Consortium for HIV/AIDS Vaccine Development

艾滋病毒/艾滋病疫苗开发联盟

• 批准号: 10664947
• 负责人: Dennis R. Burton
• 金额: $ 3020.48万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664947
• 关键词: Animal Model; Animals; Antibodies; Antibody Response; Antigens; Biological Assay; Cells; Clinical Trials; Dedications; Development; Exposure to; Future; Glycoproteins; Goals; HIV; HIV Infections; HIV Vaccine Trials Network; HIV envelope protein; HIV vaccine; Human; Immunoglobulin Somatic Hypermutation; Immunologics; Individual; Infection; Mucous Membrane; Phase I Clinical Trials; Pre-Clinical Model; Procedures; Regimen; Research Support; Sampling; Series; Site; Structure; Technology; Testing; Translating; Vaccines; Virion; Virus; design; experience; flexibility; in vivo; innovation; manufacture; mouse model; neutralizing antibody; nonhuman primate; novel; operation; pre-clinical; product development; programs; protective efficacy; research clinical testing; success; translational goal; vaccination strategy; vaccine development

Project Summary/Abstract (30 lines) The overarching goal of this CHAVD is to develop a sequential HIV vaccine regimen that induces sustained protective levels of broadly neutralizing antibodies (bnAbs) in humans. bnAbs provide complete protection against HIV infection in preclinical models. We hypothesize that an effective HIV vaccine will need to consistently induce bnAbs against 2-3 different sites on the HIV Envelope glycoprotein (Env) of the virus in most (>90%) of vaccine recipients. Targeting multiple sites is necessary to provide adequate coverage against the huge diversity of global isolates. We propose a sequential strategy in which a series of designed immunogens guide antibody responses from precursors to bnAbs. We are intensely developing and testing immunogens. We have shown proof-of-principle of the sequential strategy in preclinical models and our first three immunogens are entering manufacturing or clinical trials shortly. The second major goal of this CHAVD is to generate immunogens that induce protective non- neutralizing antibody (nnAb) responses that can either act alone or augment the protective activity of bnAb responses. To accomplish this goal, we propose a tiered approach in which the ability of nnAbs to capture infectious virions and to clear infected cells in vivo in two established mouse models will be explored. The most effective nnAbs, alone and in combination with other nnAbs and bnAbs, will then be assessed for their ability to protect nonhuman primates against virus challenge. Protective nnAbs will be used as templates for immunogen design. To support our translational effort, we have organized state-of the-art Manufacturing, Clinical Trials Sample Analysis and Management and Operations units. In addition, we have established twelve Scientific Research Support Units, headed by leaders in their fields, to underpin the diverse scientific and technical capabilities required to execute our comprehensive and highly integrated vaccine program Finally, this CHAVD proposal is built upon a highly successful, innovative and efficient CHAVI- ID program that has made major scientific contributions to the HIV vaccine field. The CHAVD provides the opportunity to advance and translate these contributions into an HIV vaccine.

项目概要/摘要（30行） 该CHAVD的首要目标是开发一种连续的艾滋病毒疫苗方案， 在人体中诱导持续的保护性水平的广泛中和抗体（bnAb）。bnAbs 在临床前模型中提供针对HIV感染的完全保护。我们假设 有效的HIV疫苗将需要持续诱导bnAbs针对2-3个不同的位点， HIV包膜糖蛋白（Env）在大多数（>90%）疫苗接种者中存在。靶向 多个站点是必要的，以提供足够的覆盖面，对巨大的多样性，全球 分离株我们提出了一种顺序策略，其中一系列设计的免疫原引导 从前体到bnAb的抗体应答。我们正在加紧开发和测试 免疫原我们已经在临床前模型中证明了序贯策略的原理 我们的前三种免疫原很快就会进入生产或临床试验阶段。 该CHAVD的第二个主要目标是产生诱导保护性非免疫原的免疫原。 中和抗体（nnAb）反应，可以单独发挥作用或增强保护性 bnAb反应的活性。为了实现这一目标，我们提出了一种分层方法， nnAb捕获感染性病毒体和清除体内感染细胞的能力在两个建立的 将探索小鼠模型。最有效的nnAb，单独使用和与其他药物组合使用， nnAb和bnAb，然后将评估它们保护非人灵长类动物免受 病毒挑战保护性nnAb将用作免疫原设计的模板。 为了支持我们的翻译工作，我们组织了最先进的制造、临床 试验样品分析和管理及业务股。此外，我们还建立了 12个科学研究支持单位，由各自领域的领导人领导，以支持 执行我们的全面和高度的科学和技术能力所需的多样化 综合疫苗计划 最后，这个CHAVD建议是建立在一个非常成功的，创新的和有效的CHAVI- 该项目为艾滋病毒疫苗领域做出了重大科学贡献。CHAVD 提供了一个机会，推动和转化这些贡献到艾滋病毒疫苗。

项目成果

Structural and Biochemical Characterization of Cysteinylation in Broadly Neutralizing Antibodies to HIV-1.

• DOI: 10.1016/j.jmb.2021.167303
• 发表时间: 2021-12-03
• 期刊: Journal of molecular biology
• 影响因子: 5.6
• 作者: Omorodion O;Wilson IA
• 通讯作者: Wilson IA

Site-specific steric control of SARS-CoV-2 spike glycosylation

• DOI: 10.1101/2021.03.08.433764
• 发表时间: 2021-03
• 期刊: bioRxiv
• 作者: Joel D. Allen;H. Chawla;Firdaus Samsudin;Lorena Zuzic;A. T. Shivgan;Yasunori Watanabe;Wan-ting He;Sean Callaghan;G. Song;Peter Yong;P. Brouwer;Yutong Song;Yongfei Cai;Helen M. E. Duyvesteyn;T. Malinauskas;J. Kint;P. Pino;Maria J. Wurm;M. Frank;Bing Chen;D. Stuart;R. Sanders;R. Andrabi;D. Burton;Sai Li;P. Bond;M. Crispin

Introductory article for Immunological Reviews, Vol 310.

《免疫学评论》的介绍性文章，第 310 卷。

• DOI: 10.1111/imr.13128
• 发表时间: 2022
• 期刊: Immunological reviews
• 影响因子: 8.7
• 作者: Burton,DennisR;Feinberg,MarkB
• 通讯作者: Feinberg,MarkB

Vaccine genetics of IGHV1-2 VRC01-class broadly neutralizing antibody precursor naïve human B cells.

• DOI: 10.1038/s41541-021-00376-7
• 发表时间: 2021-09-06
• 期刊: NPJ vaccines
• 影响因子: 9.2
• 作者: Lee JH;Toy L;Kos JT;Safonova Y;Schief WR;Havenar-Daughton C;Watson CT;Crotty S
• 通讯作者: Crotty S

Engineering SARS-CoV-2 neutralizing antibodies for increased potency and reduced viral escape pathways.

• DOI: 10.1016/j.isci.2022.104914
• 发表时间: 2022-09-16
• 期刊: ISCIENCE
• 影响因子: 5.8
• 作者: Zhao, Fangzhu;Keating, Celina;Ozorowski, Gabriel;Shaabani, Namir;Francino-Urdaniz, Irene M.;Barman, Shawn;Limbo, Oliver;Burns, Alison;Zhou, Panpan;Ricciardi, Michael J.;Woehl, Jordan;Tran, Quoc;Turner, Hannah L.;Peng, Linghang;Huang, Deli;Nemazee, David;Andrabi, Raiees;Sok, Devin;Teijaro, John R.;Whitehead, Timothy A.;Ward, Andrew B.;Burton, Dennis R.;Jardine, Joseph G.
• 通讯作者: Jardine, Joseph G.