Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models
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.
Authors
- John E. Warner (ORCID: https://orcid.org/0009-0001-1043-1643)
- Zhenfei Xie (ORCID: https://orcid.org/0009-0006-9341-4721)
- Andrea Carfı́ (ORCID: https://orcid.org/0000-0001-5508-3809)
- Usha Nair (ORCID: https://orcid.org/0000-0002-1927-6889)
- Jon M. Steichen (ORCID: https://orcid.org/0000-0002-4586-3251)
- Maria Bottermann (ORCID: https://orcid.org/0000-0002-8178-100X)
- Abigail M. Jackson (ORCID: https://orcid.org/0000-0001-9749-9431)
- Kimmo Rantalainen (ORCID: https://orcid.org/0000-0002-3158-9183)
- Sunny Himansu (ORCID: https://orcid.org/0000-0002-7954-9674)
- Paula Maldonado Villavicencio (ORCID: https://orcid.org/0009-0008-2321-9669)
- Eleonora Melzi (ORCID: https://orcid.org/0000-0002-1520-735X)
- Gabriel Ozorowski (ORCID: https://orcid.org/0000-0002-9695-8138)
- Torben Schiffner (ORCID: https://orcid.org/0000-0001-6772-8870)
- Christopher A. Cottrell (ORCID: https://orcid.org/0000-0002-3364-3083)
- Stephanie R. Weldon (ORCID: https://orcid.org/0000-0001-5384-9946)
- M. Krystal (ORCID: https://orcid.org/0000-0001-6519-2531)
- Yu Yan (ORCID: https://orcid.org/0000-0002-2756-4899)
- Claudia T. Flynn
- William R. Schief (ORCID: https://orcid.org/0000-0002-1120-0150)
- Jonathan L. Torres (ORCID: https://orcid.org/0000-0003-0137-8497)
- Facundo D. Batista (ORCID: https://orcid.org/0000-0002-1130-9463)
- Xuesong Wang (ORCID: https://orcid.org/0009-0003-8996-1501)
- Thavaleak Prum (ORCID: https://orcid.org/0009-0004-6973-5053)
- Jordan Renae Ellis-Pugh
Institutions
- Scripps Research Institute (US)
- International AIDS Vaccine Initiative (US)
- Harvard University (US)
- Ragon Institute of MGH, MIT and Harvard (US)
- Moderna Therapeutics (United States) (US)
- Massachusetts Institute of Technology (US)
- Leipzig University (DE)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1126/sciimmunol.adu7961
- Citations
- 6
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 6.22