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.

项目摘要/摘要生殖器疱疹型病毒2（HSV-2）感染影响了美国超过6000万人，超过536人全球百万。目前无法使用FDA批准的生殖器疱疹疫苗。初次感染后阴道粘膜组织（VMC），病毒扩散并在感觉神经元的感觉神经元中建立潜伏期区域背根神经节（DRG）。该病毒从潜伏期中偶尔重新激活，并脱落在生殖器中区域，可能会引起严重的复发性病变。我们的长期目标是开发一种治疗性疫苗防止复发的生殖器疱疹。在过去的5年中，我们在确定方面取得了重大进展候选HSV-2抗原以及表征抗病毒CD4+和CD8+ T细胞的表型和功能与血清阳性女性和豚鼠复发性生殖器疱疹模型的保护：（a）我们发现两个HSV-2 TEGUMEMENT VIRION蛋白（VP16和VP22）和两个核糖核苷酸还原亚基蛋白质（RR1和RR2）主要由“自然”保护的CD4+和CD8+ T细胞靶向妇女（那些被感染的dospite从未出现过复发的生殖器疱疹）；（b）类似地，VP16，VP22， RR1和RR2蛋白是由组织居民CD4+和CD8+ T细胞识别的主要HSV-2抗原这位于受保护的不对称豚鼠的DRG和VMC中；（c）表型和转录组RNA- 受保护的豚鼠中DRG和愈合的VMC居民CD4+和CD8+ T细胞的SEQ分析表明它们拥有功能性组织居民CXCR3+ CD4+和CXCR3+ CD8+ T细胞的所有标志；（d）治疗时 RR2抗原接种在HSV-2感染的豚鼠，VP16，VP22和 RR1抗原提供了适度的保护；（e）用神经旋转的HSV-2感染的豚鼠表达豚鼠CXCL11趋化因子（CXCR3配体）的腺相关病毒载体（AAV8）增强 CD4+和CD8+ T细胞的数量特别是在感染的DRG和VMC中，并改善了保护。基于这些已发表的初步结果，我们假设，增强了强大而持久的抗病毒组织居民CD4+和CD8+ T细胞在DRG和VMC中本地的响应将产生更强大/持续的防止HSV-2重新激活和脱落并减少复发性生殖器疱疹。为了检验这一假设，我们提出了两个具体目标：目标1。在豚鼠生殖器中评估安全性和保护效率疱疹模型，一种创新的素/拉动疗法方法，包括：（1）用T细胞启动T细胞 VP16，VP22，RR1和RR2抗原；（2）“拉”底漆的T细胞通过A进入感染的DRG和VMC组织使用神经机AAV8的局部T细胞吸引趋化因子CXCL9，CXCL10和/或CXCL11 向量。目的2。确定是否增加了抗病毒组织居住的CD4+和功能的数量和功能 CD8+ T细胞内：（1）DRG（中央神经元免疫史）；（2）VMC（外周上皮免疫史）相关防止生殖器疱疹。这项临床前研究的目的是将主要/拉动疫苗带到诊所。