Induction of bnAbs against HIV-1 gp41.

针对 HIV-1 gp41 的 bnAb 的诱导。

• 批准号: 10603692
• 负责人: Michael W Cho
• 金额: $ 29.73万
• 依托单位: NEOVAXSYN, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10603692
• 关键词: AIDS Vaccines; AIDS vaccine development; Acquired Immunodeficiency Syndrome; Affinity; Amino Acids; Anti-Retroviral Agents; Antibodies; Antibody Response; Antigen-Antibody Complex; Antigens; B-Lymphocytes; C-terminal; Cells; Cellular Membrane; Chimeric Proteins; Complex; Crystallization; Development; Epitopes; Evaluation; Face; Feasibility Studies; Genes; Goals; Government; HIV-1; Human; Immune system; Immunize; Immunologics; Infection; Iowa; Lead; Length; Membrane; Molecular Conformation; Monoclonal Antibodies; Mus; NF1 gene; Patients; Peptide antibodies; Peptides; Persons; Pharmaceutical Preparations; Phase; Research Proposals; Scaffolding Protein; Side; Small Business Innovation Research Grant; Structure; Surface; Testing; Training; Transgenic Mice; Universities; Vaccines; Vaccinia virus; Variant; Viral; Virus; alpha helix; commercialization; flexibility; gp160; innovation; nanomolar; neutralizing antibody; neutralizing monoclonal antibodies; new technology; novel; novel vaccines; pandemic disease; phase 1 study; prevent; synergism; vaccine candidate; vaccine strategy

PROJECT SUMMARY/ABSTRACT Despite the availability of effective anti-retroviral drugs, there are still about 38 million people living with HIV-1 infection and about 1.5 million people became newly infected just in 2020. A vaccine is critically needed to stop the AIDS pandemic. Induction of broadly neutralizing antibodies (bnAbs) against HIV-1 is the utmost critical goal towards the development of a protective AIDS vaccine. In this R43 Phase I SBIR proposal, we will evaluate a novel “Antibody- Stabilized, Epitope Presentation” (ASEP) vaccine strategy to elicit 10E8-like bnAbs against HIV-1. 10E8, a bnAb isolated from an HIV-1-infected patient that targets the membrane proximal external region (MPER) of HIV-1 gp41, has been shown to neutralize ~98% of all HIV-1 isolates tested. Developing immunogens and/or establishing vaccine strategies that can induce 10E8-like bnAbs would be a major milestone towards AIDS vaccine development. Thus, our proposal is highly significant and, if successful, this project will have great impact in the AIDS vaccine field and immunogens we generate will be commercially valuable. The major innovation and the focus of this proposal is our ASEP vaccine strategy, in which precisely defined immune complexes are used as immunogens. This proposal is founded on three scientific premises. (1) A vaccine that can induce high titers of 10E8-like bnAbs will be protective against HIV-1 infections. (2) Although short peptides are good for focusing antibody responses, they are not ideal B-cell immunogens because they are highly flexible and can exist in many different conformations. (3) The conformation of a peptide can be fixed into a rigid structure when it is bound to an antibody. The primary objective of this Phase I R43 feasibility study is to demonstrate MPER/Antibody immune complexes can be used to elicit 10E8-like bnAbs against HIV-1. Successful completion of this study would overcome a critical roadblock towards development of a protective AIDS vaccine.

项目摘要/摘要 尽管有有效的抗逆转录病毒药物可用，但仍有大约3800万人患有HIV-1 感染和约150万人仅在2020年才新受到新感染。迫切需要一种疫苗来阻止艾滋病 大流行。诱导对HIV-1的广泛中和抗体（BNAB）是实现的最大关键目标 开发受保护的艾滋病疫苗。在此R43 I期SBIR提案中，我们将评估一种新颖的“抗体 - 稳定，表位表现”（ASEP）疫苗策略，以引起10E8样BNAB对HIV-1。10E8，一个分离的BNAB 已经显示了针对HIV-1近端外部区域（MPER）HIV-1 GP41的HIV-1感染患者 中和约98％的所有HIV-1分离株。开发免疫原子和/或建立可以 诱导10E8样的BNAB将是艾滋病疫苗开发的主要里程碑。那，我们的建议很高 重要的，如果成功的话，该项目将对我们产生的艾滋病疫苗领域和免疫原子产生巨大影响 将在商业上有价值。该提案的主要创新和重点是我们的ASEP疫苗策略，其中 精确定义的免疫复合物用作免疫原子。该提案建立在三个科学前提下。 （1）a 可以诱导10E8样BNAB的高滴度的疫苗将受到保护，以免HIV-1感染。 （2）虽然很短 肽非常适合聚焦抗体反应，它们不是理想的B细胞免疫原子，因为它们是高度灵活的 并且可以存在于许多不同的构象中。 （3）当肽的构象可以固定到刚性结构中 与抗体结合。该阶段I R43可行性研究的主要目的是证明MPER/抗体 免疫复合物可用于引起10E8样的BNAB针对HIV-1。成功完成这项研究将 克服朝着受保护的艾滋病疫苗开发的关键障碍。