Epitope-targeted Vaccines for HIV-1 Prevention

用于预防 HIV-1 的表位靶向疫苗

• 批准号: 8789431
• 负责人: XIANGPENG KONG
• 金额: $ 213.52万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-23 至 2016-01-22
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789431
• 关键词: Administrative Coordination; Advanced Development; Animals; Antibodies; Antibody Formation; Antigens; Antiviral Agents; Biochemical; Bioinformatics; Cameroon; Cellular Immunity; Collaborations; Complex; DNA; Data; Elements; Epitopes; Failure; Glycoproteins; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV vaccine; HIV-1; Human; Immune response; Immunization; Immunology; Indium; Individual; Infection; Influenza; Mediating; Methods; Modality; Modeling; Molecular Biology; Molecular Models; Monoclonal Antibodies; Neisseria; Oryctolagus cuniculus; Participant; Peptides; Pilot Projects; Positioning Attribute; Prevalence; Prevention; Production; Productivity; Program Research Project Grants; Proteins; Protocols documentation; Recombinants; Relative (related person); Scaffolding Protein; Scientist; Serum; Site; Specificity; Specimen; Structural Models; Structure; T-Lymphocyte; Testing; Vaccine Clinical Trial; Vaccine Design; Vaccines; Viral; Viral Physiology; Virion; Virus; Wit; Work; antibody-dependent cell cytotoxicity; base; design; engineering design; env Gene Products; experience; immunogenic; immunogenicity; improved; molecular modeling; neutralizing antibody; nonhuman primate; novel; novel vaccines; pathogen; programs; protein B; research study; response; scaffold; scale up; simian human immunodeficiency virus; structural biology; success; tool; vaccine candidate; vaccine development; vaccinology; virology; virus envelope

DESCRIPTION (provided by applicant): The recent RV144 clinical vaccine trial induced modest and transient protection in healthy individuals against HIV-1 infection, and is considered to be a marginal success. To improve the efficacy and duration of the antibody (Ab) response, better immunogens are required. We postulate that Abs induced by novel vaccine constructs will have higher specific activity, with stronger Ab titers and, within the total Ab response, a greater proportion of the Abs needed for protection. Such novel constructs, which could present viral epitopes in a context other than that of the whole envelope (Env), may also obviate the problems of the transient Ab response associated with whole Env. We and other have demonstrated that, by focusing the Ab response on V3, cross-clade neutralizing Abs are elicited which are detectable >1 year after immunization. Therefore, we now propose to extend the platform we previously developed for designing and developing V3-scaffold immunogens in order to create and test new epitope-scaffold protein immunogens that will focus the Ab response on two additional sites of vulnerability in Env: the V2 loop and the cluster of quaternary neutralizing epitopes (QNEs) composed of portions of V2 and V3. The HIVRAD will be composed of: Project 1: Vaccines to Induce Functional Abs Targeting the V2 Loop; Project 2: Rational Design of Immunogens Targeting the HIV-1 V2/V3 Quaternary Neutralizing Epitopes; Core A: Administrative Core; Core B: Protein Production Core; and, Core C: Animal Studies Core. The epitope-scaffold immunogens to be developed can be used individually or in combination, and will constitute powerful new tools for inducing broad and potent protective Abs. Many of the participants have worked together for >20 years to develop and characterize >100 human mAbs to HIV and other pathogens. Recently, the team has worked collaboratively and synergistically, preparing and analyzing >25 crystals of monoclonal Abs (mAbs) and mAb/epitope complexes, developing DNA Env primes and epitope-scaffold immunogens, and performing immunization experiments. Our experience places us in a strong position to extend our studies to epitopes that only recently have been recognized as important for protection from HIV infection. By the completion of the proposed Program, we plan to have identified epitope-targeting immunogens and immunization protocols that will generate Abs with protective anti-viral functions directed specifically toward the conserved regions of the V2 loop and the V2/V3 quaternary neutralizing epitopes of HIV-1 gp120.

描述（由申请人提供）：最近的RV144临床疫苗试验在健康个体中诱导了对HIV-1感染的适度和短暂的保护，并且被认为是一个边际成功。为了提高抗体（Ab）反应的疗效和持续时间，需要更好的免疫原。我们假设，由新型疫苗结构诱导的抗体将具有更高的特异性活性，具有更强的抗体滴度，并且在总抗体反应中，具有更大的抗体滴度