Targeting HIV reservoirs in children with HIVIS DNA and MVA-CMDR vaccines

使用 HIVIS DNA 和 MVA-CMDR 疫苗针对儿童中的 HIV 储存者

• 批准号: 10088377
• 负责人: Paolo Palma
• 金额: $ 98.67万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088377
• 关键词: 18 year old; Adherence; Adjuvant; Adult; Age-Months; Agonist; Antibodies; Antigens; Binding; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cervarix; Child; DNA; Data; Dendritic Cells; Disease remission; Epidemic; Failure; Frequencies; Goals; HIV; HIV vaccine; Human Papillomavirus; Immune; Immune response; Immunity; Immunologic Surveillance; Infant; Intervention; Italy; Knowledge; Life; Measures; Military Personnel; Mississippi; PHEMX gene; Participant; Pediatrics; Pharmaceutical Preparations; Population; Prior Therapy; RNA; RNA Splicing; Randomized; Reporting; Research; Safety; South Africa; T cell response; TLR4 gene; Thailand; Therapeutic; Vaccinated; Vaccination; Vaccines; Viral; Virus; Youth; adaptive immune response; aged; antibody-dependent cell cytotoxicity; antiretroviral therapy; base; cohort; cost; immunogenicity; neutralizing antibody; novel; perinatal HIV; post intervention; programs; vaccine trial; virology

Summary This will be the first combined therapeutic HIV vaccine study in pediatrics. Our goal is to develop therapeutic HIV vaccines to reduce the HIV reservoirs in children and youth with HIV. Our scientific premise is that the prime-boost HIVIS DNA and MVA-CMDR vaccines induce cellular and humoral immune responses important for clearing infected cells. They were selected for children based on ample adult safety data. We include early treated children because of their healthy immunity and small HIV reservoirs. Other novel components include giving a licensed vaccine against human papilloma virus that contains toll-like receptor (TLR) 4 agonist adjuvant to boost immune responses to HIVIS DNA. We will also give MVA-CMDR to the only 10 HIV-infected children worldwide that previously had HIVIS DNA as this late boost strategy was shown in adults to enhance immunity to vaccines. We will include children from South Africa, Thailand and Italy infected with different clades of HIV - a strength that will support the generalizability of the results to the global epidemic. The project will be conducted under the umbrella of the EPIICAL Consortium and the US. Military HIV Research Program that is dedicated to developing therapeutic HIV vaccines as a strategy towards an HIV remission. Thirty-five participants will be in this 48-week study including 25 that are 9 to 18 years old who started HIV medications prior to 6 months of age and are virally suppressed. They will be randomly assigned to HIV vaccines (n=10) vs. HIV vaccines+TLR4 agonist (n=10) vs. control (no interventions) (n=5). Vaccines will be given at weeks 0, 4 and 12 for HIVIS DNA and TLR4 agonist, and weeks 24 and 36 for MVA-CMDR. The MVA-CMDR late boost 7 years after HIVIS DNA will be evaluated in 10 Italian youth aged 14 to 24 years old. We will extensively measure the changes of HIV reservoirs and immune responses post interventions. Aim 1: To quantitate and characterize the HIV reservoirs before and after HIVIS DNA ± TLR4 agonist and MVA-CMDR vaccination Aim 2: To characterize HIV-specific cellular and humoral immune responses before and after vaccination and assess their relationship to the HIV reservoir endpoints. Aim 3: To quantitate and characterize the immunogenicity and HIV reservoir endpoints in youth previously vaccinated with HIVIS DNA and receiving MVA-CMDR late boost. The knowledge generated will contribute to the optimization of therapeutic HIV vaccine strategies and exert sustained influence on HIV cure research for children and youth.

摘要 这将是儿科首个联合治疗性艾滋病毒疫苗研究。我们的目标是开发出治疗方法 艾滋病毒疫苗，以减少艾滋病毒携带者儿童和青年中的艾滋病毒蓄积物。我们的科学前提是 Prime-Boost HiVis DNA和MVA-Cmdr疫苗诱导细胞和体液免疫应答 用于清除受感染的细胞。它们是根据大量的成人安全数据为儿童选择的。我们包括EARTY 治疗儿童的原因是他们健康的免疫力和较小的艾滋病毒宿主。其他新颖的组件包括 给出一种含有Toll样受体(TLR)4激动剂的人乳头瘤病毒特许疫苗 佐剂，以增强对HIV DNA的免疫反应。我们还将为仅有的10名艾滋病毒感染者提供MVA-Cmdr 世界各地以前携带HIV DNA的儿童在成年人中显示出这种晚期增强策略 对疫苗的免疫力。我们将包括来自南非、泰国和意大利的儿童感染不同的 艾滋病毒的分支--这一力量将支持将结果推广到全球流行病。该项目 将在EPIICAL财团和美国的保护下进行。军事艾滋病毒研究计划 它致力于开发治疗性艾滋病毒疫苗，作为缓解艾滋病毒的战略。 35名参与者将参加这项为期48周的研究，其中25名9岁至18岁的人开始感染艾滋病毒 在6个月前服用药物，并被病毒抑制。他们将被随机分配到艾滋病毒 疫苗(n=10)与HIV疫苗+TLR4激动剂(n=10)与对照组(无干预)(n=5)。疫苗将是 HIVis DNA和TLR4激动剂在0、4和12周给药，MVA-Cmdr在24和36周给药。这个 在HiVis DNA 7年后，将对10名14至24岁的意大利青年进行MVA-Cmdr晚期增强试验。 我们将广泛测量干预后HIV宿主和免疫反应的变化。 目的1：定量和表征HiVis DNA±TLR4激动剂和 MVA-Cmdr疫苗接种 目的2：研究疫苗接种前后HIV特异性细胞和体液免疫反应的特征 评估它们与艾滋病毒储存库终点的关系。 目的3：量化和表征先前在青年中的免疫原性和HIV储存库终点 接种HIVis DNA疫苗，接受MVA-Cmdr晚期加强免疫。 所产生的知识将有助于优化治疗性艾滋病毒疫苗策略，并发挥 对儿童和青年艾滋病毒治疗研究的持续影响。