Future of an "Asymptomatic" T-cell Epitope-Based Therapeutic Herpes Simplex Vaccine

Abstract

Considering the limited success of the recent herpes clinical vaccine trial [1], new vaccine strategies are needed. Infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) in the majority of men and women are usually asymptomatic and results in lifelong viral latency in neurons of sensory ganglia (SG). However, in a minority of men and women HSV spontaneous reactivation can cause recurrent disease (i.e., symptomatic individuals). Our recent findings show that T cells from symptomatic and asymptomatic men and women (i.e. those with and without recurrences, respectively) recognize different herpes epitopes. This finding breaks new ground and opens new doors to assess a new vaccine strategy: mucosal immunization with HSV-1 & HSV-2 epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic men and women (designated here as "asymptomatic" protective epitopes") could boost local and systemic "natural" protective immunity, induced by wild-type infection. Here we highlight the rationale and the future of our emerging "asymptomatic" T cell epitope-based mucosal vaccine strategy to decrease recurrent herpetic disease.

Fig. 1. Identification of “protective” asymptomatic HSV-1 T cell epitopes from HSV-1 and HSV-2

(A) “Asymptomatic” T cell epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from asymptomatic individuals are selected. (B) “Symptomatic” T cell epitopes that induce strong in vitro CD4 and CD8 T cell responses from PBMC derived from symptomatic individuals are excluded. (C) “Asymptomatic” T cell epitopes that are protective in HLA transgenic mice and rabbits are selected. (D) “Symptomatic” T cell epitopes that are pathogenic in HLA transgenic mice and rabbits are excluded. (E) A few overlapping epitopes may be strongly recognized by T cells from both symptomatic and asymptomatic individuals and are also excluded. (F) Only some epitopes recognized by T cells from symptomatic individuals are immunogenic in vivo in animal are also excluded. (G) Although some epitopes are immunogenic in vivo in animal models they are neither protective nor pathogenic and are therefore also excluded. The successful combination of the above criteria will determine the final asymptomatic epitopes (H) that will be included in a future multivalent “asymptomatic” vaccine against ocular herpes. Note that the selected asymptomatic epitopes also induce a weak T cell response in symptomatic individuals. Thus a repertoire of “asymptomatic” T cells do exist in the symptomatic individuals do exist but it must to be boosted by the future “asymptomatic therapeutic vaccine in order to induce protection.