Induction of bnAbs against HIV-1 gp41.

项目摘要/摘要 尽管有有效的抗逆转录病毒药物可用，但仍有约3800万艾滋病毒携带者 仅在2020年，就有大约150万人新感染。迫切需要一种疫苗来阻止艾滋病 大流行。诱导针对HIV-1的广谱中和抗体(BNAbs)是实现 开发保护性艾滋病疫苗。在这个R43阶段的SBIR方案中，我们将评估一种新的“抗体-- 稳定的表位呈现“(ASEP)疫苗策略，以诱导抗HIV-1的10E8样bNAb。10E8，一株分离的bNab 来自一名HIV-1感染患者，靶向HIV-1 gp41的膜近端外部区域(MPER) 中和约98%的测试HIV-1分离株。开发免疫原和/或建立疫苗策略，以 诱导类似10E8的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 如果成功，这个项目将对艾滋病疫苗领域和我们生产的免疫原产生重大影响 将具有商业价值。这项提案的主要创新和重点是我们的ASEP疫苗战略，其中 精确定义的免疫复合体被用作免疫原。这项提议建立在三个科学前提之上。(1)A类 能够诱导高滴度类似10E8的bNAbs的疫苗将对HIV-1感染具有保护作用。(2)虽短 多肽有利于集中抗体反应，但它们不是理想的B细胞免疫原，因为它们具有高度的灵活性 并且可以以多种不同的构象存在。(3)肽的构象可以固定在刚性结构中，当它 与一种抗体相结合。这项第一阶段R43可行性研究的主要目标是证明MPER/抗体 免疫复合体可用于诱导10E8样抗HIV-1的bNAb。成功完成这项研究将 克服开发保护性艾滋病疫苗的关键障碍。

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.