Vaccines to Generate Neutralizing Anti-HIV Antibodies

产生中和抗 HIV 抗体的疫苗

基本信息

批准号：
7460760
负责人：
Richard Syd Kornbluth
金额：
$ 13.6万
依托单位：
VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
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：
2007-07-15 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7460760
关键词：
Adjuvant Antibodies Antibody Formation Antigens Apoptosis B-Lymphocytes BAX gene Bax protein Binding CD40 Antigens CD8B1 gene Cell membrane Cell surface Cells Cytolysis Cytoplasmic Tail Cytotoxic T-Lymphocytes DNA DNA Vaccines Epitopes Gagging Germ Cells Goals HIV HIV Antibodies HIV Envelope Protein gp120 HIV vaccine HIV-1 Herpesviridae Immunoglobulin A Immunologic Adjuvants Individual Infection Influenza Intramuscular Length Ligands MHC Class I Genes Macaca Mediating Membrane Modeling Molecular Conformation Muscle Muscle Cells Ovalbumin Plasmids Process Proteins Reporting Research Role Serum Simplexvirus Site Smallpox Structure Surface T-Lymphocyte T-Lymphocyte Epitopes TNF gene TNFSF5 gene Testing Vaccination Vaccines Variant Viral Vaccines Viral hepatitis Virion Virus West Nile virus Work base biodefense concept cytotoxic density gp160 improved innovation insight lymph nodes lymphatic circulation neutralizing antibody neutralizing monoclonal antibodies plasmid DNA prevent receptor research study response vaccine development

项目摘要

DESCRIPTION (provided by applicant): A major goal of HIV vaccine development is to create vaccines that elicit broadly neutralizing antibodies (NAbs) to the gp120/gp41 envelope (Env) spikes on virions. Efforts to accomplish this goal have met with three obstacles: (1) it is difficult to replicate the structure of gp120/gp41 trimers in a vaccine; (2) NAbs should be at the highest possible titer on exposed mucosal surfaces; and (3) extensive variation in Env has made it difficult to find the best Env sequence for use in a vaccine. This project will study innovative ways to overcome these roadblocks through three Aims. Aim 1 will use intramuscular DNA vaccination with an Env plasmid along with a plasmid to generate CD8+ T cells that are cytotoxic for the transfected muscle cells. This strategy utilizes the ability of plasmid DNA to express Env in its correctly folded native conformation on the membranes of cells at the vaccination site. The addition of a DNA vaccine for cytotoxic CD8+ T cells will enable cell debris expressing native Env to reach B cells in the draining lymph nodes, based on the previously unexploited finding that CD8+ T cells markedly enhance antibody responses to DNA vaccines for nonsecreted antigens. We call this approach 'CD8+ T cell-mediated Antibody-Eliciting Vaccine' (CAEVac). Aim 2 will test the abilty of DNA vaccines encoding high epitope density forms of Env to augment the anti-Env antibody response. Aim 3 will test the adjuvant effects of CD40L, GITRL, BAFF, and APRIL, four TNF superfamily ligands, on the antibody responses to the DNA vaccines of Aim 1. BAFF in particular has potential as an adjuvant for mucosal IgA responses. When this innovation project is complete, new concepts for vaccines that elicit HIV NAbs will have been evaluated for advancement to further studies in the HIV vaccine pipeline. This project will develop new immunostimulants that could significantly improve the strength of viral vaccines. While this research is focused on HIV, the same immunostimulants could be applied to vaccines against many other infections including influenza, viral hepatitis, West Nile virus, smallpox, and agents of biodefense significance.

描述（由申请人提供）：HIV疫苗开发的主要目标是创建对GP120/GP41 INVELOPE（ENV）对病毒体上的GP120/GP41 INVELOPE（ENV）尖峰的广泛中和抗体（NABS）的疫苗。实现这一目标的努力已经遇到了三个障碍：（1）很难在疫苗中复制GP120/GP41三聚体的结构；（2）NABS在暴露的粘膜表面上应处于最高滴度；（3）ENV的广泛差异使得很难找到用于疫苗的最佳ENV序列。该项目将通过三个目标研究创新的方法来克服这些障碍。 AIM 1将使用肌肉内DNA疫苗接种与ENV质粒以及质粒一起产生用于转染的肌肉细胞细胞毒性的CD8+ T细胞。该策略利用质粒DNA在疫苗接种部位的细胞膜上正确折叠的天然构象中表达ENV的能力。基于先前未开发的发现CD8+ T细胞明显增强对非二十次抗原的DNA疫苗的抗体反应，添加用于细胞毒性CD8+ T细胞的DNA疫苗将使表达天然ENV的细胞碎片能够到达排水淋巴结中的B细胞。我们将这种方法称为“ CD8+ T细胞介导的抗体 - 引导疫苗”（CAEVAC）。 AIM 2将测试编码高表位密度ENV的DNA疫苗的效果，以增强抗ENV抗体反应。 AIM 3将测试CD40L，GITRL，BAFF和4月的辅助作用，四个TNF超家族配体对AIM 1的DNA疫苗的抗体反应。特别是BAFF具有粘膜IGA反应的辅助物。当这个创新项目完成后，将评估引起HIV NABS的疫苗的新概念，以进步以进一步研究HIV疫苗管道。该项目将开发新的免疫刺激剂，可以显着提高病毒疫苗的强度。尽管这项研究的重点是HIV，但可以将相同的免疫刺激剂应用于疫苗，以针对许多其他感染，包括流感，病毒肝炎，西尼罗河病毒，天花和生物粘度意义的药物。