PROTECTIVE IMMUNITY AGAINST RECURRENT OCULAR HERPES INDUCED WITH SELF-ASSEMBLING PROTEIN NANOPARTICLES
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Principal Investigator: Lbachir BenMohamed Organization: UNIVERSITY OF CALIFORNIA-IRVINE Fiscal Year: 2020 Award: $210,375 Funding agency: National Institute of Allergy and Infectious Diseases PROJECT SUMMARY/ABSTRACT A staggering number of individuals—over 3 billion worldwide—are currently infected with herpes simplex virus type 1 (HSV-1), which causes frequent, and often lifelong, bouts of recurrent corneal herpetic disease. This potentially blinding disease is a result of corneal re-infection following reactivation of latent HSV-1 from sensory neurons of the trigeminal ganglia (TG). Our long-term goal is to develop a vaccine to protect against ocular herpes infection and disease. The most recent herpes vaccine clinical trials that used a recombinant HSV glycoprotein D (gD)-based subunit antigen vaccine mixed with monophosphoryl lipid A (MPLA) adjuvant and delivered intramuscularly failed to protect despite inducing strong HSV-specific neutralizing antibodies. Results from those clinical trials emphasize two major gaps in knowledge: (1) The need to design an alternative antigen delivery system that will induce cell-mediated immune responses (in addition to humoral responses). (2) The need to design an ocular herpes vaccine that will include T cell-induced HSV antigens (Ags), other than the gD. HSV-specific TG-resident CD8+ T cells play a critical role in aborting reactivation of HSV-1 from latently infected sensory neurons, and the involvement of ocular mucosal surface- (OMS-) resident CD4+ T cells is gaining wider acceptance. Our recently published and preliminary data demonstrate that: (A) CD8+ T cells from “naturally protected” HSV-seropositive ASYMP individuals mainly recognize T cell epitopes from HSV tegument proteins VP16 and VP22. (B) Immunization of B6 mice with Self Assembling Protein Nanoparticles (SAPNs) that incorporate an HSV-1 CD8+ T cell epitope together with a CD4+ T helper epitope and flagellin/CpG1585 adjuvants induced strong and long-lasting CD8+ T cell responses and protected against ocular herpes. Building on the above published and preliminary data, we hypothesize that a SAPNs-based delivery system that incorporates human CD4+ and CD8+ T cell epitopes, recently identified in our lab from the VP16 and VP22 tegument proteins, can boost the number and function of protective TG- and OMS-resident CD4+ and CD8+ T cells and prevent or reduce recurrent ocular herpes disease. To test this hypothesis, we propose two Specific Aims: Aim 1: Test the hypotheses that therapeutic immunization of latently infected HLA double transgenic mice with SAPNs-based herpes vaccines delivering the VP16 and VP22 tegument proteins will boost HSV-specific TG- and OMS-resident CD4+ and CD8+ T cells and protect against UVB-induced recurrent ocular herpes infection and disease. Aim 2: Test the hypotheses that therapeutic immunization of latently infected HLA double transgenic mice with SAPNs- based herpes vaccines incorporating multiple pairs of immunodominant VP16 and VP22 CD4+ and CD8+ T cell epitopes will boost HSV-specific TG- and OMS-resident CD4+ and CD8+ T cells and protect against recurrent ocular herpes. Successful completion of the proposed work should help build a solid foundation toward developing an effective SAPNs-based ocular herpes vaccine. Terms: <Adjuvant><Afferent Neurons><Antibody Response><Antigenic Determinants><Antigens><Architecture><Binding Determinants><Blindness><Blood Serum><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Clinical Trials><Cornea><Data><Disease><Disorder><Educational workshop><Engineering / Architecture><Epitopes><Failure><Flagellin><Foundations><Gasser's Ganglion><Gasserian Ganglion><Glycoproteins><Goals><HSV><HSV-1><HSV1><Herpes Simplex Keratitis><Herpes Simplex Virus><Herpes Simplex Virus 1><Herpes Simplex Virus Type 1><Herpes infection><Herpes labialis Virus><Herpesviridae Infections><Herpesviridae disease><Herpesvirus 1><Herpesvirus Infections><Herpetic Keratitis><Human><Immune mediated therapy><Immunity><Immunization><Immunize><Immunoactivators><Immunoadjuvants><Immunologic Adjuvants><Immunologic Sensitization><Immunologic Stimulation><Immunological Adjuvant><Immunological Sensitization><Immunological Stimulation><Immunologically Directed Therapy><Immunopotentiators><Immunostimulants><Immunostimulation><Immunotherapeutic agent><Immunotherapy><Individual><Infection><Intramuscular><Keratitis><Knowledge><Lipid A><Mice><Mice Mammals><Modern Man><Mucosa><Mucosal Tissue><Mucous Membrane><Murine><Mus><NIH><National Institutes of Health><Ocular Herpes Simplex><Ocular Herpetic Disease><Outcome><Phase><Play><Proteins><Publishing><Recombinants><Recurrence><Recurrent><Role><Semilunar Ganglion><Sensory Cell Afferent Neuron><Sensory Ganglia><Sensory Neurons><Serum><Simplexvirus><Solid><Structure of trigeminal ganglion><Surface><System><T cell response><T-Cell Epitopes><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Transgenic Mice><Treatment Efficacy><Trigeminal Ganglias><Trigeminal Ganglion><UVB induced><United States National Institutes of Health><VP 16><VP16><Vaccine Antigen><Vaccine Clinical Trial><Vaccines><Viral Latency><Virus><Virus Latency><Work><Workshop><base><cell mediated immune response><clinical applicability><clinical application><corneal><design><designing><develop a vaccine><development of a vaccine><global health><herpes simplex i><immune adjuvant><immune drugs><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunogenicity><immunologic preparation><immunologic therapeutics><immunotherapeutics><immunotherapy agent><intervention efficacy><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><new vaccines><next generation><next generation vaccines><novel><novel vaccines><ocular herpes><pre-clinical><pre-clinical study><preclinical><preclinical study><prevent><preventing><protective efficacy><reactivation from latency><response><seropositive><social role><therapeutic efficacy><therapeutic immunization><therapeutic nanoparticles><therapeutic vaccine><therapeutically effective><therapy efficacy><thymus derived lymphocyte><treatment vaccines><ultraviolet B induced><vaccine candidate><vaccine development><vaccine for the treatment><vaccine for treatment><vaccine formulation><vision loss><visual loss>