Heterologous prime-boost vaccination drives early maturation of HIV broadly neutralizing antibody precursors in humanized mice

Sci Transl Med. 2024 May 22;16(748):eadn0223. doi: 10.1126/scitranslmed.adn0223. Epub 2024 May 22.


A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.

MeSH terms

  • AIDS Vaccines* / immunology
  • Animals
  • Antibodies, Neutralizing* / immunology
  • Broadly Neutralizing Antibodies / immunology
  • HIV Antibodies* / immunology
  • HIV Infections / immunology
  • HIV Infections / prevention & control
  • HIV-1 / immunology
  • Humans
  • Immunization, Secondary
  • Mice
  • Vaccination


  • AIDS Vaccines
  • Antibodies, Neutralizing
  • HIV Antibodies
  • Broadly Neutralizing Antibodies