Linking Antibody Cooperativity and Effector Cell Engagement

将抗体协同性和效应细胞参与联系起来

基本信息

批准号：
10670258
负责人：
Guido Ferrari
金额：
$ 95.8万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-25 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670258
关键词：
Address Antibodies Antibody Response Antibody Specificity Autologous Binding Biophysics Cells Clinical Research Clinical Trials Collaborations Data Effector Cell Epitopes Fc Receptor Foundations Genetic Genetic Complementation Test Genetic Variation Genotype Goals HIV-1 HIV-1 vaccine Heterogeneity Human IgG Receptors IgG1 IgG3 Immune response Immunoglobulin A Immunoglobulin Allotypes Immunoglobulin G In Situ Incubated Individual Infection Inflammatory Knowledge Link Lymphoid Tissue Macaca mulatta Mediating Membrane Modeling Monoclonal Antibodies Mucous Membrane NK Cell Activation Natural Killer Cells Nature Phagocytosis Phenotype Plasma Preparation Prevention Prevention strategy Property Reporting Research Personnel Serum Specificity Testing Therapeutic Tissues Translating Vaccine Design Vaccines Viral Viral Physiology Virion Virus Replication Work cytokine defined contribution design genetic variant immunoprophylaxis improved in vivo infection risk monocyte neutralizing antibody neutralizing monoclonal antibodies nonhuman primate novel vaccines polyclonal antibody preclinical study programs recruit response synergism transcriptomics translational impact vaccine candidate vaccine strategy vaccine trial vaccine-induced antibodies

项目摘要

ABSTRACT_Project 2 A key goal for HIV-1 vaccine design is the induction of broadly neutralizing responses. Although this goal has not been achieved, preclinical studies in non-human primates have identified several vaccine strategies that achieved some level of protection without inducing broadly neutralizing antibodies. These findings and emerging data from the field indicate that an achievable path forward is to leverage a polyclonal response comprised of multiple antibody responses that work together to eliminate virus replication. A critical gap in knowledge is the nature of vaccine-elicited polyclonal antibody responses that can achieve protection against infection within mucosal tissues in the non-human primates in order to translate into protection in human clinical trials. Moreover, there is a lack of information on how best to design polyclonal combinations of non- neutralizing and neutralizing antibodies to recruit Fc-Receptor bearing cells at the mucosal compartment to leverage different antibody combinations for improved protection. Our central hypothesis is that the composition of polyclonal Ab responses significantly impacts recruitment of monocytes and NK cells and their cooperation for Fc-mediated functions. To test our primary hypothesis, we will evaluate combinations of monoclonal antibody and polyclonal vaccine-induced plasma antibodies for their ability to more efficiently kill infected cells by examining antibody-dependent cellular mediated killing and/or phagocytosis of infected cells. We will define the transcriptomic profile of Fc-receptor bearing cells recruited by effective polyclonal preparations to understand the optimal FcR-bearing cells that should be recruited by effective vaccine-induced antibodies. These signatures will enable to understand how species-specific FcR and cellular diversity impact translation from rhesus macaques to humans. Lastly, we will determine differences in the interaction between FcR-bearing cells recruited by optimal mAb combinations for their ability to eliminate infected cells and secrete antiviral cytokines with limited pro-inflammatory profile. These questions will be addressed in the following Aims: Aim 1. Define contribution of IgG1, IgG3, and IgA for recognition of infected cells and virus particles. Aim 2. Identify the functional properties of effector cell subsets recruited by IgG1, IgG3, and polyclonal Ab combinations. Aim 3. Determine whether monocytes and NK cells are serially recruited to eliminate infected cells.

摘要_项目 2 HIV-1 疫苗设计的一个关键目标是诱导广泛的中和反应。虽然这个目标已经尽管尚未实现，但对非人类灵长类动物的临床前研究已经确定了几种疫苗策略，在不诱导广泛中和抗体的情况下实现了一定程度的保护。这些发现和来自该领域的新数据表明，可实现的前进道路是利用多克隆反应由多种抗体反应组成，这些抗体反应共同作用以消除病毒复制。关键差距知识是疫苗引起的多克隆抗体反应的本质，可以实现预防非人类灵长类动物粘膜组织内的感染，以转化为人类的保护临床试验。此外，缺乏关于如何最好地设计非-多克隆组合的信息。中和和中和抗体招募粘膜区室中携带 Fc 受体的细胞利用不同的抗体组合来改善保护。我们的中心假设是多克隆抗体反应的组成显着影响单核细胞和 NK 细胞的募集及其 Fc 介导功能的合作。为了检验我们的主要假设，我们将评估以下组合单克隆抗体和多克隆疫苗诱导的血浆抗体能够更有效地杀死病毒通过检查抗体依赖性细胞介导的受感染细胞的杀伤和/或吞噬作用来检测受感染的细胞。我们将定义通过有效的多克隆抗体招募的带有 Fc 受体的细胞的转录组谱。准备工作以了解最佳的 FcR 携带细胞，这些细胞应通过有效的疫苗诱导招募抗体。这些特征将有助于了解物种特异性 FcR 和细胞多样性如何影响从恒河猴到人类的翻译。最后，我们将确定之间相互作用的差异通过最佳 mAb 组合招募携带 FcR 的细胞，以消除受感染的细胞并分泌具有有限促炎作用的抗病毒细胞因子。这些问题将在下文中解答目标：目标 1. 定义 IgG1、IgG3 和 IgA 对识别感染细胞和病毒颗粒的贡献。目标 2. 鉴定 IgG1、IgG3 和多克隆招募的效应细胞亚群的功能特性抗体组合。目标 3. 确定单核细胞和 NK 细胞是否连续募集以消除感染细胞。