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

Sci Immunol. 2024 Aug 30;9(98):eadk9550. doi: 10.1126/sciimmunol.adk9550. Epub 2024 Aug 30.

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.

MeSH terms

  • AIDS Vaccines* / immunology
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Neutralizing* / immunology
  • Binding Sites / immunology
  • CD4 Antigens* / immunology
  • Female
  • HIV Antibodies* / immunology
  • HIV Infections / immunology
  • HIV Infections / prevention & control
  • HIV-1* / immunology
  • Humans
  • Mice
  • Vaccination

Substances

  • AIDS Vaccines
  • HIV Antibodies
  • Antibodies, Neutralizing
  • CD4 Antigens
  • Antibodies, Monoclonal