Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site,Science Immunology

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Germline-targeting HIV vaccination induces neutralizing antibodies to the CD4 binding site
Science Immunology ( IF 17.6 ) Pub Date : 2024-08-30 , DOI: 10.1126/sciimmunol.adk9550
Tom G Caniels _{1,

2} , Max Medina-Ramìrez _{1,

2} , Shiyu Zhang ₃ , Sven Kratochvil ₄ , Yuejiao Xian ₃ , Ja-Hyun Koo ₄ , Ronald Derking _{1,

2} , Jakob Samsel _{5,

6} , Jelle van Schooten _{1,

2} , Simone Pecetta ₄ , Edward Lamperti ₄ , Meng Yuan ₃ , María Ríos Carrasco _{1,

2} , Iván Del Moral Sánchez _{1,

2} , Joel D Allen ₇ , Joey H Bouhuijs _{1,

2} , Anila Yasmeen ₈ , Thomas J Ketas ₈ , Jonne L Snitselaar _{1,

2} , Tom P L Bijl _{1,

2} , Isabel Cuella Martin _{1,

2} , Jonathan L Torres ₃ , Albert Cupo ₈ , Lisa Shirreff ₉ , Kenneth Rogers ₉ , Rosemarie D Mason ₅ , Mario Roederer ₅ , Kelli M Greene ₁₀ , Hongmei Gao ₁₀ , Catarina Mendes Silva _{1,

2} , Isabel J L Baken _{1,

2} , Ming Tian ₁₁ , Frederick W Alt ₁₁ , Bali Pulendran ₁₂ , Michael S Seaman ₁₃ , Max Crispin ₇ , Marit J van Gils _{1,

2} , David C Montefiori ₁₀ , Adrian B McDermott ₅ , François J Villinger ₉ , Richard A Koup ₅ , John P Moore ₈ , Per Johan Klasse ₈ , Gabriel Ozorowski ₃ , Facundo D Batista ₁₄ , Ian A Wilson _{3,

15} , Andrew B Ward ₃ , Rogier W Sanders _{1,

2,

8}

Affiliation

Amsterdam UMC, location AMC, University of Amsterdam, Department of Medical Microbiology and Infection Prevention, Amsterdam, Netherlands.
Amsterdam Institute for Infection and Immunity, Infectious Diseases, Amsterdam, Netherlands.
Department of Integrative Structural and Computational Biology, Scripps Research Institute, La Jolla, CA, USA.
Ragon Institute of Mass General, MIT, and Harvard, Cambridge, MA, USA.
Vaccine Research Center (VRC), NIAID, NIH, Bethesda, MD, USA.
Institute for Biomedical Sciences, George Washington University, Washington, DC, USA.
School of Biological Sciences, University of Southampton, Southampton, UK.
Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY, USA.
New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, LA, USA.
Duke University Medical Center, Durham, NC, USA.
Howard Hughes Medical Institute, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA.
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
Skaggs Institute for Chemical Biology, Scripps Research Institute, La Jolla, CA, USA.

Eliciting potent and broadly neutralizing antibodies (bnAbs) is a major goal in HIV-1 vaccine development. Here, we describe how germline-targeting immunogen BG505 SOSIP germline trimer 1.1 (GT1.1), generated through structure-based design, engages a diverse range of VRC01-class bnAb precursors. A single immunization with GT1.1 expands CD4 binding site (CD4bs)–specific VRC01-class B cells in knock-in mice and drives VRC01-class maturation. In nonhuman primates (NHPs), GT1.1 primes CD4bs-specific neutralizing serum responses. Selected monoclonal antibodies (mAbs) isolated from GT1.1-immunized NHPs neutralize fully glycosylated BG505 virus. Two mAbs, 12C11 and 21N13, neutralize subsets of diverse heterologous neutralization-resistant viruses. High-resolution structures revealed that 21N13 targets the same conserved residues in the CD4bs as VRC01-class and CH235-class bnAbs despite its low sequence similarity (~40%), whereas mAb 12C11 binds predominantly through its heavy chain complementarity-determining region 3. These preclinical data underpin the ongoing evaluation of GT1.1 in a phase 1 clinical trial in healthy volunteers.

中文翻译：

种系靶向 HIV 疫苗接种可诱导针对 CD4 结合位点的中和抗体

引发有效且广泛中和的抗体 (bnAb) 是 HIV-1 疫苗开发的主要目标。在这里，我们描述了通过基于结构的设计生成的种系靶向免疫原 BG505 SOSIP 种系三聚体 1.1 (GT1.1) 如何与多种 VRC01 类 bnAb 前体结合。 GT1.1 的单次免疫可扩展敲入小鼠体内 CD4 结合位点 (CD4bs) 特异性 VRC01 类 B 细胞，并驱动 VRC01 类成熟。在非人灵长类动物 (NHP) 中，GT1.1 引发 CD4bs 特异性中和血清反应。从 GT1.1 免疫的 NHP 中分离出的精选单克隆抗体 (mAb) 可中和完全糖基化的 BG505 病毒。两种 mAb（12C11 和 21N13）可中和多种异源中和抗性病毒的子集。高分辨率结构显示，21N13 与 VRC01 类和 CH235 类 bnAb 靶向 CD4b 中相同的保守残基，尽管其序列相似性较低 (~40%)，而 mAb 12C11 主要通过其重链互补决定区 3 结合。这些临床前数据支持了在健康志愿者中进行的 GT1.1 1 期临床试验的持续评估。

更新日期：2024-08-30

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