The challenges and opportunities for the development of a T-cell epitope-based herpes simplex vaccine

Abstract

The infections with herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a half billion individuals worldwide. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. HSV-1 infections are more prevalent than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. While genital herpes in mainly caused by HSV-2 infections, in recent years, there is an increase in the proportion of genital herpes caused by HSV-1 infections in young adults, which reach 50% in some western societies. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries their development has been notoriously difficult. During the most recent National Institute of Health (NIH) workshop titled "Next Generation Herpes Simplex Virus Vaccines: The Challenges and Opportunities", basic researchers, funding agencies, and pharmaceutical representatives gathered: (i) to assess the status of herpes vaccine research; and (ii) to identify the gaps and propose alternative approaches in developing a safe and efficient herpes vaccine. One “common denominator” among previously failed clinical herpes vaccine trials is that they either used a whole virus or whole viral proteins, which contain both pathogenic “symptomatic” and protective “asymptomatic” antigens/epitopes. In this report, we continue to advocate that using an “asymptomatic” epitope-based vaccine strategy that selectively incorporates protective epitopes which: (i) are exclusively recognized, in vitro, by effector memory CD4+ and CD8+ TEM cells from “naturally” protected seropositive asymptomatic individuals; and (ii) protect, in vivo, human leukocyte antigen (HLA) transgenic animal models from ocular and genital herpes infections and diseases, could be the answer to many of the scientific challenges facing HSV vaccine development. We review the role of animal models in herpes vaccine development and discuss its current status, challenges, and prospects.

Human Asymptomatic Epitopes Identified from the Herpes Simplex Virus Tegument Protein VP13/14 (UL47) Preferentially Recall Polyfunctional Effector Memory CD44highCD62LlowCD8+TEMCells and Protect Humanized HLA-A*02:01 Transgenic Mice against Ocular Herpesvirus Infection

“…Herpes simplex virus 1 (HSV-1) is one of the most successful human pathogens, infecting up to 80% of people worldwide (2,4,13,15,20). The HSV-1-derived tegument virion phosphoproteins (VPs), which are located between the capsid and the outer viral envelope proteins, contain a large number of possible protective CD8 ϩ T-cell epitopes (11).…”

“…In HSV-seropositive SYMP individuals, sporadic reactivation of the virus from latency and its shedding in tears can cause blinding recurrent herpetic stromal keratitis (rHSK), a T-cell-mediated immunopathological lesion of the cornea (2,19,20). Vaccine clinical trials throughout the last 2 decades have concentrated on the antibody responses induced by HSV envelope glycoproteins gB and gD, which have failed to produce protective immunity (21,22).…”

Therapeutic Immunization with a Mixture of Herpes Simplex Virus 1 Glycoprotein D-Derived “Asymptomatic” Human CD8 + T-Cell Epitopes Decreases Spontaneous Ocular Shedding in Latently Infected HLA Transgenic Rabbits: Association with Low Frequency of Local PD-1 + TIM-3 + CD8 + Exhausted T Cells

“…A staggering 1 billion individuals worldwide currently carry herpes simplex virus 1 (HSV-1) which causes a wide range of diseases throughout their lives (1)(2)(3)(4)(5). Following ocular or orofacial primary infection, HSV-1 establishes latency in sensory neurons of the trigeminal ganglia (TG) (6).…”

“…Traditional vaccines, although protective against primary acute infection in mice, have failed therapeutically in clinical trials (15,16) One "common denominator" among previously failed clinical trials is that they used either the whole virus or whole HSV proteins (e.g., HSV glycoprotein D [gD]), which deliver protective epitopes, nonprotective epitopes, and maybe even pathogenic epitopes (i.e., infection-or disease-enhancing epitopes) (reviewed in reference 17). Thus, although these traditional vaccines were intended to target only HSV-specific protective immunity, antigen processing might have also generated HSV-derived epitopes that elicit nonprotective responses and possibly even harmful responses (1). We recently found that symptomatic (SYMP) patients (with a history of numerous episodes of recurrent ocular herpes disease) tend to develop CD8 ϩ T cells that strongly recognize a subset of HSV-1 gD epitopes that differs from HSV-1 gD epitopes that are strongly recognized by CD8 ϩ T cells from HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease), and vice versa (1)(2)(3)(4)(5).…”

“…Thus, although these traditional vaccines were intended to target only HSV-specific protective immunity, antigen processing might have also generated HSV-derived epitopes that elicit nonprotective responses and possibly even harmful responses (1). We recently found that symptomatic (SYMP) patients (with a history of numerous episodes of recurrent ocular herpes disease) tend to develop CD8 ϩ T cells that strongly recognize a subset of HSV-1 gD epitopes that differs from HSV-1 gD epitopes that are strongly recognized by CD8 ϩ T cells from HSV-1-seropositive healthy asymptomatic (ASYMP) individuals (who have never had clinical herpes disease), and vice versa (1)(2)(3)(4)(5). The former epitopes are designated "symptomatic" (SYMP) epitopes, and the latter are designated "asymptomatic" (ASYMP) epitopes.…”