mRNA-LNP prime boost evolves precursors toward VRC01-like broadly neutralizing antibodies in preclinical humanized mouse models

Sci Immunol. 2024 May 10;9(95):eadn0622. doi: 10.1126/sciimmunol.adn0622. Epub 2024 May 16.


Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.

MeSH terms

  • AIDS Vaccines / immunology
  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing / immunology
  • Broadly Neutralizing Antibodies* / immunology
  • Female
  • HIV Antibodies / immunology
  • HIV Infections / immunology
  • HIV-1 / immunology
  • Humans
  • Lipids / immunology
  • Liposomes
  • Mice
  • Nanoparticles* / chemistry
  • RNA, Messenger* / genetics
  • RNA, Messenger* / immunology


  • Lipid Nanoparticles
  • VRC01 monoclonal antibody