Evolution of rational vaccine designs for genital herpes immunotherapy

•Early genital herpes immunotherapy aimed at inducing neutralizing antibodies.•Herpes-specific T cell responses may be as important as antibody for disease control.•Technologic improvements in screening methods identify relevant T cell antigens.•Augmentation of local herpes-specific immune responses is critical to immunotherapy.•Escape from immune evasion and mucosal targeting may improve vaccine efficacy. Immunotherapeutic vaccines have emerged as a novel treatment modality for genital herpes, a sexually transmitted disease mainly caused by herpes simplex virus type 2. The approaches to identify potential vaccine antigens have evolved from classic virus attenuation and characterization of antibody and T cell responses in exposed, but seronegative individuals, to systematic screens for novel T cell antigens. Combined with implementation of novel vaccine concepts revolving around immune evasion and local recruitment of immune effectors, the development of a safe and effective therapeutic vaccine is within reach. Here, we describe the vaccine approaches that currently show promise at clinical and pre-clinical stages and link them to the evolving scientific strategies that led to their identification.