Rational Approach to Optimize Immune Potency of DNA Vaccines

优化 DNA 疫苗免疫效力的合理方法

基本信息

批准号：
8676649
负责人：
Nirbhay Kumar
金额：
$ 18.81万
依托单位：
TULANE UNIVERSITY OF LOUISIANA
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：
2013-06-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8676649
关键词：
Accounting Acute Animals Antibodies Antibody Formation Antigen Targeting Antigen-Presenting Cells Antigens Automobile Driving B-Lymphocytes Biological Assay Cells Cessation of life Chronic Clinical Code Communicable Diseases Control Groups Culicidae DNA Vaccines Development Disease Dose Enhancing Antibodies Ensure Enzyme-Linked Immunosorbent Assay Epitopes Evaluation Exposure to Functional disorder Goals Health Human Immune Immune response Immune system Immunologics Inbred Mouse Infection Laboratories Lead Ligands Ligation Malaria Malaria Vaccines Mammals Membrane Methods MicroRNAs Modeling Molecular Mus Outcome Parasites Parasitic infection Phenotype Plasmids Production Proteins RNA RNA Interference Relative (related person)Research Route Safety Specificity Staging Synapses T-Cell Receptor T-Lymphocyte Testing Translations Up-Regulation Vaccine Antigen Vaccines Viral base cost effective cytokine design exhaustion feeding immunogenic immunogenicity immunological synapse in vivo novel pathogen plasmid DNA prevent programs promoter public health relevance receptor response tool transmission process uptake vaccine candidate vaccine development vector

Accounting Acute Animals Antibodies Antibody Formation Antigen Targeting Antigen-Presenting Cells Antigens Automobile Driving B-Lymphocytes Biological Assay Cells Cessation of life Chronic Clinical Code Communicable Diseases Control Groups Culicidae DNA Vaccines Development Disease Dose Enhancing Antibodies Ensure Enzyme-Linked Immunosorbent Assay Epitopes Evaluation Exposure to Functional disorder Goals Health Human Immune Immune response Immune system Immunologics Inbred Mouse Infection Laboratories Lead Ligands Ligation Malaria Malaria Vaccines Mammals Membrane Methods MicroRNAs Modeling Molecular Mus Outcome Parasites Parasitic infection Phenotype Plasmids Production Proteins RNA RNA Interference Relative (related person)Research Route Safety Specificity Staging Synapses T-Cell Receptor T-Lymphocyte Testing Translations Up-Regulation Vaccine Antigen Vaccines Viral base cost effective cytokine design exhaustion feeding immunogenic immunogenicity immunological synapse in vivo novel pathogen plasmid DNA prevent programs promoter public health relevance receptor response tool transmission process uptake vaccine candidate vaccine development vector

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项目摘要

DESCRIPTION (provided by applicant): Vaccines have provided the most cost-effective tool to control infectious diseases caused by viral and bacterial pathogens. However, there are no vaccines against any human parasitic infections and the development of an effective malaria vaccine remains an unachieved goal. Malaria infections account for nearly a million deaths out of ~ 300 million clinical cases globally on an annual basis. Vaccines based on antigens targeting the sexual stages of the parasite provide a direct approach to reduce malaria transmission. Antibodies recognizing specific conformational epitopes in these proteins are potent blockers of infectivity of malaria parasites in the mosquito. In this R21 application we propose to assess cellular, molecular and immune correlates of efficacy and safety of modified DNA vaccines using a well characterized malaria vaccine candidate, Pfs25, as a model immunogen. DNA vaccines induce a good initial immune response; however, in larger mammals they require heterologous boosting, eg. adjuvanted proteins to sustain functional antibody titers. Poor immunogenicity of DNA vaccines could result from an immune phenomenon described as T cell exhaustion or dysfunction resulting from upregulation of the programmed death 1 (PD-1) receptor in activated T cells and PD-L1 on antigen presenting cells. We propose to test this hypothesis through the novel addition of an RNAi sequence (designed to knockdown PD-L1) to a DNA vaccine and expect enhanced immunogenicity of DNA vaccines reflected in higher titer and longer lasting antibody responses. We will test our hypothesis by pursuing the following specific aims. In specific aim 1 we will develop DNA vaccines capable of silencing PD-L1 and expressing vaccine antigen within the same cell. Studies in specific aim 2 will provide a proof-of-principle through in vivo evaluation of potency of modified DNA vaccines and associated TFH cell responses. These studies will provide a better understanding of the cellular and molecular correlates of immunogenic efficacy and safety of DNA vaccines, and also provide the basis for more in depth studies on vaccine development across a broad spectrum.

描述（由申请人提供）：疫苗为控制由病毒和细菌病原体引起的传染病提供了最具成本效益的工具。但是，没有针对任何人类寄生虫感染的疫苗，而有效的疟疾疫苗的发展仍然是未能实现的目标。疟疾感染每年在全球范围内造成近3亿个临床病例中的近一百万次死亡。基于针对寄生虫性阶段的抗原的疫苗提供了一种直接的方法来减少疟疾传播。这些蛋白质中识别特定构象表位的抗体是蚊子中疟原虫感染性的有效阻滞剂。在此R21应用中，我们建议使用良好表征的疟疾疫苗PFS25作为模型免疫原，以评估改性DNA疫苗功效和安全性的细胞，分子和免疫相关性。 DNA疫苗可诱导良好的初始免疫反应；但是，在较大的哺乳动物中，它们需要异源提升，例如。辅助蛋白以维持功能性抗体滴度。 DNA疫苗的免疫原性差可能是由一种免疫现象引起的，称为T细胞衰竭或功能障碍是由激活的T细胞中编程死亡1（PD-1）受体上调引起的，而PD-L1在抗原呈递细胞上引起的。我们建议通过在DNA疫苗中添加新的RNAi序列（旨在敲低PD-L1）来检验这一假设，并期望在较高滴度和持久抗体反应中反射的DNA疫苗的免疫原性增强。我们将通过追求以下特定目标来检验我们的假设。在特定的目标1中，我们将开发能够使PD-L1沉默并在同一细胞内表达疫苗抗原的DNA疫苗。特定目标2中的研究将通过体内评估改良的DNA疫苗和相关TFH细胞反应的效力来提供原则证明。这些研究将更好地了解DNA疫苗的免疫原性和安全性的细胞和分子相关性，并为广泛频谱中疫苗发育的深入研究提供了更多的基础。