Development of an mRNA-Based Therapeutic HIV/AIDS Vaccine

开发基于 mRNA 的治疗性 HIV/AIDS 疫苗

• 批准号: 10585914
• 负责人: Afamefuna Okoye
• 金额: $ 84.05万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-05 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585914
• 关键词: Acute; Address; Antigens; B-Lymphocytes; Binding; Blood; CD8-Positive T-Lymphocytes; Cellular Immunity; Clinical; Clinical Research; Clinical assessments; Collaborations; DNA; Data; Development; Disease Progression; Disease remission; Dose; Economic Burden; Ensure; Epitope Mapping; Epitopes; Frequencies; GAG Gene; Generations; Genes; Germany; Goals; HIV; HIV Infections; HIV vaccine; Health; Human; Immune; Immune response; Immunity; Immunologics; Individual; Infection; Injections; Life; Life Expectancy; Lymphoid Tissue; Macaca mulatta; Measurable; Mediating; Messenger RNA; Patients; Peptides; Persons; Plasma; Positioning Attribute; Primary Infection; Prognosis; RNA; RNA vaccine; Recrudescences; Regimen; Risk; Route; SIV; SIV Vaccines; Site; Societies; Specificity; Stains; T cell response; T-Lymphocyte Epitopes; Technology; Therapeutic; Time; Vaccinated; Vaccination; Vaccine Design; Vaccine Therapy; Vaccines; Viral; Viral Load result; Viral reservoir; Virus; Virus Diseases; Virus Replication; Withdrawal; anti-CD20; antiretroviral therapy; antiviral immunity; biopharmaceutical industry; clinical translation; cohort; cytokine; design; experimental study; immunogenic; improved; lymph nodes; novel therapeutic intervention; prevent; relapse prevention; response; safety and feasibility; therapeutic vaccine; therapy design; tool; tositumomab; vaccination protocol; vaccination schedule; vaccination strategy; vaccine efficacy; vaccine platform; vector; vector control; vector vaccine; viral rebound

PROJECT SUMMARY Although the advent of combination antiretroviral therapy (cART) has dramatically improved the prognosis of people living with human immunodeficiency virus (HIV), cART alone cannot eradicate the infection and, therefore, daily treatment must be maintained for life to prevent relapse of uncontrolled viral replication and resumption of disease progression. However, lifelong treatment entails both health risks to treated individuals and a significant economic burden to society. As such, there is a pressing need to develop novel therapeutic interventions to cure HIV. Since most examples of stringent, long-term, spontaneous and vaccine-associated immune control of HIV and simian immunodeficiency virus (SIV) infection are either known, or strongly suspected to be CD8+ T cell-mediated, therapeutic strategies designed to exploit CD8+ T cell immunity hold great promise for achieving durable control of virus replication in the absence of cART, often referred to as a “functional cure”. However, in most people, naturally occurring CD8+ T cell responses induced by HIV infection are often ineffective at controlling the virus. As such, any HIV cure strategy based on enhancing CD8+ T cell immunity would need to elicit immune responses that are qualitatively and/or quantitatively different from those that emerge during primary infection and are subsequently maintained during cART. In addition, in the setting of cure where the rebound-competent viral reservoir is systemically distributed, having high frequencies of effector- differentiated and functionally potent anti-viral CD8+ T cell responses pre-positioned in sites of potential viral rebound (even in immune privileged sites such as B cell follicles) at the time of cART cessation is likely to be critical for achieving durable post-cART viral control. In this project, we will determine whether a therapeutic vaccination strategy that utilizes the messenger ribonucleic acid (mRNA)-based vaccine platform RNActive, can enhance cellular immunity in SIV-infected rhesus macaques (RM) on cART and establish high-level, long- term control of SIV replication after cART cessation. The choice of this vector is based on preliminary data demonstrating RNActivevaccines with SIV gene inserts (mRNA/SIV) are highly immunogenic in RM, with the capacity to elicit potent, systemically distributed, SIV-specific CD8+ T cells with broad epitope recognition. Here we will assess whether mRNA/SIV vaccination alone or in combination with anti-CD20 B cell depletion (to disrupt B cell follicles) can facilitate immediate interception of rebounding viral reservoirs to facilitate durable control of SIV replication after cART cessation. Any finding of vaccine efficacy in this project will provide strong impetus for clinical assessment of the RNActiveplatform in cART-suppressed HIV+ patients and potentially lead to a clinically translatable therapeutic approach to achieve HIV infection remission off cART.

项目概要 尽管联合抗逆转录病毒疗法（cART）的出现极大地改善了患者的预后 对于感染人类免疫缺陷病毒 (HIV) 的人，仅使用 cART 无法根除感染，并且 因此，必须终生维持日常治疗，以防止不受控制的病毒复制复发和 疾病进展的恢复。然而，终身治疗会给接受治疗的个人带来健康风险 并给社会带来重大的经济负担。因此，迫切需要开发新的治疗方法 治愈艾滋病毒的干预措施。由于大多数严格的、长期的、自发的和与疫苗相关的例子 HIV 和猿猴免疫缺陷病毒 (SIV) 感染的免疫控制要么是已知的，要么是强烈怀疑的 由于 CD8+ T 细胞介导，旨在利用 CD8+ T 细胞免疫的治疗策略前景广阔 在没有 cART 的情况下实现病毒复制的持久控制，通常被称为“功能性治愈”。 然而，在大多数人中，由 HIV 感染诱导的自然发生的 CD8+ T 细胞反应通常是 无法有效控制病毒。因此，任何基于增强 CD8+ T 细胞免疫的 HIV 治疗策略 需要引发与那些在质量和/或数量上不同的免疫反应 在原发感染期间出现，随后在 cART 期间维持。另外，在治愈的情况下 其中具有反弹能力的病毒库是系统分布的，具有高频率的效应子 预先定位在潜在病毒位点的分化且功能有效的抗病毒 CD8+ T 细胞反应 cART 停止时的反弹（甚至在 B 细胞滤泡等免疫特权部位）很可能是 对于实现持久的 cART 后病毒控制至关重要。在这个项目中，我们将确定是否有治疗方法 利用基于信使核糖核酸 (mRNA) 的疫苗平台 RNActive 的疫苗接种策略， 可以增强 CART 感染 SIV 的恒河猴 (RM) 的细胞免疫，并建立高水平、长期 cART 停止后 SIV 复制的长期控制。该向量的选择基于初步数据 证明带有 SIV 基因插入 (mRNA/SIV) 的 RNActive 疫苗在 RM 中具有高度免疫原性， 能够引发有效的、系统性分布的、具有广泛表位识别的 SIV 特异性 CD8+ T 细胞。这里 我们将评估是否单独进行 mRNA/SIV 疫苗接种或与抗 CD20 B 细胞耗竭相结合（以破坏 B细胞滤泡）可以促进立即拦截反弹的病毒库，从而促进持久控制 cART 停止后 SIV 复制。该项目中任何疫苗功效的发现都将提供强大的推动力 用于对 cART 抑制的 HIV+ 患者中的 RNActive 平台进行临床评估，并可能导致 通过 cART 实现 HIV 感染缓解的临床可转化治疗方法。