Optimization of a Therapeutic HIVSIV Multi-Antigen DNA Vaccine

治疗性 HIVSIV 多抗原 DNA 疫苗的优化

• 批准号: 9319619
• 负责人: Kenneth C Bagley
• 金额: $ 83.85万
• 依托单位: PROFECTUS BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9319619
• 关键词: Adjuvant; Animals; Antibodies; Antigens; Blood; CD8B1 gene; Cessation of life; Clinical Trials; Containment; DNA; DNA Vaccines; DNA delivery; Developed Countries; Developing Countries; Devices; Drug Combinations; Electroporation; Employee Strikes; Enterotoxins; Epitopes; Formulation; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Heterophile Antigens; Highly Active Antiretroviral Therapy; Homing; Human; Immune; Immune Targeting; Immune response; Immunization; Immunocompetent; Immunomodulators; Infection; Intramuscular; Lead; Macaca; Macaca mulatta; Mediating; Muscle; Mutation; Performance; Phase; Plasma; Plasmids; Prevention program; Public Health; Recording of previous events; Regimen; Residual state; Risk; Route; SIV; Site; Skin; Small Business Innovation Research Grant; Specificity; T cell response; T-Lymphocyte; Therapeutic; Tissues; Toxic effect; Vaccination; Vaccine Antigen; Vaccines; Viral; Viral Load result; Viral reservoir; Viremia; Virus; Virus Diseases; Virus Replication; antiretroviral therapy; base; combat; compare effectiveness; gene gun; gp160; improved; novel; pandemic disease; prevent; public health relevance; response; therapeutic DNA; therapeutic vaccine; viral rebound

DESCRIPTION: The HIV pandemic is one of the greatest public health challenges in history. It is estimated that 33 million people are living with HIV and 2.7 million of those are newly infected In a number of developed countries, the risk of death associated with HIV-1 infection has sharply declined due to the use of highly active antiretroviral therapy (HAART). Unfortunately, the rate of new HIV infections remains undiminished, even with the ever increasing availability of prevention programs and HAART. For these reasons, a vaccine that could prevent or control the spread of HIV is urgently needed. A recent study showed that a skin-delivered therapeutic DNA vaccine co-formulated with a novel adjuvant stimulated mucosal T cell responses in SIV-infected macaques and led to durable viral suppression in a subset of animals after stopping ART. These results are in striking contrast to previous therapeutic vaccines employing intramuscular delivery of DNA that failed to induce an effect or at best, induced a 1-2 log reduction in viremia or transient control of viral rebound. We propose to make therapeutic DNA vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a more potent adjuvant strategy that increases DNA vaccine induction of antibody and T cell responses and stimulates homing of these responses to gut associated lymphoid tissues, and 3) using a novel electroporation DNA delivery device that more efficiently delivers DNA into the skin (a more immunocompetent site than muscle for induction of systemic and mucosal responses). Our overarching hypothesis is that a vaccine-induced functional cure will be mediated by strong mucosal responses, and that increasing and focusing these responses to the gut in maximally suppressed infections via use of an optimized mucosal adjuvant and delivery into skin will maximally reduce or prevent residual viruses from emerging from the gut reservoir after stopping cART. To this end, we have assembled a panel of four DNA-based adjuvants that we hypothesize will induce robust anti-HIV mucosal and systemic immune responses when combined. Under this fast track SBIR, we will investigate adjuvant combinations with our HIV/SIV multi-antigen (MAG) DNA vaccine consisting of plasmids expressing env (gp160), a gag/pol fusion, and a nef/tat/vif fusion. We anticipate that an optimal combination of these adjuvants will elevate the performance of our MAG DNA vaccine to a level worthy of human trials.

描述：艾滋病大流行是历史上最大的公共卫生挑战之一。据估计，有3 300万人感染了艾滋病毒，其中270万人是新感染的。在一些发达国家，由于使用了高效抗逆转录病毒疗法，与1型艾滋病毒感染有关的死亡风险已急剧下降。不幸的是，即使预防方案和HAART的可用性不断提高，新的艾滋病毒感染率仍然没有下降。由于这些原因，迫切需要一种能够预防或控制艾滋病毒传播的疫苗。最近的一项研究表明，一种皮肤递送的治疗性DNA疫苗与一种新型佐剂共同配制，可刺激siv感染的猕猴的粘膜T细胞反应，并在停止抗逆转录病毒治疗后，在一部分动物中导致持久的病毒抑制。这些结果与以前采用肌肉注射DNA的治疗性疫苗形成鲜明对比，后者未能诱导效果，或充其量诱导病毒血症减少1-2个对数或短暂控制病毒反弹。我们建议通过以下方式使治疗性DNA疫苗更加有效：1)使用更有效的药物组合（cART）来最大化疫苗的效果；2)使用更有效的佐剂策略，增加DNA疫苗对抗体和T细胞反应的诱导，并刺激这些反应归巢到肠道相关淋巴组织。3)使用一种新型的电穿孔DNA递送装置，该装置可以更有效地将DNA递送到皮肤（比肌肉更具有免疫活性的部位，可诱导全身和粘膜反应）。我们的首要假设是，疫苗诱导的功能性治愈将由强烈的粘膜反应介导，通过使用优化的粘膜佐剂并将其递送到皮肤中，在最大限度地抑制感染中增加和集中这些对肠道的反应，将最大限度地减少或防止在停止cART后从肠道储存库中出现残留病毒。为此，我们组装了一组四种基于dna的佐剂，我们假设当组合时将诱导强大的抗hiv粘膜和全身免疫反应。在这个快速通道SBIR下，我们将研究佐剂与我们的HIV/SIV多抗原（MAG） DNA疫苗的组合，该疫苗由表达env （gp160）、gag/pol融合和nef/tat/vif融合的质粒组成。我们预计，这些佐剂的最佳组合将把我们的MAG DNA疫苗的性能提升到值得人体试验的水平。