Investigation into the activation of multiple bnAb precursors using structure-designed immunogens and Ig knock-in mice

使用结构设计的免疫原和 Ig 敲入小鼠研究多种 bnAb 前体的激活

• 批准号: 10619836
• 负责人: Daniel Kulp
• 金额: $ 84.31万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-03 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10619836
• 关键词: Affinity; Animals; Antibodies; Antibody Repertoire; Antibody Response; Antigens; Area; B cell repertoire; B-Lymphocytes; Binding Sites; Biological Models; Cessation of life; Clinic; Clinical; Clinical Research; Custom; Data; Development; Engineering; Epitopes; Frequencies; Goals; HIV; HIV vaccine; HIV-1; HIV-1 vaccine; Human; Immune response; Immunization; Immunoglobulins; Individual; Investigation; Knock-in Mouse; Knowledge; Modeling; Mus; Mutation; Pathway interactions; Persons; Phase; Physiological; Population; Pre-Clinical Model; Productivity; Protein Engineering; Public Health; Research; Series; Structure; Technology; Testing; Vaccination; Vaccine Design; Vaccines; Virus; Yeasts; biophysical properties; design; experience; global health; innovation; interest; lead candidate; member; mosaic; mouse model; nanoparticle; neutralizing antibody; next generation sequencing; nonhuman primate; novel strategies; pandemic disease; programs; prophylactic; response; success; synergism; tool; vaccination strategy; vaccine effectiveness; vaccine-induced antibodies

Project Summary HIV-1 vaccines that can elicit broadly neutralizing antibodies (bnAbs) are a primary goal. To date, it has been demonstrated that a single bnAb lineage (VRC01-class) can be specifically activated in human trials. Antibodies from this trial do not neutralize HIV-1 and heterologous sequential immunization is thought to be required to develop bnAbs. Heterologous sequential immunization has been employed to generate bnAbs in pre-clinical models. While VRC01-class antibodies isolated from infected individuals can be quite broad, the limit of breadth for VRC01-class antibodies induced by these types of vaccination strategies in people is unknown. Therefore, we are developing an alternative bnAb lineage targeting vaccine (VH1-46 class) through advanced protein engineering approaches and assessment in newly generated human immunoglobulin knock-in mice harboring VH1-46 germline antibodies. Further, we are pursuing innovative approaches to develop a dual bnAb lineage targeting vaccine which could synergize with current VRC01-class vaccines. Individual lineage targeting vaccines may not succeed at fully maturating these lineages, thus severely limiting the neutralization breadth and ultimate effectiveness of these vaccines. Dual lineage targeting may be critical for success of the first bnAb- eliciting HIV-1 vaccine.

项目摘要 可以引发广泛中和抗体（bnAb）的HIV-1疫苗是主要目标。迄今为止， 证明了单一bnAb谱系（VRC 01类）可以在人体试验中特异性激活。抗体 从该试验中获得的免疫不能中和HIV-1，并且认为需要异源顺序免疫， 开发bnAbs。异源性序贯免疫已被用于在临床前免疫中产生bnAb。 模型虽然从受感染个体分离的VRC 01类抗体可以相当广泛，但宽度的限制是有限的。 对于由这些类型的疫苗接种策略在人群中诱导的VRC 01类抗体，尚不清楚。因此，我们认为， 我们正在开发一种替代的bnAb谱系靶向疫苗（VH 1 -46类），通过先进的蛋白质， 在新产生的人免疫球蛋白基因敲入小鼠中的工程方法和评估 VH 1 -46生殖系抗体。此外，我们正在寻求创新方法来开发双bnAb谱系， 靶向疫苗，可与现有的VRC 01类疫苗协同作用。个体谱系靶向 疫苗可能不能成功地使这些谱系完全成熟，从而严重限制了中和宽度 这些疫苗的最终效果。双谱系靶向可能是第一个bnAb成功的关键- 引发HIV-1疫苗。