Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models

Sci Immunol. 2025 Oct 17;10(112):eadu7961. doi: 10.1126/sciimmunol.adu7961. Epub 2025 Oct 17.

Abstract

Germline-targeting is a promising approach to HIV vaccine development that begins with the elicitation of precursors to broadly neutralizing antibodies (bnAbs), but it remains unclear whether simultaneous elicitation of precursors to multiple epitopes on the HIV envelope (Env) would be inhibited by competition. This study used preclinical mouse models with physiologically relevant frequencies of bnAb precursor-bearing B cells to compare precursor elicitation by coadministration of multiple protein or mRNA lipid nanoparticle (mRNA-LNP) germline-targeting immunogens. These immunogens activate multiple bnAb precursor classes targeting distinct epitopes on Env but with evidence of potential competition. Simultaneous delivery of immunogens encoded by mRNA-LNPs, however, drove maturation across different precursor frequencies and immunogen doses. Furthermore, administration of a cocktail of mRNA-LNP immunogens (N332-GT5 gp151, ApexGT5 gp151, eOD-GT8 60mer, and 10E8-GT12 24mer) led to balanced activation of four distinct bnAb precursor classes, indicating that multiepitope HIV bnAb precursor priming might be successfully implemented in humans but might be immunogen dependent.

MeSH terms

  • AIDS Vaccines* / immunology
  • Animals
  • Antibodies, Neutralizing* / immunology
  • Broadly Neutralizing Antibodies* / immunology
  • Disease Models, Animal
  • Epitopes* / immunology
  • Female
  • HIV Antibodies* / immunology
  • HIV Infections* / immunology
  • HIV Infections* / prevention & control
  • HIV-1* / immunology
  • Humans
  • Liposomes
  • Mice
  • Nanoparticles* / administration & dosage
  • RNA, Messenger* / immunology
  • env Gene Products, Human Immunodeficiency Virus / immunology

Substances

  • AIDS Vaccines
  • HIV Antibodies
  • RNA, Messenger
  • Epitopes
  • Broadly Neutralizing Antibodies
  • Lipid Nanoparticles
  • Antibodies, Neutralizing
  • env Gene Products, Human Immunodeficiency Virus
  • Liposomes