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）：2 型单纯疱疹病毒 (HSV-2) 是生殖器溃疡的主要原因，感染全世界 5 亿人。生殖器疱疹令人精神痛苦，对分娩过程中感染的新生儿有生命危险，并且是感染和传播艾滋病毒的主要危险因素。每日抑制性抗病毒治疗是目前唯一的治疗方法可用于复发性生殖器疱疹感染的治疗；然而，这种方法在预防疫情方面仅部分成功，并且在减少艾滋病毒感染方面无效。我们将评估两种免疫治疗疫苗在控制 HSV-2 复发感染方面的功效。这些疫苗是我们实验室首创的；一种涉及 HSV-2 复制能力减毒活病毒 (gE2-del)，另一种涉及三价亚单位抗原疫苗 (gC2/gD2/gE2)。目前使用具有复制能力的水痘带状疱疹活病毒疫苗来预防带状疱疹，这是一种由密切相关的疱疹病毒引起的复发性感染。我们将单独和结合评估活病毒和亚单位抗原疫苗，期望活病毒疫苗将刺激CD4+和CD8+ T细胞反应，而gC2/gD2/gE2亚单位抗原疫苗将改善体液免疫。 HSV-2 gD 可增强中和抗体，gD2 和 gE2 可刺激阻止细胞间传播的抗体，gC2 和 gE2 可产生防止抗体和补体免疫逃避的抗体。三价亚单位抗原作为小鼠原发性生殖器疱疹的预防性疫苗的令人印象深刻的功效支持了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单位抗原疫苗降低豚鼠生殖器复发感染频率和严重程度的能力。我们将确定免疫疗法是否会减少允许 HIV 复制（R33 期）的 CD4+ T 细胞对生殖器组织的浸润。我们将通过测量 HSV-2 感染豚鼠的先天免疫反应、抗体和 T 细胞免疫反应来评估预防复发性生殖器感染的免疫相关性，这些豚鼠要么进行模拟疫苗接种，要么用效果最佳的治疗性疫苗（R33 期）进行免疫。定义保护的免疫相关性将有助于未来的研究，解决 HSV-2 感染人类是否可以产生类似的免疫反应。我们将通过使用单基因组扩增（SGA）技术比较病毒接种物、急性感染期间分离的病毒和病毒中检测到的突变体，确定使用gC2/gD2/gE2亚基抗原的治疗性免疫是否会选择体内免疫压力下出现的突变体。治疗性免疫后分离（R21 和 R33 阶段）。 SGA 为病毒库中的微小突变变体提供了准确的检测方法，与其他测序方法相比，它对于检测构象表位中的突变更加敏感，并且是一种创新方法，可以识别其他成功的免疫治疗疫苗可能产生的不良后果。