Germline-targeting HIV-1 Env vaccination induces VRC01-class antibodies with rare insertions

Tom G. Caniels, Max Medina-Ramírez, Jinsong Zhang, Anita Sarkar, Sonu Kumar, Alex LaBranche, Ronald Derking, Joel D. Allen, Jonne L. Snitselaar, Joan Capella-Pujol, Iván del Moral Sánchez, Anila Yasmeen, Marilyn Diaz, Yoann Aldon, Tom P. L. Bijl, Sravani Venkatayogi, Joshua S. Martin Beem, Amanda Newman, Chuancang Jiang, Wen-Hsin LeeMaarten Pater, Judith A. Burger, Mariëlle J. van Breemen, Steven W. de Taeye, Kimmo Rantalainen, Celia LaBranche, Kevin O. Saunders, David Montefiori, Gabriel Ozorowski, Andrew B. Ward, Max Crispin, John P. Moore, Per Johan Klasse, Barton F. Haynes, Ian A. Wilson, Kevin Wiehe, Laurent Verkoczy, Rogier W. Sanders

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


Targeting germline (gl-) precursors of broadly neutralizing antibodies (bNAbs) is acknowledged as an important strategy for HIV-1 vaccines. The VRC01-class of bNAbs is attractive because of its distinct genetic signature. However, VRC01-class bNAbs often require extensive somatic hypermutation, including rare insertions and deletions. We describe a BG505 SOSIP trimer, termed GT1.2, to optimize binding to gl-CH31, the unmutated common precursor of the CH30-34 bNAb lineage that acquired a large CDRH1 insertion. The GT1.2 trimer activates gl-CH31 naive B cells in knock-in mice, and B cell responses could be matured by selected boosting immunogens to generate cross-reactive Ab responses. Next-generation B cell sequencing reveals selection for VRC01-class mutations, including insertions in CDRH1 and FWR3 at positions identical to VRC01-class bNAbs, as well as CDRL1 deletions and/or glycine substitutions to accommodate the N276 glycan. These results provide proof of concept for vaccine-induced affinity maturation of B cell lineages that require rare insertions and deletions.
Original languageEnglish
Article number101003
JournalCell Reports Medicine
Issue number4
Publication statusPublished - 18 Apr 2023


  • HIV-1 Env
  • NGS
  • bNAbs
  • deletions
  • germline-targeting
  • insertions
  • mouse model
  • neutralizing antibodies
  • vaccines

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