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A Novel Prime/Pull Therapeutic Vaccine Strategy to Prevent Recurrent Genital Herpes

预防复发性生殖器疱疹的新型初免/拉动治疗疫苗策略

基本信息

批准号：
10318146
负责人：
Lbachir BenMohamed
金额：
$ 61.29万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-01-10 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10318146
关键词：
Adult Affect Afferent Neurons Age-Years Animal Model Antibodies Antibody Response Antigens Antiviral Agents Axon B-Lymphocytes Back CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CXCL10 gene CXCL11 gene CXCL9 gene CXCR3 gene Cavia Cessation of life Clinic Clinical Trials Data Disease Disease Outbreaks Epithelial FDA approved Foundations Goals HIV Herpesviridae Infections Human Human Herpesvirus 2 Immunity Infection Knowledge Lead Lesion Ligands Medical Memory Mission Modeling National Institute of Allergy and Infectious Disease Neurons Newborn Infant Peripheral Persons Pharmacotherapy Phenotype Plant Roots Prevalence Primary Infection Protein Subunits Proteins Publishing Recurrence Ribonucleotide Reductase Subunit Risk Safety Scientist Simplexvirus Site Spinal Ganglia Subunit Vaccines Surface Symptoms System T cell response T memory cell T-Lymphocyte Testing Therapeutic Tissues Travel United States Ursidae Family VP 16 Vaccine Research Vaccine Therapy Vaccines Vagina Virion Virus Virus Latency Virus Replication Woman adeno-associated viral vector base chemokine design genital herpes guinea pig model healing human disease improved innovation insight latent infection men multidisciplinary nanoparticle neonate nervous system disorder neurotropic novel pre-clinical preclinical study prevent prophylactic protective efficacy psychologic reactivation from latency reproductive tract seropositive therapeutic vaccine transcriptome sequencing transcriptomics translational goal vaccine strategy vaginal infection vector viral transmission

项目摘要

PROJECT SUMMARY/ABSTRACT Genital herpes simplex type virus-2 (HSV-2) infection affects over 60 million people in the U.S. and over 536 million worldwide. An FDA-approved genital herpes vaccine is currently unavailable. After primary infection of the vaginal mucocutaneous tissue (VMC), the virus spreads and establishes latency in sensory neurons of regional dorsal root ganglia (DRG). The virus reactivates sporadically from latency and sheds back in the genital tract, where it can cause severe recurrent lesions. Our long-term goal is to develop a therapeutic vaccine to prevent recurrent genital herpes. Over the last 5 years, we have made significant progress in identifying candidate HSV-2 antigens and characterizing the phenotype and function of antiviral CD4+ and CD8+ T cells that associate with protection in seropositive women and in the guinea pig recurrent genital herpes model: (A) We found that two HSV-2 tegument virion proteins (VP16 and VP22) and two ribonucleotide reductase subunit proteins, (RR1 and RR2) are mainly targeted by CD4+ and CD8+ T cells from “naturally” protected asymptomatic women (those who, despite being infected, never develop recurrent genital herpes); (B) Similarly, VP16, VP22, RR1, and RR2 proteins were the main HSV-2 antigens recognized by tissue-resident CD4+ and CD8+ T cells that reside in DRG and VMC of protected asymptomatic guinea pigs; (C) Phenotypic and transcriptomic RNA- Seq profiling of DRG- and healed VMC-resident CD4+ and CD8+ T cells in protected guinea pigs show that they bear all the hallmarks of functional tissue-resident CXCR3+CD4+ and CXCR3+CD8+ T cells; (D) While therapeutic vaccination with RR2 antigen produced strong protection in HSV-2 infected guinea pigs, the VP16, VP22 and RR1 antigens provided modest protection; and (E) Treatment of HSV-2 infected guinea pigs with a neurotropic adeno-associated virus vector (AAV8) expressing the guinea pig CXCL11 chemokine (a CXCR3 ligand) boosted the number of CD4+ and CD8+ T cells specifically in infected DRG and VMC and improved protection. Based on these published and preliminary results, we hypothesize that boosting strong and long-lasting antiviral tissue- resident CD4+ and CD8+ T cell responses locally in DRG and VMC would produce a more robust/sustained protection against HSV-2 reactivation and shedding and reduce recurrent genital herpes. To test this hypothesis, we propose two Specific Aims: Aim 1. To evaluate the safety and protective efficacy, in the guinea pig genital herpes model, of an innovative prime/pull therapeutic vaccine approach that consists of: (1) Priming T cells with VP16, VP22, RR1, and RR2 antigens; and (2) “Pulling” primed T cells into infected DRG and VMC tissues by a local delivery of T-cell attracting chemokines, CXCL9, CXCL10 and/or CXCL11, using a neurotropic AAV8 vector. Aim 2. To determine whether increasing the number and function of antiviral tissue-resident CD4+ and CD8+ T cells within: (1) DRG (central neuronal immunity); and (2) VMC (peripheral epithelial immunity) correlates with protection against genital herpes. The goal of this pre-clinical study is to bring a prime/pull vaccine to clinic.

项目总结/文摘