Targeting Neutralizing Epitopes in the HIV Envelope

靶向 HIV 包膜中的中和表位

• 批准号: 7923784
• 负责人: Susan W Barnett
• 金额: $ 468.81万
• 依托单位: NOVARTIS VACCINES AND DIAGNOSTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7923784
• 关键词: Targeting; Neutralizing; Epitopes; HIV; Envelope

DESCRIPTION (provided by applicant): One of the biggest challenges we face in the development of a prophylactic vaccine against HIV/AIDS is to design an envelope (Env) immunogen that can induce protective neutralizing antibodies effective against the diversity of virus strains that characterize the global pandemic. We propose to evaluate novel candidate envelope (Env) vaccines that can induce potent, durable, and broadly protective neutralizing antibody and T cell responses against HIV. The central hypothesis that we seek to test if successful in the proposed research is the following: A vaccine composition that raises potent and durable neutralizing antibody responses with broad reactivity against a diverse primary HIV-1 isolates will protect against HIV infection. The three major objectives are: 1) Using the tools of modern structural biology and biochemistry, to design, produce, and characterize in vitro novel Env immunogens; 2) To identify structures and formulations that can induce potent, broad, and durable neutralizing antibody and T-cell responses in vivo in animal models; and 3) To identify candidate Env vaccines that can induce broad immunity and protection in non-human primate virus challenge models. The program comprises 3 projects and 3 scientific cores plus an Administrative Core that will manage the consortium. The three projects will focus on complementary strategies to design novel HIV Env immunogens for the induction of broadly reactive neutralizing antibodies based on current structural information regarding HIV-1 envelope surface (gp120) and transmembrane (gp41) glycoproteins. The scientific cores will be: the Vaccine Technologies Core and the Nonhuman Primate Studies Core and the Peptide Structure and Dynamics Core. Novel delivery scaffolds, adjuvants, and viral vector delivery systems, will be employed to deliver peptide-based and protein antigens. Antigenic structures will be characterized using atomic force microscopy (AFM) to determine their overall size and structure, and cryogenic electron microscopy (EM) will be used to achieve 3D reconstructions with angstrom level resolution. These analyses should provide molecular level understanding of the structures and interactions that lead to enhanced immune responses. Overall, this program should provide for the performance of well-controlled comparative in vitro and in vivo evaluations of the proposed vaccines. Env immunogens will be systematically screened in small animals and non-human primate vaccine/challenge studies using well-defined immunologic and virologic endpoints. These efforts are expected to lead to the identification of improved candidate vaccines for future clinical evaluations.

描述（由申请人提供）：我们在开发艾滋病毒/艾滋病预防性疫苗时面临的最大挑战之一是设计一种包膜（Env）免疫原，该免疫原可以诱导有效对抗多种病毒株的保护性中和抗体，这些病毒株的多样性特征是全球大流行。我们建议评估新型候选包膜 (Env) 疫苗，这些疫苗可以诱导针对 HIV 的有效、持久和广泛保护性中和抗体和 T 细胞反应。我们试图测试拟议研究是否成功的中心假设如下：一种疫苗组合物能够产生有效且持久的中和抗体反应，并且对多种主要 HIV-1 分离株具有广泛的反应性，从而可以防止 HIV 感染。三个主要目标是：1）利用现代结构生物学和生物化学工具，设计、生产和表征体外新型Env免疫原； 2) 确定能够在动物模型体内诱导有效、广泛和持久的中和抗体和 T 细胞反应的结构和配方； 3) 确定可在非人灵长类病毒攻击模型中诱导广泛免疫和保护的候选 Env 疫苗。该计划包括 3 个项目和 3 个科学核心，以及一个管理该联盟的行政核心。这三个项目将重点关注互补策略，根据有关 HIV-1 包膜表面 (gp120) 和跨膜 (gp41) 糖蛋白的当前结构信息，设计新型 HIV 包膜免疫原，用于诱导广泛反应性中和抗体。科学核心将是：疫苗技术核心、非人类灵长类动物研究核心以及肽结构和动力学核心。新型递送支架、佐剂和病毒载体递送系统将用于递送基于肽的抗原和蛋白质抗原。将使用原子力显微镜 (AFM) 来表征抗原结构，以确定其整体大小和结构，并使用低温电子显微镜 (EM) 来实现埃级分辨率的 3D 重建。这些分析应提供对导致增强免疫反应的结构和相互作用的分子水平理解。总体而言，该计划应为所提议的疫苗提供良好控制的体外和体内比较评估。将使用明确的免疫学和病毒学终点在小动物和非人灵长类动物疫苗/挑战研究中系统地筛选 Env 免疫原。预计这些努力将有助于确定改进的候选疫苗，用于未来的临床评估。

项目成果

Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site.

• DOI: 10.1128/jvi.00811-17
• 发表时间: 2017-10-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Bogers WMJM;Barnett SW;Oostermeijer H;Nieuwenhuis IG;Beenhakker N;Mortier D;Mooij P;Koopman G;Remarque E;Martin G;Lai RP;Dey AK;Sun Y;Burke B;Ferrari G;Montefiori D;Martin L;Davis D;Srivastava I;Heeney JL
• 通讯作者: Heeney JL

Mucosal B Cells Are Associated with Delayed SIV Acquisition in Vaccinated Female but Not Male Rhesus Macaques Following SIVmac251 Rectal Challenge.

• DOI: 10.1371/journal.ppat.1005101
• 发表时间: 2015-08
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Tuero I;Mohanram V;Musich T;Miller L;Vargas-Inchaustegui DA;Demberg T;Venzon D;Kalisz I;Kalyanaraman VS;Pal R;Ferrari MG;LaBranche C;Montefiori DC;Rao M;Vaccari M;Franchini G;Barnett SW;Robert-Guroff M
• 通讯作者: Robert-Guroff M

A simple one-step method for the preparation of HIV-1 envelope glycoprotein immunogens based on a CD4 mimic peptide.

一种简单的一步法，用于制备基于 CD4 模拟肽的 HIV-1 包膜糖蛋白免疫原。

• DOI: 10.1016/j.virol.2008.08.039
• 发表时间: 2008
• 期刊: Virology
• 影响因子: 3.7
• 作者: Martin,Grégoire;Sun,Yide;Heyd,Bernadette;Combes,Olivier;Ulmer,JeffreyB;Descours,Anne;Barnett,SusanW;Srivastava,IndreshK;Martin,Loïc
• 通讯作者: Martin,Loïc

Immunogens Modeling a Fusion-Intermediate Conformation of gp41 Elicit Antibodies to the Membrane Proximal External Region of the HIV Envelope Glycoprotein.

• DOI: 10.1371/journal.pone.0128562
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Vassell R;He Y;Vennakalanti P;Dey AK;Zhuang M;Wang W;Sun Y;Biron-Sorek Z;Srivastava IK;LaBranche CC;Montefiori DC;Barnett SW;Weiss CD
• 通讯作者: Weiss CD

Enhanced Delivery and Potency of Self-Amplifying mRNA Vaccines by Electroporation in Situ.

• DOI: 10.3390/vaccines1030367
• 发表时间: 2013-08-22
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Cu Y;Broderick KE;Banerjee K;Hickman J;Otten G;Barnett S;Kichaev G;Sardesai NY;Ulmer JB;Geall A
• 通讯作者: Geall A