DNA Vaccine for Induction of Mucosal Immunity

用于诱导粘膜免疫的 DNA 疫苗

基本信息

批准号：
8720869
负责人：
DAVID B. WEINER
金额：
$ 22.05万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-15 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8720869
关键词：
Address Adjuvant Administrator Antigens Area B-Lymphocytes Biological Assay Biological Models CCL25 gene CCL27 gene CD4 Positive T Lymphocytes CD8B1 gene Cells Cellular Immunity Cloning DNA DNA Vaccines Data Development Education Enzyme-Linked Immunosorbent Assay Gagging Generations Goals HIV HIV vaccine Homing Humoral Immunities Immune Immune response Immunization Immunoglobulin A Immunoglobulin G Immunohistochemistry Immunologic Adjuvants Individual Influenza Interferon Type II Intramuscular Laboratories Lamina Propria Lung Lymphocyte Lymphoid Macaca Measurement Mediating Memory Methods Modeling Modification Mucosal Immune Responses Mucosal Immunity Mucous Membrane Mus Nature Organ Outcome Peripheral Phenotype Plasmids Population Primates Recombinants Reporting Rodent Model Role Route Saliva Sampling Serum Sexually Transmitted Diseases Signal Transduction Site Spleen T-Lymphocyte Testing Vaccination Vaccine Adjuvant Vaccines Vaccinia Vaccinium Vagina Viral Western Blotting Work base cell mediated immune response chemokine enzyme linked immunospot assay experience immunogenicity imprint improved in vivo meetings mouse model mucosal site mucosal vaccine novel novel strategies programs research study response success trafficking vaccination strategy vaccine development

项目摘要

DESCRIPTION (provided by applicant): Based on a multitude of data there are several features desired in an HIV Vaccine immunogen. Such an immunogen should induce strong and broad humoral and cellular immunity. Furthermore, as HIV is in general a sexually transmitted disease and the cells of the gut are preferentially targeted for viral destruction, an immunogen should be capable of inducing in particular mucosal as well as systemic immune responses. Currently there is no approach that can be simply administered that induces such a response. This proposal will focus on the induction of mucosal immune responses through a systemic vaccination strategy. We believe that this proposal has important implications for the development of HIV vaccines. There are 3 highly interrelated and highly novel projects that comprise this program. Project 1 (D. Weiner) will test the hypothesis in rodent models that a systemic vaccination which redirects T cells from mucosal sites to systemic sites in vivo can result in enhanced mucosal humoral and cellular immunity. Project 2 (P. Marx) Will extend the studies and test the mucosal redirection hypothesis in the critically important the macaque model. Project 3 (M. Betts) Will test several hypotheses regarding the functional nature of the induced immune responses using the latest polyfunctional immune methods in both mice and macaques in concert with project 1 and 2. Program Oversight is provided by an experienced Administrative Core (D. Weiner). The specific Aims of the Administrative core are: Aim 1: Administration and coordination of the entire program project. Aim 2: Organizing the Annual SAB meeting. A stellar Scientific Advisory Board will provide additional guidance and direction to facilitate the success of the overall program. PROJECT 1: DNA Vaccine for Induction of Mucosal Immunity (Weiner, D.) PROJECT 1 DESCRIPTION (provided by applicant): Based on a multitude of data there are several features desired in an HIV Vaccine immunogen. Such an immunogen should induce strong and broad humoral and cellular immunity. Furthermore, as HIV is in general a sexually transmitted disease and the cells of the gut are preferentially targeted for viral destruction, an immunogen should be capable of inducing in particular mucosal as well as systemic immune responses. Currently there is no approach that can be simply administered that induces such a response. In this regard, Dr. Weiner's laboratory first reported that they could redirect immune cells in vivo using chemokines encoded as part of a DMA vaccine cocktail, and recent work further confirmed and elegantly extended these findings through modification of vaccine induced immune cell trafficking by utilizing chemokines (immune trafficking signals) to attract peripheral immune cell populations. It is now the goal of this application to extend this work and develop a mucosal vaccine strategy that will result in the redirection of cells of the mucosal compartment in response to a DNA vaccine administered in the systemic compartment. Our preliminary data support that this strategy generates features of mucosal immunity by systemic vaccination. This application will further investigate this novel approach in this exceptionally important area of vaccine development. We will study the ability of specific chemokines as DNA vaccine adjuvants to modulate immune cell trafficking and redirect effector T and B cell responses to mucosal sites. There are 4 Specific Aims outlined in Project 1 of this program that will address the following questions: First, will delivery of chemokine immunoadjuvants systemically by DNA vaccines induce antigen specific immune responses in mucosal sites, and secondly, can mucosal-derived chemokine-induced immunogenicity be explained by a mechanism in which chemokines induce "retrafficking" of organ specific homing routes? Alternatively, is it such that the "imprinting" dogma for peripheral/mucosal immune cells, in fact, is reversible, resulting from chemokine-induced activation and "re-education" of target cells displaying new homing potentials. Finally, we will test whether chemokine adjuvants can elicit physiologically relevant cellular and humoral immune responses that can protect mice from a lethal mucosal challenge. This project will also generate all constructs for the macaque studies for Project 2 and support the polyfunctional flow studies in Project 3. These studies have great significance for our basic understanding of lymphocyte homing to the gut, mucosal phenotype commitment and for the development of an HIV vaccine that delivers antigens to generate mucosal immunity.

描述（由申请人提供）：基于大量数据，HIV 疫苗免疫原具有几个所需的特征。这种免疫原应诱导强而广泛的体液和细胞免疫。此外，由于HIV通常是一种性传播疾病，并且肠道细胞优先成为病毒破坏的目标，因此免疫原应该能够诱导特别是粘膜以及全身免疫反应。目前还没有可以简单地施用来诱导这种反应的方法。该提案将重点关注通过全身疫苗接种策略诱导粘膜免疫反应。我们相信这一提议对艾滋病毒疫苗的开发具有重要意义。该计划由 3 个高度相关且高度新颖的项目组成。项目 1 (D. Weiner) 将在啮齿动物模型中测试这一假设，即全身性疫苗接种将 T 细胞从粘膜部位重定向到体内全身部位，可以增强粘膜体液和细胞免疫。项目 2（P. Marx）将在至关重要的猕猴模型中扩展研究并测试粘膜重定向假说。项目 3 (M. Betts) 将与项目 1 和 2 一起使用最新的多功能免疫方法在小鼠和猕猴中测试有关诱导免疫反应的功能性质的几个假设。项目监督由经验丰富的管理核心 (D维纳）。行政核心的具体目标是：目标 1：整个计划项目的管理和协调。目标 2：组织 SAB 年度会议。一流的科学顾问委员会将提供额外的指导和指导，以促进整个计划的成功。项目 1：诱导粘膜免疫的 DNA 疫苗 (Weiner, D.) 项目 1 描述（由申请人提供）：基于大量数据，HIV 疫苗免疫原有几个所需的特征。这种免疫原应诱导强而广泛的体液和细胞免疫。此外，由于HIV通常是一种性传播疾病，并且肠道细胞优先成为病毒破坏的目标，因此免疫原应该能够诱导特别是粘膜以及全身免疫反应。目前还没有可以简单地施用来诱导这种反应的方法。在这方面，Weiner 博士的实验室首先报告说，他们可以使用 DMA 疫苗混合物中编码的趋化因子在体内重定向免疫细胞，最近的工作通过利用趋化因子修改疫苗诱导的免疫细胞运输，进一步证实并优雅地扩展了这些发现（免疫运输信号）吸引外周免疫细胞群。现在本申请的目标是扩展这项工作并开发一种粘膜疫苗策略，该策略将导致粘膜区室的细胞响应于全身区室中施用的DNA疫苗而重定向。我们的初步数据支持该策略通过全身疫苗接种产生粘膜免疫的特征。该应用将在疫苗开发这一极其重要的领域进一步研究这种新方法。我们将研究特定趋化因子作为 DNA 疫苗佐剂调节免疫细胞运输并将效应 T 和 B 细胞反应重定向至粘膜部位的能力。该计划的项目 1 概述了 4 个具体目标，将解决以下问题：首先，通过 DNA 疫苗全身递送趋化因子免疫佐剂是否会在粘膜部位诱导抗原特异性免疫反应，其次，粘膜来源的趋化因子是否可以诱导免疫原性可以用趋化因子诱导器官特异性归巢路线“重新运输”的机制来解释吗？或者，外周/粘膜免疫细胞的“印记”法则实际上是可逆的，这是由于趋化因子诱导的激活和显示新归巢潜力的靶细胞的“再教育”造成的。最后，我们将测试趋化因子佐剂是否可以引发生理相关的细胞和体液免疫反应，从而保护小鼠免受致命的粘膜攻击。该项目还将为项目 2 的猕猴研究生成所有构建体，并支持项目 3 中的多功能流研究。这些研究对于我们对淋巴细胞归巢至肠道、粘膜表型承诺的基本了解以及 HIV 的发展具有重要意义。传递抗原以产生粘膜免疫的疫苗。

项目成果

期刊论文数量（18）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Selected approaches for increasing HIV DNA vaccine immunogenicity in vivo.

DOI：
10.1016/j.coviro.2011.08.003
发表时间：
2011-10
期刊：
CURRENT OPINION IN VIROLOGY
影响因子：
5.9
作者：
Hutnick, Natalie A.;Myles, Devin J. F.;Bian, Chaoran Billie;Muthumani, Karuppiah;Weiner, David B.
通讯作者：
Weiner, David B.

Synthetic DNA immunogen encoding hepatitis B core antigen drives immune response in liver.