Conserved Elements Therapeutic DNA Vaccine for HIV

HIV 保守元件治疗性 DNA 疫苗

• 批准号: 8606654
• 负责人: Deborah H. Fuller
• 金额: $ 95.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606654
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Animals; Antigens; Avidity; Blood; CD8B1 gene; Combined Vaccines; Conserved Sequence; Control Animal; DNA; DNA Vaccines; Disease; Drug Combinations; Elements; Epidermis; Epitopes; Evolution; Exhibits; Failure; Frequencies; Gagging; Goals; Gut associated lymphoid tissue; HIV; HIV Envelope Protein gp120; HIV-1; Highly Active Antiretroviral Therapy; Immune; Immune Targeting; Immune response; Immunization; Indium; Infection; Inflammatory disease of the intestine; Lead; Macaca; Macaca mulatta; Measures; Mediating; Methods; Mutate; Mutation; Patients; Pharmaceutical Preparations; Pharmacotherapy; Plasma; Proteins; Regimen; Residual state; Role; SIV; Specificity; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Tissues; Treatment Efficacy; Vaccinated; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viremia; Virus; antiretroviral therapy; cost; design; fitness; frontier; gene gun; improved; novel; novel therapeutics; prevent; prototype; public health relevance; response; therapeutic vaccine

DESCRIPTION (provided by applicant): Our previous studies have shown that therapeutic DNA vaccine induction of mucosal responses correlated with significant reduction of virus in the gut of SIV-infected macaques despite the use of a suboptimal ART regimen. This vaccine stimulated T cell responses that suppressed virus to low/undetectable levels and afforded a durable "functional cure" in ~50% of the animals after stopping ART. We propose here to make therapeutic vaccination even more effective by 1) using a more potent combination of drugs (cART) to maximize the effects of the vaccine, 2) using a mucosal adjuvant (LT) to target immune responses to residual virus in gut associated lymphoid tissue, and 3) use of a novel SIV conserved elements (CE) DNA vaccine to focus T cell responses against highly conserved viral sequences that if mutated will impose greater fitness cost. Our overarching hypothesis is that vaccine-induced functional cure is mediated by strong mucosal CD8 responses, and that focusing these responses to the gut in maximally suppressed infections and against more conserved epitopes, which suppress a wider range of possible viral variants and select for more fitness-costing escape mutations, will maximally disable the ability of residual viruses to emerge from the latent reservoir after stopping cART. Operationally, using optimized cART and mucosal targeting we will compare a traditional whole antigen and a CE DNA vaccine for the ability to increase the frequency and strength of mucosal and systemic CD8 responses against conserved viral sequences, and for their impact on viral evolution and fitness, and determine the role of these factors in a functional cure. Our specific aims are to: 1) Determine therapeutic efficacy of an LT-adjuvanted traditional SIV DNA vaccine expressing whole antigens when used with more potent cART. 2) Determine if an SIV CE immunogen will improve therapeutic efficacy. 3) Define immune and virological mechanisms underlying functional cures. Through the proposed studies we will define the virological and immune profile of a vaccine-induced functional cure and determine the feasibility of a novel CE DNA vaccine to induce a functional cure of SIV infection.

描述（由申请人提供）： 我们以前的研究表明，尽管使用了次优的ART方案，但治疗性DNA疫苗诱导的粘膜反应与SIV感染的猕猴肠道中病毒的显著减少相关。这种疫苗刺激T细胞反应，将病毒抑制到低/不可检测的水平，并在停止ART后约50%的动物中提供持久的“功能性治愈”。我们在这里提出通过1）使用更有效的药物组合（cART）使疫苗的效果最大化，2）使用粘膜佐剂（LT）来靶向针对肠相关淋巴组织中残留病毒的免疫应答，和3）使用新的SIV保守元件（CE）DNA疫苗将T细胞反应集中在高度保守的病毒序列上，如果突变，将产生更大的适应性成本。我们的总体假设是，疫苗诱导的功能性治愈是由强烈的粘膜CD 8应答介导的，并且将这些应答集中于肠道，最大限度地抑制感染，并针对更保守的表位，这些表位抑制更广泛的可能的病毒变体并选择更多的适应性逃逸突变，将最大限度地禁用残留病毒在停止cART后从潜伏库中出现的能力。在操作上，使用优化的cART和粘膜靶向，我们将比较传统的全抗原和CE DNA疫苗的能力，以增加针对保守病毒序列的粘膜和全身CD 8应答的频率和强度，以及它们对病毒进化和适应性的影响，并确定这些因素在功能性治愈中的作用。我们的具体目标是：1）确定当与更有效的cART一起使用时，表达完整抗原的LT佐剂化的传统SIV DNA疫苗的治疗功效。2)确定SIV CE免疫原是否会提高治疗效果。3)定义功能性治疗的免疫和病毒学机制。通过拟议的研究，我们将确定疫苗诱导的功能性治愈的病毒学和免疫学特征，并确定一种新的CE DNA疫苗诱导SIV感染的功能性治愈的可行性。