A NOVEL IMMUNO-PROTEOMIC APPROACH TO A GENITAL HERPES VACCINE

DESCRIPTION provided by applicant Over a half billion individuals worldwide are infected with herpes simplex virus type and or type HSV andamp HSV which cause genital herpes Most HSV seropositive individuals are asymptomatic ASYMP and never have any recurrent herpetic disease In contrast a small proportion is symptomatic SYMP with frequent often lifelong bouts of recurrent herpetic disease a result of reactivation of latent HSV from sensory neurons of the dorsal root ganglia DRG Our long term goal is to develop an immunotherapeutic vaccine to prevent virus reactivation from latency and protect against recurrent genital herpes disease The most recent vaccine clinical trials that used HSV glycoprotein D gD failed to protect despite inducing strong HSV specific neutralizing antibodies This proposal emphasizes two major gaps in knowledge The need to induce cell mediated immune responses in addition to humoral responses for better protection The need to identify novel herpes T cell antigens Ags to be incorporated into next generation HSV vaccines A critical role for HSV specific sensory ganglia resident CD T cells in aborting HSV reactivation has been established and the involvement of CD T cells is gaining wider acceptance Paradoxically HSV specific genital tract GT resident CD and CD T cells are also involved in herpes pathogenicity The Ag specificities of protective and pathogenic CD and CD T cells remain to be elucidated Our recent published and preliminary data demonstrate that A CD and CD T cells from HSV seropositive SYMP and ASYM individuals differ in their HSV Ag specificities phenotype and function B Immunization of novel susceptible Human Leukocyte Antigen HLA A DR double transgenic mice HLA Tg mice with ASYMP Ags but not SYMP Ags induced a strong T cell dependent protective immunity against genital herpes Building on the above published and preliminary data in both humans and HLA Tg mice we hypothesize that CD and CD T cells specific to HSV Ags can be either protective or pathogenic and A vaccine strategy that can boost the number and or function of DRG resident protective CD and CD T cells will prevent or reduce virus reactivation and hence protect against recurrent genital herpes Our Specific Aims are Aim To confirm the hypothesis that there is a set of HSV Ags that are recognized mostly by CD and CD T cells from ASYMP individuals and a different set of Ags that are recognized mostly by CD and CD T cells from SYMP individuals Aim To test the hypothesis that immunization of HLA double Tg mice with immunodominant ASYMP Ags but not with SYMP Ags will induce DRG resident CD and CD T cells and protect against genital herpes infection and disease Successful completion of the proposed work should help build a strong foundation toward developing an effective genital herpes vaccine PUBLIC HEALTH RELEVANCE Genital herpes disease caused by HSV and HSV infections is a major global health problem This proposal focuses on both an antigen selection and delivery platform by performing high throughput screening of HSV and HSV genome to select the sets of HSV Ags that are exclusively recognized by CD and CD T cells from HSV seropositive ASYMP individuals with a history of controlled herpes disease and then using the selected ASYMP protective Ags as a vaccine against genital herpes Results from this preclinical study will pave the way toward developing a novel andquot ASYMPandquot vaccine for clinical application