Herpes Simplex Immunotherapeutic Targeting CD8 T cells

About This Grant

Project Summary Genital herpes (GH) is caused by herpes simplex virus (HSV) infection of epithelial cells, which leads to permanent infection of neurons in anatomically connected ganglia and then periodic recurrences with genital lesions, pain, live virus shedding, and potential transmission. Currently, GH is incurable. Responding to RFA- AI-24-068 “New Therapeutic Strategies for Genital Herpes”, we propose the optimization and advanced pre- clinical development of an immunotherapeutic to boost the levels and localization of HSV-specific T cells. This could lead to a functional cure. T cells are mobile cells the express hypervariable, specific surface T cell receptor (TCR) molecules, which, like antibody molecules, specifically bind short regions of HSV. We target T cell boosting for several reasons: T cell immune deficiency pre-disposes to severe GH, T cell candidates can be effective in animal models, and specific T cells can be programmed to traffic to infected sites and to persist at sites of HSV-2 epithelial lytic infection and ganglionic latency. Importantly, antibody-targeting GH immunotherapeutics have had low or no efficacy in clinical trials. T cells occur in two major types expressing the CD4 or CD8 surface co-receptor. The prior antibody-targeting GH products have elicited/boosted CD4 Th1 T cells. No data have been reported for a GH immunotherapeutic from a clinical trial using a format suitable for boosting CD8 T cells. In the 2025 competitive landscape, trials of the Moderna mRNA candidate that is somewhat CD8-targeting is underway. Based on our in-house data obtained during NIAID Large Scale Epitope Discovery contracts, we believe that we can improve on CD8 T cell human population coverage and HSV-1 cross-reactivity compared to this candidate. NIH and WHO preferred product profiles (PPP) prioritize covering HSV-2 and HSV-1. We have therefore defined several hundred CD8 T cell epitopes in HLA-diverse and therefore race/ethnicity-diverse persons and have designed a prototype poly-epitope “string of pearls” HSV-2 immunotherapeutic and performed initial in vitro/in vivo tests. Preliminary data are positive for human population coverage, HSV-1 cross-reactivity, and in vivo antigenicity. In addition to boosting CD8 T cells, a GH immunotherapeutic GH should boost specific CD4 T cells. For this, we plan to use a mutated version of HSV-2 gD2 unable to perform a putative immune evasion function. gD2 has shown safety and immunogenicity in human trials and has been a component of prior candidates with some clinical activity. The R21 Aims are to optimize a polyepitope CD8 candidate to cover diverse HSV strains and human populations while avoiding immunodominance, self cross-reactivity, and potential cytotoxicity pitfalls, and to test prototypes in vivo in an immune memory context to rank nucleic avid formats including novel mucosal homing strategies. Milestones for the R21 → R33 transition are relevant to these Aims are provided. The R33 Aims encompass more advanced preclinical development in the realms of further optimization in the murine model, and efficacy in the guinea pig GH therapy model with support from the NIAID Pre-Clinical Services (PCS) program.