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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要能够引发广泛中和抗体（bnAb）的 HIV-1 疫苗是一个主要目标。迄今为止，已经证明单一 bnAb 谱系（VRC01 类）可以在人体试验中被特异性激活。抗体该试验中的病毒不能中和 HIV-1，因此认为需要异源序贯免疫开发bnAb。异源序贯免疫已被用于在临床前产生bnAb 模型。虽然从感染个体中分离出的 VRC01 类抗体可能相当广泛，但广度的限制这些类型的疫苗接种策略在人体中诱导产生的 VRC01 类抗体尚不清楚。所以，我们正在通过先进的蛋白质开发替代 bnAb 谱系靶向疫苗（VH1-46 类）新生人类免疫球蛋白敲入小鼠的工程方法和评估 VH1-46 种系抗体。此外，我们正在寻求创新方法来开发双 bnAb 谱系可以与现有 VRC01 类疫苗产生协同作用的靶向疫苗。个体谱系定位疫苗可能无法成功地使这些谱系完全成熟，从而严重限制中和广度以及这些疫苗的最终有效性。双谱系靶向可能对于第一个 bnAb 的成功至关重要引发 HIV-1 疫苗。