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Evaluating anti-idiotypic antibodies as novel vaccine candidates against HIV-1

评估抗独特型抗体作为针对 HIV-1 的新型候选疫苗

基本信息

批准号：
10540731
负责人：
Andrew McGuire
金额：
$ 36.91万
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/10540731
关键词：
Adoptive Transfer Affinity Amino Acids Animal Model Animals Anti-Idiotypic Antibodies Antibodies Antibody Binding Sites Antibody Formation Antigens B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes Binding Binding Sites Biological Assay CD4 Positive T Lymphocytes Cattle Cell Separation Cloning Collaborations Cross Reactions Data Development Engineering Epitope Mapping Epitopes Failure Frustration Gene Targeting Genes Genetic Glycoproteins Goals Growth HIV Infections HIV-1 HIV-1 vaccine Human Immune response Immunization Immunodominant Epitopes Immunoglobulin Idiotypes In Vitro Individual Infection Infection prevention Knock-in Knock-in Mouse Light Llama Longevity Modeling Monoclonal Antibodies Mus Mutation Peptides Peripheral Blood Mononuclear Cell Process Reaction Reagent Recombinant Antibody Recombinants Research Sampling Sequence Homology Site Specificity Structure of germinal center of lymph node Surface T cell response T-Lymphocyte Testing Transgenic Mice Vaccination Vaccines Viral Virion Work antigen binding design experimental study humanized mouse immunogenic immunogenicity improved in vivo insight knockin animal mouse model neutralizing antibody novel novel vaccines progenitor recruit response tool vaccine candidate

项目摘要

Project Summary/Abstract Broadly neutralizing antibodies (bNAbs) that bind to the HIV-1 Envelope glycoprotein (Env) are expected to be an important component of the immune response elicited by an effective HIV-1 vaccine. However, efforts to elicit bNAbs through vaccination with recombinant Env have not yet been successful. VRC01-class antibodies are among the broadest and most potent bNAbs that have been isolated from infected individuals, and their elicitation would be an ideal goal of a vaccine. VRC01-class antibodies have been isolated from multiple donors, and they all interact with Env in a nearly identical manner; are derived from the same antibody heavy chain gene, VH1-2*02; and have an unusually short third complimentary determining region (CDRL3) on the light chain. During the course of infection, VRC01-class antibodies acquired a number of mutations in their antibody genes that allow them recognize and neutralize diverse HIV-1 viral isolates. Using sequence homology, one can predict the sequence of the B-cell receptor (BCR) on the naive B cell that gave rise to each VRC01-class antibody. Previous work from our group and others has demonstrated that these inferred-germline versions of VRC01-class antibodies fail to recognize diverse recombinant Envs. Thus, conventional Env immunogens are likely ineffective at binding to and activating naive B cells that can give rise to VRC01-class antibodies. The structural similarity and shared genetics of VRC01-class antibodies have led to the proposal that immunogens designed to specifically to engage VRC01-class precursor B cells could, at the very least, start the process of VRC01-class antibody production. Indeed we, and others, have designed Env-based immunogens that can activate B cells expressing VRC01-class precursor BCRs in vitro and in vivo. However, these immunogens also present off-target, potentially immunodominant epitopes that could ultimately frustrate the development of VRC01-class antibodies in competitive germinal center reactions. As an alternative to Env-derived immunogens, we have produced and isolated anti-idiotypic antibodies that are highly specific for the antigen binding site of VRC01-class precursor BCRs. Importantly, because they are non-Env derived, they lack the off-target epitopes present on other germline-targeting immunogens. Our overarching hypothesis is that if used as a vaccine prime, anti-idiotypic antibodies can selectively seek out and expand rare VRC01-class B cells, such that the expanded pool will have a selective advantage over other B cells that respond to off-target epitopes following a boost with germline-targeting Env. This hypothesis will be tested in transgenic mouse models as part of this HIVRAD application, in collaboration with Drs. Stamatatos and Nussenzweig. The focus of this project is to evaluate the ability of these novel immunogens to seek out rare VRC01-class precursor B cells from human PBMC samples and from mice expressing a diverse human-derived BCR repertoire, and to engineer multivalent aiMAb derivatives to improve immunogenicity.

项目总结/文摘