Nucleoside modified mRNA based HIV vaccine

基于核苷修饰 mRNA 的 HIV 疫苗

• 批准号: 9117861
• 负责人: DREW WEISSMAN
• 金额: $ 86万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-20 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9117861
• 关键词: Adverse event; Antibodies; Antibody Formation; Antibody Response; Antigens; Avidity; Binding; Binding Sites; Biological Assay; CD4 Positive T Lymphocytes; Carbohydrates; Cell surface; Cellular biology; Clinical Trials; Cold Chains; Collaborations; Complement; Complex; Data; Development; Effectiveness; Epidemic; Epitopes; Formulation; Generations; Goals; Grant; HIV; HIV Envelope Protein gp120; HIV vaccine; Heating; Helper-Inducer T-Lymphocyte; Human; Immune response; Immunoglobulin G; Immunology; Indium; Life; Lipids; Macaca; Macaca mulatta; Mediating; Membrane; Messenger RNA; Methodology; Methods; Minority; Modeling; Modification; Molecular Biology; Molecular Conformation; Mus; Nucleic Acids; Nucleosides; Oryctolagus cuniculus; Parents; Phase III Clinical Trials; Physiological; Poxviridae; Production; Proteins; Protocols documentation; RNA; Route; Safety; Serum; Small Interfering RNA; System; T cell response; Testing; Therapeutic; Thermodynamics; Translations; V3 Loop; Vaccination; Vaccines; Viral; Viral Physiology; Virus; Virus Diseases; Work; base; cost; cost effective; env Gene Products; experience; immune RNA; immunogenicity; improved; in vivo; large scale production; long term memory; monomer; nanoparticle; neutralizing antibody; novel; novel strategies; novel vaccines; preclinical study; product development; public health relevance; research study; response; sensor; therapeutic protein; vaccine response; vaccinology; virology; virus envelope

 DESCRIPTION (provided by applicant): A single HIV vaccine in human clinical trials demonstrated low level and short-term effectiveness, RV144. This vaccine used Pox virus prime - protein boost methodology, which because of the live virus prime, presents difficulties for large scale production and safety. We have developed a new approach to the prime portion of an HIV vaccine that uses nucleoside modified mRNA composed entirely of physiologic components that is simple and cost effective to produce, does not require a cold chain, and should have no adverse events due to the mRNA. The mRNA is complexed in a lipid nanoparticle (LNP) whose formulation has entered phase 3 clinical trials for siRNA with no adverse events due to the lipids and is delivered by the intradermal route. To complement this novel method of priming an immune response, we have also developed a new immunogen that is an HIV envelope that does not require CD4 binding to infect a cell (CD4 independent). This envelope has a more open conformation, and we have demonstrated that it induces higher levels of Env-specific IgG, Tier-1 and 2 neutralization, and V1/V2 directed responses compared to their parents. In 3 specific aims, we will developed a new CD4 independent immunogen from a transmitted/founder clade C virus, compare it to already produced CD4i immunogens in the rabbit model and downselect for study in Rhesus macaques. We will also analyze boost proteins, comparing gp120 monomers to SOSIP trimers, in rabbits for use as a boost in macaques. We will then compare single immunogen prime-boost to multi-genic vaccination. We believe this new vaccine approach will be effective, in that it will develop high levels of Env-specific IgG, Tier-1 and 2 neutralization, and V1/V2 directed responses. In addition, we have demonstrated that the nucleoside modified mRNA-LNP prime induces very high levels (half of the total antigen-specific CD4+ T cell response) of antigen-specific T follicular helper (Tfh) cell that are critical in both the generation of high avidity IgG and long term memory, both of which are critical elements in the development of an effective HIV vaccine. This grant will move a new approach to vaccine priming and optimize immunogens for the prime and boost for testing in rabbits and Rhesus macaques. The data generated will be capable of moving this vaccine approach to clinical trial development with a minority of additional experiments.

 描述（由申请人提供）：人类临床试验中的单一 HIV 疫苗 RV144 表现出低水平和短期有效性。该疫苗采用痘病毒初免-蛋白加强方法，由于是活病毒初免，因此给大规模疫苗接种带来了困难。 规模生产和安全。我们开发了一种 HIV 疫苗主要部分的新方法，该方法使用完全由生理成分组成的核苷修饰 mRNA，其生产简单且具有成本效益，不需要冷链，并且不会因 mRNA 产生不良事件。 mRNA 复合在脂质纳米颗粒 (LNP) 中，其配方已进入 siRNA 的 3 期临床试验，没有因脂质引起的不良事件，并通过皮内途径递送。为了补充这种引发免疫反应的新方法，我们还开发了一种新的免疫原，它是一种 HIV 包膜，不需要 CD4 结合来感染细胞（不依赖 CD4）。该包膜具有更开放的构象，我们已经证明，与父母相比，它能诱导更高水平的 Env 特异性 IgG、Tier-1 和 2 中和以及 V1/V2 定向反应。在 3 个具体目标中，我们将从传播/创建分支 C 病毒中开发出一种新的 CD4 独立免疫原，将其与兔子模型中已产生的 CD4i 免疫原进行比较，并向下选择在恒河猴中进行研究。我们还将分析兔体内的加强蛋白，将 gp120 单体与 SOSIP 三聚体进行比较，以用作猕猴的加强蛋白。然后，我们将比较单一免疫原初免增强与多基因疫苗接种。我们相信这种新的疫苗方法将是有效的，因为它将产生高水平的 Env 特异性 IgG、Tier-1 和 2 中和以及 V1/V2 定向反应。此外，我们还证明，核苷修饰的 mRNA-LNP 引发剂可诱导非常高水平（占抗原特异性 CD4+ T 细胞总反应的一半）的抗原特异性滤泡辅助 T (Tfh) 细胞，这些细胞对于高亲合力 IgG 和长期记忆的生成至关重要，而这两者都是开发有效 HIV 疫苗的关键要素。这笔赠款将推动一种新的疫苗初免方法，并优化兔子和恒河猴测试的初免和加强免疫原。生成的数据将能够通过少量的额外实验将这种疫苗方法推向临床试验开发。