Innate/ SIV DNA vaccine induced immunity in the protected macaque mucosa

先天/SIV DNA 疫苗在受保护的猕猴粘膜中诱导免疫

• 批准号: 7988643
• 负责人: Michael A Murphey-Corb
• 金额: $ 76.8万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7988643
• 关键词: ALVAC Vaccine; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Affect; Animals; Automobile Driving; Avidity; Binding; Biological Assay; Blood; CCL20 gene; Cell physiology; Cells; Copy Number Polymorphism; Cryopreserved Tissue; DNA; DNA Vaccines; Defensins; Distal; Dose; Environment; Epitopes; Event; Exhibits; Exposure to; Failure; Gagging; Generations; Genes; Genetic; Genetic Polymorphism; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV vaccine; Heart; Human; Immune; Immune response; Immune system; Immunity; Immunization; Immunohistochemistry; In Situ Hybridization; Individual; Infection; Infection prevention; Macaca; Measures; Mediating; Memory; Modeling; Molecular; Monkeys; Mucous Membrane; Natural Immunity; Nature; Outcome; Participant; Peptides; Phenotype; Plasma; Play; Population; Predisposition; Prevention; Process; Property; Proteins; RANTES; Recruitment Activity; Rectum; Reporting; Resistance; Risk; Role; SIV; Sampling; Sexual Transmission; Sexually Transmitted Diseases; Shapes; Site; Staining method; Stains; T cell response; T memory cell; T-Cell Immunologic Specificity; T-Lymphocyte; Testing; Thailand; Therapeutic Intervention; Time; Transcript; Vaccinated; Vaccines; Vagina; Viral; Virus; Virus Activation; Virus Diseases; Virus Replication; adaptive immunity; chemokine; cohort; design; genetic analysis; novel; novel strategies; particle; prevent; prophylactic; rectal; research study; response; simian immunodeficiency virus gp120; tool; vaccine development; vaccine-induced immunity

DESCRIPTION (provided by applicant): The recent report that the ALVAC-HIV prime: gp120 protein (AIDSVAX B/E) boost has prevented infection in a small, but significant number of participants, provides hope that a vaccine that can prevent HIV sexual transmission is possible. This study is supported by results with other vaccines evaluated in the SIV:macaque model for AIDS, including our own using a particle mediated epidermal delivery (PMED) DNA vaccine. This vaccine prevented infection in 40% of vaccinates challenged intrarectally with a high dose of a heterologous primary SIV isolate, thereby demonstrating that immune correlates of mucosal protection observed in the SIV:macaque model will mimic mucosal protection in humans. Using a mucosal model developed by our group that enables repetitive sampling of the GALT in vaccinated macaques, we will identify the critical components of the mucosal protective immune response induced by the PMED DNA vaccine. We will test the following hypotheses: (1) A vaccine confers protection not by preventing infection but by blocking virus escape from the mucosal compartment; (2) The host response to viral infection must be present at the mucosal portal of entry to prevent sexual transmission - a condition requiring direct analysis of the mucosal tissues; (3) The ability to appropriately prime and/or recall virus-specific protective immunity in the mucosa are intrinsic propert(ies) of the individual that modulate either virus replication and/or expression of defensins/chemokines comprising the mucosal innate immune system; (4) The induction of virus-specific poly-functional T cells with an effector memory T-cell phenotype recognizing a broad repertoire of epitopes in the mucosal tissues is required for mucosal protection; (5) A PMED DNA vaccine increases the breadth of the T cell responses in the gut by induction of high-avidity T cell clones that localize to the mucosal compartment. We will address these hypotheses in the following aims: Aim 1: Drs. Martinson and Reinhart will directly determine the relationship of host-specific expression of mucosally relevant defensins and chemokines to vaccine-mediated protection by quantifying expression in the GALT and identifying related polymorphisms in protected and unprotected animals. Aim 2: Dr. Fuller will identify adaptive immune correlates of protection in the mucosa and determine their relationship to innate immunity. Aim 3: Dr. Murphey-Corb will determine the tripartite interplay among mucosal virus burden and escape, innate and adaptive responses, and protection induced by the PMED DNA vaccine. Together, these studies will identify novel approaches to enhance vaccine-induced protective immunity and reveal the impact of repetitive low dose (sexual) exposure on vaccine prevention. The objective of this application is to determine the molecular events that occur as a result of sexual exposure to HIV so that we may better understand why some people get infected while others do not. Understanding just what occurs at the site of initial exposure is highly relevant to the development of a vaccine that can prevent sexual transmission of HIV.

描述（由申请人提供）： 最近的报告称，ALVAC-HIV prime：gp120 蛋白（AIDSVAX B/E）增强剂已在少数但数量可观的参与者中预防了感染，这为预防艾滋病毒性传播的疫苗成为可能带来了希望。这项研究得到了在 SIV:猕猴艾滋病模型中评估的其他疫苗结果的支持，包括我们自己使用的颗粒介导表皮递送 (PMED) DNA 疫苗。该疫苗在直肠内用高剂量异源原代 SIV 分离株进行攻击的疫苗中，40% 预防了感染，从而证明在 SIV：猕猴模型中观察到的粘膜保护的免疫相关性将模拟人类的粘膜保护。使用我们小组开发的粘膜模型，可以对接种疫苗的猕猴中的 GALT 进行重复采样，我们将确定 PMED DNA 疫苗诱导的粘膜保护性免疫反应的关键组成部分。我们将检验以下假设：（1）疫苗不是通过预防感染而是通过阻止病毒从粘膜区逸出来提供保护； (2) 宿主对病毒感染的反应必须存在于粘膜入口处，以防止性传播——这种情况需要对粘膜组织进行直接分析； (3) 在粘膜中适当启动和/或恢复病毒特异性保护性免疫的能力是个体的固有特性，其调节病毒复制和/或构成粘膜先天免疫系统的防御素/趋化因子的表达； (4) 粘膜保护需要诱导病毒特异性多功能 T 细胞，该细胞具有识别粘膜组织中广泛表位的效应记忆 T 细胞表型； (5) PMED DNA 疫苗通过诱导定位于粘膜区室的高亲和力 T 细胞克隆来增加肠道中 T 细胞反应的广度。我们将在以下目标中解决这些假设： 目标 1：Drs。 Martinson 和 Reinhart 将通过量化 GALT 中的表达并识别受保护和未受保护动物中的相关多态性，直接确定粘膜相关防御素和趋化因子的宿主特异性表达与疫苗介导的保护之间的关系。目标 2：Fuller 博士将识别粘膜保护的适应性免疫相关性，并确定它们与先天免疫的关系。目标 3：Murphey-Corb 博士将确定粘膜病毒负荷和逃逸、先天和适应性反应以及 PMED DNA 疫苗诱导的保护之间的三方相互作用。这些研究将共同​​确定增强疫苗诱导的保护性免疫力的新方法，并揭示重复低剂量（性）接触对疫苗预防的影响。该应用的目的是确定因性接触艾滋病毒而发生的分子事件，以便我们更好地理解为什么有些人会被感染，而另一些人则不会。了解初次接触部位发生的情况与开发预防艾滋病毒性传播的疫苗密切相关。