Blocking immune evasion as a novel immunotherapy for recurrent HSV-2 infection

阻断免疫逃逸作为复发性 HSV-2 感染的新型免疫疗法

基本信息

批准号：
8720691
负责人：
SITA AWASTHI
金额：
$ 20万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720691
关键词：
Accounting Acute Address Animal Model Antibodies Antibody Formation Antigens Antiviral Therapy Attenuated Attenuated Live Virus Vaccine Biological Assay Blocking Antibodies CD4 Positive T Lymphocytes CD8B1 gene Cavia Cells Cellular Immunity Chickenpox Child Childbirth Complement DNA Detection Disease Disease Outbreaks Distress Enhancing Antibodies Epitopes Escape Mutant Event Flow Cytometry Frequencies Future Gene Mutation Genes Genital system Genome Glycoproteins Goals HIV HIV Infections HSV glycoprotein C Herpes zoster disease Herpesviridae Human Human Herpesvirus 2 Humoral Immunities Immune Immune response Immunization Immunohistochemistry Immunotherapeutic agent Immunotherapy In Vitro Individual Infection Infiltration Lesion Life Measures Methods Minor Monoclonal Antibodies Mucosal Immune Responses Mus Mutation Natural Immunity Newborn Infant Phase Recurrence Resistance Risk Risk Factors Severities Sexual Partners Simplexvirus Subunit Vaccines Supporting Cell T cell response T-Lymphocyte Technology Therapeutic Tissues Ulcer Vaccinated Vaccination Vaccine Antigen Vaccines Vagina Variant Virus Virus Diseases acquired immunity expectation genital herpes genital infection glycoprotein D-herpes simplex virus type 2 improved in vivo innovation mutant neutralizing antibody novel pressure prevent prophylactic public health priorities public health relevance response success therapeutic vaccine transmission process vaccine candidate vaccine efficacy

项目摘要

DESCRIPTION (provided by applicant): Herpes simplex virus type 2 (HSV-2) is the leading cause of genital ulcers and infects a half-billion people worldwide. Genital herpes is emotionally distressing, is life threatening to newborns infected during delivery, and is a major risk factor fr acquiring and transmitting HIV infection. Daily suppressive antiviral therapy is currently the only treatment available for recurrent genital herpes infections; however, this approach is only partially successful in preventing outbreaks and is ineffective in reducing HIV acquisition. We will evaluate the efficacy of two immunotherapeutic vaccines at controlling HSV-2 recurrent infection. The vaccines were pioneered in our lab; one involves a HSV-2 replication competent, attenuated live virus (gE2-del) and the other a trivalent subunit antigen vaccine (gC2/gD2/gE2). A replication competent varicella zoster live virus vaccine is currently used to prevent shingles, which is a recurrent infection caused by a closely related herpes virus. We will evaluate the live virus and subunit antigen vaccines individually and in combination with the expectation that the live virus vaccine will stimulate CD4+ and CD8+ T-cell responses, while the gC2/gD2/gE2 subunit antigen vaccine will improve humoral immunity. HSV-2 gD is included to enhance neutralizing antibodies, gD2 and gE2 to stimulate antibodies that block cell-to-cell spread, and gC2 and gE2 to produce antibodies that prevent immune evasion from antibody and complement. The impressive efficacy of the trivalent subunit antigens as a prophylactic vaccine for primary genital herpes in mice supports the concept of blocking immune evasion as immunotherapy for recurrent infections. In the R21 phase, we will evaluate the live virus and trivalent subunit antigen vaccines for their ability to reduce the frequency and severity of recurrent genital infection in guinea pigs. We will determine whether immunotherapy reduces the infiltration into genital tissues of CD4+ T-cells that are permissive for HIV replication (R33 phase). We will evaluate the immune correlates of protection against recurrent genital infection by measuring innate, antibody and T cell immune responses in HSV-2 infected guinea pigs that are either mock-vaccinated or immunized with the best-performing therapeutic vaccine (R33 phase). Defining the immune correlates of protection will facilitate future studies that address whether comparable immune responses can be generated in HSV-2 infected humans. We will determine whether therapeutic immunization with gC2/gD2/gE2 subunit antigens selects for mutants that emerge under immune pressure in vivo by using single genome amplification (SGA) technology to compare mutant variants detected in the virus inoculum, virus isolated during acute infection and virus isolated after therapeutic immunization (R21 and R33 phases). SGA provides an accurate detection assay for minor mutant variants within a virus pool that is more sensitive for detecting mutations in conformational epitopes that other sequencing methods and is an innovative approach to identify potentially unwanted consequences of an otherwise successful immunotherapeutic vaccine.

描述（由申请人提供）：单纯疱疹病毒2型（HSV-2）是生殖器溃疡的主要原因，并在全球范围内感染了五十亿人。生殖器疱疹在情感上令人沮丧，对分娩过程中感染的新生儿的生命威胁着，这是获得和传播HIV感染的主要危险因素。每日抑制性抗病毒疗法目前是唯一的可用于复发性生殖器疱疹感染的治疗；但是，这种方法仅在防止爆发方面取得了部分成功，并且在减少艾滋病毒收购方面无效。我们将评估两种免疫治疗疫苗控制HSV-2复发感染的功效。疫苗在我们的实验室中开创了；一种涉及HSV-2复制能干，减弱的活病毒（GE2-DEL），另一个是三价亚基抗原疫苗（GC2/GD2/GE2）。目前使用复制能力的水疗素皮藻活病毒疫苗来预防带状疱疹，这是由密切相关的疱疹病毒引起的复发感染。我们将分别评估活病毒和亚基抗原疫苗，并结合期望实时病毒疫苗会刺激CD4+和CD8+ T细胞反应，而GC2/GD2/GE2亚基抗原疫苗将改善体液上的免疫力。包括HSV-2 GD以增强中和抗体GD2和GE2的增强，以刺激阻断细胞到细胞扩散的抗体，以及GC2和GE2，以产生可预防免疫抗体和补体免疫的抗体。三价亚基抗原作为小鼠原代生殖器疱疹的预防疫苗的令人印象深刻的功效支持阻止免疫逃避作为复发性感染的免疫疗法的概念。在R21阶段，我们将评估活病毒和三价亚基抗原疫苗的能力，以降低豚鼠复发性生殖器感染的频率和严重程度。我们将确定免疫疗法是否会降低允许复制的CD4+ T细胞生殖器组织（R33期）。我们将通过测量由HSV-2感染的豚鼠中的先天，抗体和T细胞免疫反应来评估对复发生殖器感染的免疫相关性，这些豚鼠是模杀或以表现最佳的治疗疫苗（R33期）的最佳疫苗接种或免疫的。定义保护的免疫相关性将促进未来的研究，以解决HSV-2感染的人类是否可以产生可比的免疫反应。我们将确定使用GC2/GD2/GE2亚基抗原的治疗性免疫是否选择用于通过使用单个基因组扩增（SGA）技术在体内出现的突变体，以比较在急性感染和治疗后pH PHARE酶的病毒中检测到的突变体变体，并在治疗后隔离后（RAD21）。 SGA为病毒库中的次要突变体变体提供了准确的检测测定法，该测定法对检测其他测序方法的构象表位突变更为敏感，并且是一种创新的方法，是一种识别原本成功的免疫治疗疫苗的潜在不必要后果的创新方法。