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

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.

Authors

Institutions

Publication Details

Journal
Science Immunology
Published
2024-08-30
DOI
https://doi.org/10.1126/sciimmunol.adk9550
Citations
33
Primary Topic
HIV Research and Treatment
Type
article
Field-Weighted Citation Impact
9.69

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Adrian B. McDermott, David C. Montefiori, Ian A. Wilson, Jakob Samsel et al.
33 citations
Science Immunology
HIV Research and Treatment
9.69
article

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

Adrian B. McDermott, David C. Montefiori, Ian A. Wilson, Jakob Samsel, Rosemarie D. Mason, Kelli Greene, Marit J. van Gils, Thomas J. Ketas, Richard A. Koup, John P. Moore, Catarina Mendes Silva, Meng Yuan, Kenneth A. Rogers, Frederick W. Alt, Bali Pulendran, Edward Lamperti, Anila Yasmeen, François Villinger, Tom P. L. Bijl, Albert Cupo, Gabriel Ozorowski, Joey H. Bouhuijs, Iván del Moral-Sánchez, Max Crispin, Per Johan Klasse, Isabel Cuella Martin, Ronald Derking, Simone Pecetta, Lisa Shirreff, Hongmei Gao, Andrew B. Ward, Ming Tian, Yuejiao Xian, Jonathan L. Torres, Sven Kratochvil, Tom G. Caniels, Facundo D. Batista, Joel D. Allen, Max Medina-Ramírez, Michael S. Seaman, Jonne L. Snitselaar, Jelle van Schooten, María Ríos Carrasco, Rogier W. Sanders, Ja‐Hyun Koo, Shiyu Zhang, Mario Roederer, Isabel J. L. Baken
article en
33 citations

Abstract

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.

Science ImmunologyVol. 9(98)
Scripps Research Institute (US), Boston Children's Hospital (US), National Institutes of Health (US), Beth Israel Deaconess Medical Center (US), Howard Hughes Medical Institute (US), Harvard University (US), George Washington University (US), Cornell University (US), Ragon Institute of MGH, MIT and Harvard (US), Massachusetts General Hospital (US), Duke Medical Center (US), Amsterdam University Medical Centers (NL), University of Southampton (GB), Massachusetts Institute of Technology (US), University of Louisiana at Lafayette (US), Stanford University (US)
U.S. Department of Energy, Bill and Melinda Gates Foundation, International AIDS Vaccine Initiative, Tulane University, University of Louisiana at Lafayette, European Commission, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, National Institutes of Health, Office of Science, National Cancer Institute, National Institute of General Medical Sciences, Basic Energy Sciences, Biological and Environmental Research, Argonne National Laboratory, SLAC National Accelerator Laboratory
Good health and well-being
Openalex Percentile: Top 1%
HIV Research and Treatment
9.69
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.