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

• 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
• 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

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.

项目总结/摘要 稳定的HIV-1包膜gp 140三聚体如BG 505 SOSIP提供了一个可行的平台， 中和抗体，其可以通过各种方法进行改进以诱导异源性抗体， 中和宽度BG 505 SOSIP三聚体免疫增强恒河猴中的保护性中和抗体 猕猴，目前正在几个I期临床试验中进行测试，包括HVTN 137。在这里我们将表演 深入的研究，以确定如何抗体，中和只有自体病毒和那些也有 恒河猴BG 505 SOSIP免疫期间平行产生的抗异源病毒变体的活性 猕猴使用冷冻保存的样本。然后，我们将跟踪这些抗体的生殖系前体， 中和抗体在其他免疫恒河猴，共享等位基因，以了解为什么他们 有时候这些活动都没有开展。我们还将比较中和抗体的靶点 在BG 505 SOSIP免疫的人类受试者中对恒河猴模型中识别的那些的应答。的 HVTN 137试验也使用不同佐剂给予BG 505 SOSIP，我们将研究这些佐剂如何影响患者的免疫功能。 影响人类志愿者中的中和抗体特异性。最后，我们将分离中和性单克隆抗体， 来自所选BG 505 SOSIP免疫的恒河猴和人受试者的抗体，以比较 抗原识别的结构和生物物理性质。这些广泛的临床前和临床资源 与我们的多学科专业知识相结合，提供了一个新的环境，以解决阻碍 制定有效的艾滋病毒疫苗接种战略。如果成功，这些研究将阐明新的战略， 以改进HIV-1三聚体包膜免疫原和佐剂。