The Path Towards Effective Long-Lasting Tissue-Targeted Prime/Pull/Keep Herpes Simplex Therapeutic Vaccines

The development of vaccines against many infectious diseases has been a great success of medical science over the last century. However, despite numerous efforts, effective vaccines for herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) remain elusive. Since 1920s, a range of therapeutic vaccine candidates, primarily focusing on neutralizing antibodies, have failed to confer robust and durable protective immunity against recurrent herpes. Recent advances in omics, artificial intelligence, and deep learning have opened new horizons for the rational design of tissue-targeted herpes vaccine strategies for inducing potent and durable HSV-specific CD4⁺ and CD8⁺ T_RM cell immunity at both the sensory ganglia (central immunity), the site of latency/reactivation cycle, and the mucocutaneous epithelial tissues (peripheral immunity), the site of viral replication that causes herpetic lesions. Prime/Pull/Keep ocular and genital herpes vaccine candidates (PPK vaccines) have recently shown success in pre-clinical animal model trials of recurrent ocular and genital herpes. These PPK vaccines used "asymptomatic" epitopes/antigens to prime CD4⁺ and CD8⁺ T cells (Prime); primed T cells are then pulled towards the infected central and peripheral epithelial tissues using T cell-attracting chemokines, such as CXCL11 (Pull), followed by survival cytokines (IL-2, IL-7 and/or IL-15) or mucosal chemokines (CXCL17 and/or CCL28) to maintain the "pulled" tissue-resident T cells longer within infected tissues (Keep). We discuss recent efforts in designing a clinically adapted, all-in-one PPK mucosal therapeutic vaccine that would require a single administration to sequentially trigger all three PPK steps of priming, recruiting, and maintaining antiviral, tissue-resident, protective T cells at the primary sites of viral entry and latency.