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; 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）： 最近的报告表明，ALVAC-HIV Prime：GP120蛋白（AIDSVAX B/E）的增强剂阻止了在少量但大量的参与者中感染的希望，可以使人们希望可以预防HIV性传播的疫苗。这项研究得到了在SIV：AIV中评估的其他疫苗的结果，包括使用粒子介导的表皮递送（PMED）DNA疫苗，包括我们自己的助攻模型。这种疫苗阻止了40％的疫苗接种疫苗在直肠内挑战的疫苗，并与高剂量的异源SIV分离物分离株，从而证明了SIV中观察到的粘膜保护的免疫相关性：猕猴模型将模拟人类中的粘膜保护。使用我们的组开发的粘膜模型，该模型可以在接种的猕猴中重复采样GALT，我们将确定由PMED DNA疫苗引起的粘膜保护性免疫反应的关键成分。我们将检验以下假设：（1）疫苗不是通过防止感染而是通过阻止病毒从粘膜腔中逃脱而赋予保护； （2）宿主对病毒感染的反应必须存在于进入的粘膜入口处，以防止性传播 - 这种状况需要直接分析粘膜组织； （3）在粘膜中适当和/或召回病毒特异性保护性免疫的能力是调节病毒复制和/或表达的个体的内在特性（IES），其包含粘膜先天性免疫系统的防御素/趋化因子的表达； （4）具有效应子记忆T细胞T细胞表型诱导病毒特异性的多功能T细胞，粘膜保护需要识别粘膜组织中表位的广泛曲目； （5）PMED DNA疫苗通过诱导位于粘膜室的高避免性T细胞克隆来增加肠道中T细胞反应的宽度。我们将在以下目的中解决这些假设：AIM 1：DRS。 Martinson和Reinhart将直接确定通过量化GALT中的表达并鉴定受保护和未经保护的动物中相关的多态性，通过粘液相关防御素和趋化因子与疫苗介导的保护的宿主特异性表达与疫苗介导的保护的关系。目标2：富勒博士将确定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。 AIM 3：Murphey-Corb博士将确定粘膜病毒负担和逃生，先天和适应性反应的三方相互作用，以及PMED DNA疫苗引起的保护。这些研究将共同​​确定增强疫苗诱导的保护性免疫的新方法，并揭示重复的低剂量（性）暴露对预防疫苗的影响。该应用的目的是确定因性暴露于艾滋病毒而发生的分子事件，以便我们可以更好地理解为什么有些人被感染而另一些人不感染。了解初次接触现场发生的事情与可以防止艾滋病毒性传播的疫苗的开发高度相关。