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：
10475288
负责人：
Guido Ferrari
金额：
$ 95.74万
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/10475288
关键词：
Address Antibodies Antibody Response Antibody Specificity Autologous Biophysics Cell physiology Cells Clinical Trials Collaborations Complement Data Effector Cell Epitopes Fc Receptor Foundations Genetic 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 Translations Vaccine Design Vaccines Virion Virus Replication Work base 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 transcriptomics vaccine candidate vaccine strategy vaccine trial vaccine-induced antibodies

Address Antibodies Antibody Response Antibody Specificity Autologous Biophysics Cell physiology Cells Clinical Trials Collaborations Complement Data Effector Cell Epitopes Fc Receptor Foundations Genetic 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 Translations Vaccine Design Vaccines Virion Virus Replication Work base 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 transcriptomics vaccine candidate vaccine strategy vaccine trial vaccine-induced antibodies

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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.

Abstract_project 2 HIV-1疫苗设计的关键目标是诱导广泛中和反应。虽然这个目标有没有实现，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兴数据表明，可实现的路径是利用多克隆响应由多种抗体反应组成，它们共同消除了病毒复制。一个关键的差距知识是疫苗引诱的多克隆抗体反应的性质，可以保护非人类灵长类动物的粘膜组织内感染，以转化为人类的保护临床试验。此外，缺乏有关如何最好地设计非 - 的多克隆组合的信息在粘膜室中募集FC受体轴承细胞的中和抗体中和抗体利用不同的抗体组合来改善保护。我们的核心假设是多克隆AB反应的组成显着影响单核细胞和NK细胞的募集及其 FC介导的功能的合作。为了检验我们的主要假设，我们将评估单克隆抗体和多克隆疫苗诱导的血浆抗体具有更有效杀死的能力通过检查抗体依赖性细胞介导的杀伤和/或感染细胞的吞噬作用来感染细胞。我们将定义有效多克隆募集的FC受体轴承细胞的转录组谱图理解应通过有效疫苗诱导的应招募的最佳含FCR细胞的准备抗体。这些签名将使物种特异性的FCR和细胞多样性如何影响从恒河猕猴翻译成人类。最后，我们将确定在相互作用之间的差异通过最佳MAB组合募集的含FCR细胞，以消除感染细胞并分泌促炎症状有限的抗病毒细胞因子。这些问题将在下面解决目标： AIM 1。定义IgG1，IgG3和IgA的贡献，以识别感染细胞和病毒颗粒。目标2。确定IgG1，IgG3和多克隆募集的效应细胞子集的功能特性 AB组合。 AIM 3。确定单核细胞和NK细胞是否串行募集以消除受感染的细胞。