binding helicase (UL9), all preferentially recognized by CD8+ and CD4+ T cells from "naturally protected" HSV-1-seropositive healthy ASYMP individuals (who never had recurrent corneal herpetic disease). HLA Tg rabbits were ocularly infected with HSV-1, then during latency at day 30 post-infection, the rabbits were ocularly vaccinated with a recombinant neurotropic AAV8 vector (107GC/ eye) encoding for the 10 CD8+ T-cell peptide and 4 CD4+ T-cell peptide (prime), T-cell attracting CXCL-11 (pull), and T-cell keeping IL-2/IL-15 cytokines (keep). The rabbits were followed up for corneal disease and viral loads in tears for 28 days. The frequency, function, and protective efficacy of HSV-specific CD8+ T cells induced by the prime/pull/keep vaccine were assessed in the trigeminal ganglia (TG), cornea, spleen, and peripheral blood. Compared to the mock group (unvaccinated), the peptides/CXCL11/IL-2/IL-15 vaccine generated frequent resident CD8+ T cells that infiltrated the TG. In ocularly HSV-1-infected and prime/pull/keep vaccinated rabbits, CD8+ T cell mobilization and retention into TG were associated with a significant reduction in corneal herpes infection and disease. These findings draw attention to the novel prime/pull/keep therapeutic vaccine strategy to mobilize and retain antiviral T cells to tissues protecting them against herpetic infection and disease.

IMPORTANCE: There is an urgent need for a vaccine against widespread human herpes simplex virus infections. The present study demonstrates that immunization of humanized HLA-A*0201 transgenic rabbits with CD8+ and CD4+ T-cell epitope peptides (prime)/ CXCL11 (pull)/ IL-2/IL-15 (keep) AAV8-based vaccine triggered mobilization and retention of HSV-1-specific CD8+ T cells locally in the cornea and TG, the sites of acute and latent herpes infections. Mobilization and retention of antiviral CD8+ T cells into the cornea and TG of HSV-1-infected rabbits that received the prime/pull/keep vaccine was associated with protection against ocular herpes infection and disease. These results highlight the importance of the prime/pull/keep vaccine strategy to bolster the number and function of protective CD8+ T cells within infected tissues.