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.

项目概要/摘要 尽管有有效的抗逆转录病毒药物，但仍有约 3800 万人感染 HIV-1 仅 2020 年，就有约 150 万人新增感染。迫切需要疫苗来阻止艾滋病 诱导抗 HIV-1 的广泛中和抗体 (bnAb) 是实现这一目标的最关键目标。 开发保护性艾滋病疫苗 在 R43 I 期 SBIR 提案中，我们将评估一种新型“抗体”。 10E8，分离的 bnAb 来自 HIV-1 感染患者的靶向 HIV-1 gp41 的膜近端外部区域 (MPER) 的研究已被证明 中和约 98% 的所有测试的 HIV-1 分离株 开发免疫原和/或建立可以的疫苗策略。 诱导 10E8 样 bnAbs 将是艾滋病疫苗开发的一个重要里程碑因此，我们的建议是高度的。 意义重大，如果成功，该项目将对艾滋病疫苗领域和我们产生的免疫原产生巨大影响 该提案的主要创新和重点是我们的 ASEP 疫苗策略，其中 使用精确定义的免疫复合物作为免疫原。该提议基于三个科学前提（1）A。 能够诱导高滴度 10E8 样 bnAb 的疫苗将能够预防 HIV-1 感染 (2) 尽管时间较短。 肽有利于集中抗体反应，但它们不是理想的 B 细胞免疫原，因为它们高度灵活 (3)肽的构象可以固定成刚性结构。 该 I 期 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发针对 HIV-1 的 10E8 样 bnAb。 克服开发保护性艾滋病疫苗的关键障碍。