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.

Abstract

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) CD8T-cell peptide epitopes and 3 CD4T-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 CD8and CD4T 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 (10GC/ eye) encoding for the 10 CD8T-cell peptide and 4 CD4T-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 CD8T 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 CD8T cells that infiltrated the TG. In ocularly HSV-1-infected and prime/pull/keep vaccinated rabbits, CD8T 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 CD8and CD4T-cell epitope peptides (prime)/ CXCL11 (pull)/ IL-2/IL-15 (keep) AAV8-based vaccine triggered mobilization and retention of HSV-1-specific CD8T cells locally in the cornea and TG, the sites of acute and latent herpes infections. Mobilization and retention of antiviral CD8T 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 CD8T cells within infected tissues.