Activation of HIV-1 specific B cell precursors using novel vaccine approaches

使用新型疫苗方法激活 HIV-1 特异性 B 细胞前体

基本信息

批准号：
10540735
负责人：
Michel C Nussenzweig
金额：
$ 50.85万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-06 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10540735
关键词：
Adoptive Transfer Affinity Agreement Animal Model Animals Anti-Idiotypic Antibodies Antibodies Antibody Binding Sites Antigen Targeting Antigens Autologous B cell repertoire B-Cell Activation B-Lymphocytes Binding Binding Sites Cells Characteristics Cloning Collaborations Communicable Diseases Development Disease Epitopes Evolution Frequencies Genes Genetic Engineering Genetically Engineered Mouse HIV-1 Human Immune response Immunization Immunoglobulin Genes Induced Mutation Infection Infection prevention Knock-in Knock-in Mouse Light Llama Macaca Modeling Monkeys Mus Mutate Oryctolagus cuniculus Outcome Patients Persons Physiological Polysaccharides Positioning Attribute Productivity Regimen Reproducibility Research Role Scheme Structure of germinal center of lymph node Testing V3 Loop Vaccination Vaccines Virus Wild Type Mouse World Health Organization base design experimental study immunogenicity in vivo mouse model neutralizing antibody novel vaccines pathogen prevent progenitor recruit virus envelope

项目摘要

Project Summary According to the World Health Organization, approximately 36 million people worldwide were living with HIV-1 at the end of 2015 and 1.1 million people died from this disease during the same year. Vaccination is the most effective strategy to prevent infectious diseases, and successful vaccines are usually protective because they elicit antibodies that neutralize the pathogen (1). Although there is no protective vaccine against HIV-1, broadly neutralizing antibodies (bNAbs) isolated from infected patients are protective in animal models of infection even at relatively low concentrations. These antibodies are potent neutralizers that recognize conserved features of the virus envelope spike (Env) that are shared among diverse strains of the virus, and it is generally agreed that a vaccine that elicits bNAbs would be protective against HIV-1 infection. However, with the exception of llamas and genetically engineered mice, bNAbs have not been elicited by vaccination (2). The experiments in genetically engineered knock-in mice showed that bNAb development required germline-targeting Env-antigens that were specifically designed to activate B cells expressing the germline precursor antibodies that correspond to bNAbs (3-5). In addition, singular antigens were not sufficient, and bNAb development required a sequence of specific immunogens delivered in order (5-8). However, the immunization schemes devised in knock-in mice could not be extended to wild type (wt) mice or other animals in part because of lack of understanding of the relationship between germline antigen affinity and bNAb precursor B cell frequency in initiating a productive immune response in the presence of competing polyclonal B cells. The objects of the proposed research are to: 1. define the precise relationship between precursor B cell frequency and affinity to cognate antigen, in recruiting bNAb precursors into the germinal center; 2. test the idea that pre-expansion of specific precursors using anti-idiotypic antibodies will facilitate the development of anti-CD4bs antibodies. The relationship between affinity and precursor B cell frequency will be defined in adoptive transfer experiments using antigens provided by Drs. Stamatatos and McGuire. New vaccination approaches using anti-idiotypic antibodies to expand bNAb precursor frequency before vaccination will be tested in three different mouse models with variable levels of polyclonality: I) In HC only knock-in mice which have the lowest level of polyclonality due to variable mouse light chains II) adoptive transfer of variable numbers of knock-in B cells expressing a single Env-specific BCR into wt mice and III) fully polyclonal mice expressing human germline Ig genes. The information obtained by these experiments will advance our understanding of how to approach the problem of how to develop a protective vaccine against HIV-1.

项目概要据世界卫生组织称，全球约有 3600 万人感染 HIV-1 截至 2015 年底，同年有 110 万人死于这种疾病。疫苗接种是最重要的预防传染病的有效策略，成功的疫苗通常具有保护作用，因为它们引发中和病原体的抗体 (1)。虽然目前还没有针对 HIV-1 的保护性疫苗，但总体而言从感染患者中分离出的中和抗体（bNAb）在感染动物模型中具有保护作用，甚至在相对较低的浓度下。这些抗体是有效的中和剂，可以识别保守的特征不同病毒株共有的病毒包膜刺突 (Env)，人们普遍认为引发 bNAb 的疫苗可以预防 HIV-1 感染。然而，除了美洲驼之外和基因工程小鼠相比，bNAb 尚未通过疫苗接种产生 (2)。遗传学上的实验工程敲入小鼠表明，bNAb 的发育需要种系靶向的 Env 抗原，这些抗原是专门设计用于激活表达与 bNAb 相对应的种系前体抗体的 B 细胞（3-5）。此外，单一抗原是不够的，bNAb 的开发需要一系列特定的抗原序列。免疫原按顺序递送(5-8)。然而，在基因敲入小鼠中设计的免疫方案不能部分由于缺乏对这种关系的了解而扩展到野生型（wt）小鼠或其他动物种系抗原亲和力与 bNAb 前体 B 细胞频率在启动高效免疫中的关系存在竞争性多克隆 B 细胞时的反应。拟议研究的目的是： 1. 定义募集 bNAb 时前体 B 细胞频率与同源抗原亲和力之间的精确关系前体进入生发中心； 2. 测试使用抗独特型预扩增特定前体的想法抗体将促进抗CD4bs抗体的开发。亲和力与亲和力之间的关系前体 B 细胞频率将在过继转移实验中使用 Drs 提供的抗原进行定义。斯塔马塔托斯和麦奎尔。使用抗独特型抗体扩展 bNAb 的新疫苗接种方法疫苗接种前的前体频率将在三种不同的小鼠模型中进行测试，这些模型具有不同的水平多克隆性：I) 仅在 HC 敲入小鼠中，由于小鼠光可变，其多克隆性水平最低链 II) 将表达单个 Env 特异性 BCR 的不同数量的敲入 B 细胞过继转移至 wt 中小鼠和III)表达人类种系Ig基因的完全多克隆小鼠。这些获得的信息实验将加深我们对如何解决如何开发保护性问题的理解 HIV-1 疫苗。