A NOVEL SELF-ASSEMBLING PROTEIN NANOPARTICLES-BASED GENITAL HERPES VACCINE

ABSTRACTA staggering number of overbillion individuals worldwide are currently infected with herpes simplex virus typeand or typeHSVandampHSVwhich cause genital herpesMost HSV seropositive individuals are asymptomaticASYMPand never have any recurrent herpetic diseaseIn contrasta small proportion is symptomaticSYMPwith frequentoften lifelong bouts of recurrent herpetic diseasea result of reactivation of latent HSV from sensory neurons of the dorsal root gangliaDRGOur long term goal is to develop a vaccine to protect against genital herpesThe most recent vaccine clinical trials that used a recombinant HSVglycoprotein DgDbased subunit antigen vaccine mixed with monophosphoryl lipid AMPLAAdjuvant and delivered intramuscularlyThis gDantigen delivery system failed to protect despite inducing strong HSVspecific neutralizing antibodiesThis emphasizes two major gaps in knowledgeThe need to design an alternative antigen delivery system that will induce cell mediated immune responsesin addition to humoral responsesThe need to design HSV vaccines that will include T cell epitopes from HSV antigensAgsother than gDand or T cell epitopesA critical role for HSV specific sensory ganglia resident CDT cells in aborting reactivation of latent HSV has been establishedand the involvement of vaginal mucosaVMresident CDT cells is gaining wider acceptanceOur recent published and preliminary data demonstrate thatACDT cells fromnaturally protectedHSV seropositive ASYMP individuals mainly recognize CDT cell epitopes from HSV tegument protein ULVPBImmunization of Bmice with Self Assembling Protein NanoparticlesSAPNsthat incorporate an HSV CDT cell epitope together with a CDT helper epitope and flagellin CpGadjuvants induced strong and long lasting CDT cell responses and protected against genital herpesBuilding on the above published and preliminary datawe hypothesize that a SAPNsbased antigen delivery system and that incorporates human CDand CDT cell epitopesrecently identified in our lab from the ULtegument proteincan boost the number and or function of protective DRG resident CDand CDT cells and prevent or reduce genital herpesTo test this hypothesiswe proposesynergistic Specific AimsAimTo test the hypothesis that intravaginal immunization of HLA double transgenic mice with selfSAPNs based herpes vaccines incorporating single pairs of human CDand CDT cell epitopes identified from HSVULVPtegument protein will induce vaginal mucosaVMand DRG resident CDand CDT cells and protect against genital herpesAimTest the hypothesis that intravaginal immunization of HLA double transgenic mice with a SAPNs based herpes vaccine incorporating multiple human ULCDand CDT cell epitopes instring of pearlswill induce vaginal mucosaVMand DRG resident CDand CDT cells and protect against genital herpesSuccessful completion of the proposed work should help build a strong foundation toward developing an effective SAPNs based genital herpes vaccine PROJECT NARRATIVE Genital herpes diseasecaused by HSVand HSVinfectionsis a major global health problemThis proposal will pre clinically test a novel Self Assembling Protein NanoparticlesSAPNsbased genital herpes vaccinethat incorporate recently identified human CDand CDT cell epitopes from the HSV ULtegument proteininhumanizedHLA Tg mouse model of genital herpesResults from this pre clinical study will pave the way toward developing a novel SAPNs based genital herpes vaccine for clinical application