Structure-guided vaccination elicits broadly neutralizing antibodies targeting the HIV-1 silent face

Abstract

An effective HIV-1 vaccine will likely require broadly neutralizing antibodies (bnAbs) targeting multiple complementary epitopes on the Envelope (Env) glycoprotein. Donor-derived bnAbs targeting the conserved silent face (SF) epitope complement established bnAb classes, but the maturation pathways underlying SF bnAb development and their inducibility via vaccination remain poorly understood. Here, we elicit SF-like bnAbs by vaccination and define pathways by which these responses can be guided toward breadth. Structural analysis of the donor-derived bnAb SF10 revealed that broad neutralization depends on a minimal set of heavy chain mutations despite extensive overall somatic hypermutation. We leveraged these insights to engineer Env immunogens that engage an SF10 precursor and selectively favor breadth-associated mutations during sequential immunization in a new immunoglobulin knock-in mouse model. Vaccination reproducibly elicited heterologous neutralizing serum responses and monoclonal antibodies that acquired key SF-like improbable mutations and broad neutralizing activity. Notably, elicited antibodies combined features of distinct human SF bnAbs, demonstrating that vaccination can access alternative mutational solutions rather than precisely recapitulating a donor-derived maturation pathway. These findings establish the silent face as a tractable vaccine target and expand the bnAb specificities available for multi-epitope HIV-1 vaccine strategies.

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BibTeX RIS

BibTeX

@misc{carter2026structureguided,
  title = {{Structure-guided vaccination elicits broadly neutralizing antibodies targeting the HIV-1 silent face}},
  author = {J. J. Carter and M. B. Palacio and M. Berlaga and O. Olajide and J. J. Noh and Y. E. Lee and I. Ramos and M. R. Eso and J. Phung and T. Chen and S. Meka and M. G. Garay and M. S. Seaman and A. Escolano and C. O. Barnes},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.30.755568},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.30.755568v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Structure-guided vaccination elicits broadly neutralizing antibodies targeting the HIV-1 silent face
AU  - J. J. Carter
AU  - M. B. Palacio
AU  - M. Berlaga
AU  - O. Olajide
AU  - J. J. Noh
AU  - Y. E. Lee
AU  - I. Ramos
AU  - M. R. Eso
AU  - J. Phung
AU  - T. Chen
AU  - S. Meka
AU  - M. G. Garay
AU  - M. S. Seaman
AU  - A. Escolano
AU  - C. O. Barnes
PY  - 2026
DA  - 2026/09/30
PB  - bioRxiv
DO  - 10.64898/2026.09.30.755568
UR  - https://www.biorxiv.org/content/10.64898/2026.09.30.755568v1
AB  - An effective HIV-1 vaccine will likely require broadly neutralizing antibodies (bnAbs) targeting multiple complementary epitopes on the Envelope (Env) glycoprotein. Donor-derived bnAbs targeting the conserved silent face (SF) epitope complement established bnAb classes, but the maturation pathways underlying SF bnAb development and their inducibility via vaccination remain poorly understood. Here, we elicit SF-like bnAbs by vaccination and define pathways by which these responses can be guided toward breadth. Structural analysis of the donor-derived bnAb SF10 revealed that broad neutralization depends on a minimal set of heavy chain mutations despite extensive overall somatic hypermutation. We leveraged these insights to engineer Env immunogens that engage an SF10 precursor and selectively favor breadth-associated mutations during sequential immunization in a new immunoglobulin knock-in mouse model. Vaccination reproducibly elicited heterologous neutralizing serum responses and monoclonal antibodies that acquired key SF-like improbable mutations and broad neutralizing activity. Notably, elicited antibodies combined features of distinct human SF bnAbs, demonstrating that vaccination can access alternative mutational solutions rather than precisely recapitulating a donor-derived maturation pathway. These findings establish the silent face as a tractable vaccine target and expand the bnAb specificities available for multi-epitope HIV-1 vaccine strategies.
ER  -

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