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

Abstract

Herpes simplex virus type 1 and type 2 (HSV-1 & HSV-2) infections have been prevalent since the ancient Greek times. To this day, they still affect a staggering number of over a billion individuals worldwide. HSV-1 infections are predominant than HSV-2 infections and cause potentially blinding ocular herpes, oro-facial herpes and encephalitis. HSV-2 infections cause painful genital herpes, encephalitis, and death in newborns. While prophylactic and therapeutic HSV vaccines remain urgently needed for centuries, their development has been 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 a whole viral protein, which contain both "pathogenic symptomatic" and "protective asymptomatic" antigens and epitopes. In this report, we continue to advocate developing "asymptomatic" epitope-based sub-unit vaccine strategies that selectively incorporate "protective asymptomatic" epitopes which: (i) are exclusively recognized by effector memory CD4(+) and CD8(+) T cells (TEM cells) from "naturally" protected seropositive asymptomatic individuals; and (ii) protect human leukocyte antigen (HLA) transgenic animal models of ocular and genital herpes. We review the role of animal models in herpes vaccine development and discuss their current status, challenges, and prospects.

Keywords: Asymptomatic; Clinical trials; Epitopes; Herpes simplex virus; Immunotherapeutic; Symptomatic; Vaccines.

Figure 1

The natural history of genital (left) and oro-facial (right) herpes infection. HSV-1 and HSV-2 are transmitted by close interpersonal contact (such as during intravaginal/oral sex, during birth or eye contact), and preferentially infects muco-cutaneous epithelium around the genital tract (GT), around the lips (cold sores), nose and eyes. Right : While most of genital herpes is caused by HSV-2 reports of HSV-1 genital infection are increasing. HSV-2 infections is a major public health problem. (1) The virus replicates in the TG and then travels along nerves to the sacral ganglia (SG) that control the GT, where it establishes a latent infection. (2) Recurrent genital herpes is the most prevalent sexually transmitted disease. Left : (1) Ocular herpes is mainly caused by HSV-1, which infects the cornea and then establishes latency in sensory neurons of the trigeminal ganglia (TG). (2) Sporadic spontaneous reactivation of HSV-1 from latently infected neurons leads to viral shedding in saliva and tears which can cause symptomatic recurrent Herpes Stromal Keratitis (HSK), a blinding corneal disease.

Figure 2. Symptomatic and asymptomatic genital herpes infection in humans

(A) Following intravaginal infection with HSV-1 or HSV-2; stimulation with pathogenic “symptomatic” and protective “asymptomatic” T cell epitopes, expressed by the HSV, contributes to development of various subsets of HSV-specific memory CD8⁺ T cells: either GT and DRG-resident effector memory CD8⁺ T cells (T_EM) or lymphoid resident central memory CD8⁺ T cells (T_CM) (Fig. 2B). (B) Protective role of various subsets of HSV-specific memory CD8⁺ T cells. HSV reactivates from DRG and SPC re-infect of the GT. CD8⁺ T_CM cells in GT-DLN traffic through the bloodstream into the vaginal mucosa of GT to clear the virus. In contrast, CD8⁺ T_EM cells reside in the vaginal mucosal tissues of GT and DRG and are more rapidly mobilized upon re-infection. (See text for details).

Figure 2. Symptomatic and asymptomatic genital herpes infection in humans

(A) Following intravaginal infection with HSV-1 or HSV-2; stimulation with pathogenic “symptomatic” and protective “asymptomatic” T cell epitopes, expressed by the HSV, contributes to development of various subsets of HSV-specific memory CD8⁺ T cells: either GT and DRG-resident effector memory CD8⁺ T cells (T_EM) or lymphoid resident central memory CD8⁺ T cells (T_CM) (Fig. 2B). (B) Protective role of various subsets of HSV-specific memory CD8⁺ T cells. HSV reactivates from DRG and SPC re-infect of the GT. CD8⁺ T_CM cells in GT-DLN traffic through the bloodstream into the vaginal mucosa of GT to clear the virus. In contrast, CD8⁺ T_EM cells reside in the vaginal mucosal tissues of GT and DRG and are more rapidly mobilized upon re-infection. (See text for details).

Figure 3. CD8⁺ T-cells from HSV-seropositive symptomatic and asymptomatic individuals recognize different gB epitopes

CD8⁺ T-cells isolated from HLA-A*0201-matched symptomatic (n = 4) and asymptomatic patients (n = 16) were stimulated with autologous DC that were pulsed with 10 µg/ml of the indicated gB peptide for 5 days. The number of IFN-γ-producing CD8⁺ T-cells specific to each gB epitope was determined by IFN-γ-ELISpot assay in duplicate.