Tracking the evolutionary trajectory of neutralizing antibodies following BG505 SOSIP immunization

追踪 BG505 SOSIP 免疫后中和抗体的进化轨迹

基本信息

批准号：
10620979
负责人：
Cynthia Ann Derdeyn
金额：
$ 82.28万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-16 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10620979
关键词：
Address Adjuvant Alleles Animals Antibodies Antibody Response Antibody Specificity Antibody titer measurement Antigens Attention Autologous B-Lymphocytes Binding Binding Sites Biophysics CD4 Antigens Characteristics Clinical Cryoelectron Microscopy Cryopreservation Cyclic GMP Databases Dependence Development Epitopes Exhibits Formulation HIV HIV Envelope Protein gp120 HIV Vaccine Trials Network HIV-1 Human Human Volunteers Immunization Immunize Immunoglobulin G Immunoglobulins Individual Macaca mulatta Maps Modeling Participant Pathway interactions Phase I Clinical Trials Plasma Polysaccharides Production Resources Retrospective Studies Sampling Serum Site Structure Surface Plasmon Resonance Testing Vaccination Vaccines Variant Viral Virus X-Ray Crystallography antigen binding biophysical properties clinically significant glycosylation human subject improved multidisciplinary mutant neutralizing antibody neutralizing monoclonal antibodies non-Native nonhuman primate novel pre-clinical preclinical study simian human immunodeficiency virus vaccination strategy

项目摘要

PROJECT SUMMARY/ABSTRACT Stabilized HIV-1 envelope gp140 trimers such as BG505 SOSIP provide a viable platform to elicit protective neutralizing antibodies that can be improved upon through various approaches to induce heterologous neutralizing breadth. BG505 SOSIP trimer immunization elicits protective neutralizing antibodies in rhesus macaques and is now being tested in several phase I clinical trials, including HVTN 137. Here we will perform in-depth studies to determine how antibodies that neutralize only the autologous virus and those that also have activity against heterologous viral variants developed in parallel during BG505 SOSIP immunization of rhesus macaques using cryopreserved samples. We will then track the antibody germline precursors for these neutralizing antibodies in other immunized rhesus macaques that share the allele to understand why they sometimes failed to develop these activities. We will also compare the targets of the neutralizing antibody responses in BG505 SOSIP immunized human subjects to those recognized in the rhesus macaque model. The HVTN 137 trial is also administering BG505 SOSIP with different adjuvants and we will investigate how these impact neutralizing antibody specificities in the human volunteers. Finally, we will isolate neutralizing monoclonal antibodies from selected BG505 SOSIP immunized rhesus macaques and human subjects to compare the structural and biophysical properties of antigen recognition. These extensive pre-clinical and clinical resources combined with our multidisciplinary expertise provides a novel setting in which to address barriers that impede the development of effective HIV vaccination strategies. If successful, these studies will illuminate new strategies to improve upon HIV-1 trimer envelope immunogens and adjuvants.

项目摘要/摘要稳定的HIV-1信封GP140三聚机（例如BG505 SOSIP）提供了一个可行的平台，以引起保护可以通过各种诱导异源的方法改善的中和抗体中和广度。 BG505 SOSIP三聚体免疫引起恒河猴中和抗体的保护性中和抗体猕猴，现在正在进行I期临床试验中，包括HVTN 137。深入研究以确定如何仅中和自体病毒的抗体以及那些也具有的抗体 BG505 SOSIP免疫的恒河猴在BG505中平行开发的异源病毒变异的活性使用冷冻保存样品的猕猴。然后，我们将跟踪这些抗体种系前体中和其他免疫的恒河猕猴中的抗体，这些猕猴共享等位基因，以了解为什么它们有时无法开发这些活动。我们还将比较中和抗体的靶标 BG505 SOSIP中的反应对猕猴模型中识别的受试者进行了免疫受试者。这 HVTN 137试验也正在使用不同的佐剂管理BG505 SOSIP，我们将研究这些方法在人类志愿者中影响中和抗体特异性。最后，我们将隔离单克隆中和来自选定BG505 SOSIP免疫猕猴和人类受试者的抗体以比较抗原识别的结构和生物物理特性。这些广泛的临床前和临床资源结合我们的多学科专业知识提供了一种新颖的环境，以解决阻碍障碍的障碍开发有效的HIV疫苗接种策略。如果成功，这些研究将阐明新策略改善HIV-1三聚体包膜免疫原和佐剂。