Vaccines to Generate Neutralizing Anti-HIV Antibodies

描述（由申请方提供）：HIV疫苗开发的一个主要目标是创建疫苗，该疫苗可针对病毒体上的gp 120/gp 41包膜（Env）峰激发广泛中和抗体（NAb）。实现这一目标的努力遇到了三个障碍：（1）难以在疫苗中复制gp 120/gp 41三聚体的结构;（2）NAb在暴露的粘膜表面上应具有最高可能滴度;和（3）Env的广泛变异使得难以找到用于疫苗的最佳Env序列。该项目将研究通过三个目标克服这些障碍的创新方法。目的1将使用Env质粒沿着质粒的肌内DNA接种以产生对转染的肌细胞具有细胞毒性的CD 8 + T细胞。该策略利用质粒DNA在疫苗接种位点的细胞膜上以其正确折叠的天然构象表达Env的能力。基于先前未开发的发现，即CD 8 + T细胞显著增强对非分泌抗原的DNA疫苗的抗体应答，添加细胞毒性CD 8 + T细胞的DNA疫苗将使表达天然Env的细胞碎片到达引流淋巴结中的B细胞。我们称这种方法为“CD 8 + T细胞介导的抗体诱导疫苗”（CAEVac）。目的2检测编码高表位密度Env的DNA疫苗增强抗Env抗体应答的能力。目的3将测试CD 40 L、GITRL、BAFF和APRIL（四种TNF超家族配体）对针对目的1的DNA疫苗的抗体应答的佐剂效应。BAFF尤其具有作为粘膜伊加应答的佐剂的潜力。当这一创新项目完成时，将对引发HIV NAb的疫苗的新概念进行评估，以便在HIV疫苗管道中进行进一步研究。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。虽然这项研究的重点是艾滋病毒，但同样的免疫刺激剂可以应用于许多其他感染的疫苗，包括流感，病毒性肝炎，西尼罗河病毒，天花和生物防御意义的药剂。

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.