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: 8789075
• 负责人: Kenneth C Bagley
• 金额: $ 30万
• 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 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789075
• 关键词: Adjuvant; Animals; Antibodies; Antigens; Blood; CD8B1 gene; Cessation of life; Clinical Trials; Containment; DNA; DNA Vaccines; DNA delivery; Developed Countries; Devices; Disease; Drug Combinations; Drug Formulations; Electroporation; Employee Strikes; Epitopes; Gagging; Gut associated lymphoid tissue; HIV; HIV Infections; HIV-1; Heating; Heterophile Antigens; Highly Active Antiretroviral Therapy; Homing; Human; Immune; Immune Targeting; Immune response; Immunization; Immunocompetent; Immunomodulators; Infection; Intramuscular; Lead; Life; 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; Viremia; Virus; antiretroviral therapy; base; combat; compare effectiveness; enterotoxin LT; gene gun; gp160; improved; novel; pandemic disease; prevent; public health relevance; response; therapeutic DNA; therapeutic vaccine

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：艾滋病毒大流行是历史上最大的公共卫生挑战之一。据估计，有3300万艾滋病毒携带者，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(HAART)，与艾滋病毒-1感染相关的死亡风险急剧下降。不幸的是，即使预防方案和HAART的可用性不断增加，新的艾滋病毒感染率仍然没有减少。出于这些原因，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，与一种新型佐剂共同配制的皮肤递送治疗性DNA疫苗刺激了SIV感染猕猴的粘膜T细胞反应，并在停止ART后在一组动物中导致了持久的病毒抑制。这些结果与以前使用肌肉注射DNA的治疗性疫苗形成鲜明对比，以前的疫苗未能产生效果，或者充其量只能诱导病毒血症减少1-2个对数或暂时控制病毒反弹。我们建议通过以下方式使治疗性DNA疫苗更有效：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疫苗诱导抗体和T细胞反应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递送设备，更有效地将DNA输送到皮肤(诱导全身和粘膜反应的免疫活性比肌肉更高的部位)。我们的主要假设是，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这些反应集中在最大限度地抑制感染的肠道中，并将其输送到皮肤中，将最大限度地减少或防止停止CART后残留病毒从肠道储存库中涌出。为此，我们已经组装了一个由四种基于DNA的佐剂组成的小组，我们假设当它们组合在一起时将诱导强大的抗HIV粘膜和系统免疫反应。在这一快速通道SBIR下，我们将研究与我们的HIV/SIV多抗原(MAG)DNA疫苗的佐剂组合，该DNA疫苗由表达env的质粒(Gp160)、Gag/Poll融合和nef/Tat/vif融合组成。我们预计，这些佐剂的最佳组合将把我们的MAG DNA疫苗的性能提高到值得进行人体试验的水平。