Simultaneous induction of multiple classes of broadly neutralizing antibody precursors by combination germline-targeting immunization in nonhuman primates
Inducing broadly neutralizing antibodies (bnAbs) against HIV remains a key challenge in vaccine development. Germline-targeting immunogens have effectively primed bnAb B cell lineages to individual HIV envelope epitopes in humans and nonhuman primates. However, eliciting consistent bnAb breadth requires the induction of multiple bnAb classes. We investigated whether immunization with a combination of germline-targeting immunogens could concurrently prime multiple bnAb lineages in nonhuman primates. Animals were immunized with three immunogens, targeting distinct epitopes: the V3-glycan/N332 supersite, the V2 Apex region, and the membrane-proximal external region (MPER), either individually or in combinations of two or all three. Triple combination immunization transiently reduced V2 Apex and V3-glycan responses, but by 8 weeks postboost, bnAb precursor lineages were observed to all three epitopes. Similar somatic hypermutation was observed across groups, indicative of permissive germinal center responses. These findings support combination germline-targeting immunization as a viable strategy to prime multiple bnAb lineages simultaneously.
Authors
- Eva G. Rakasz (ORCID: https://orcid.org/0000-0001-8197-5309)
- Jon M. Steichen (ORCID: https://orcid.org/0000-0002-4586-3251)
- Danny Lu (ORCID: https://orcid.org/0000-0002-2340-3377)
- Ryan Tingle (ORCID: https://orcid.org/0000-0003-2874-7010)
- Michael Kubitz (ORCID: https://orcid.org/0000-0002-3917-453X)
- Shane Crotty (ORCID: https://orcid.org/0000-0002-6484-6262)
- Henry J. Sutton (ORCID: https://orcid.org/0000-0002-6472-7116)
- Torben Schiffner (ORCID: https://orcid.org/0000-0001-6772-8870)
- Alessia Liguori (ORCID: https://orcid.org/0000-0002-8606-574X)
- M. Krystal (ORCID: https://orcid.org/0000-0001-6519-2531)
- Nicole Phelps (ORCID: https://orcid.org/0000-0001-9613-3921)
- Claudia T. Flynn
- Nushin Alavi (ORCID: https://orcid.org/0000-0003-3848-6280)
- William R. Schief (ORCID: https://orcid.org/0000-0002-1120-0150)
- Elana Ben‐Akiva (ORCID: https://orcid.org/0000-0003-1085-5902)
- Erik Georgeson (ORCID: https://orcid.org/0000-0001-5137-4625)
- Carolyne Kifude (ORCID: https://orcid.org/0000-0002-0361-8645)
- Darrell J. Irvine (ORCID: https://orcid.org/0000-0002-8637-1405)
- Tasha K. Altheide
- Xiaoya Zhou
Institutions
- Scripps Research Institute (US)
- International AIDS Vaccine Initiative (US)
- La Jolla Institute for Immunology (US)
- Howard Hughes Medical Institute (US)
- University of Wisconsin–Madison (US)
- University of California San Diego (US)
- Moderna Therapeutics (United States) (US)
- Massachusetts Institute of Technology (US)
Publication Details
- Journal
- Science Immunology
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1126/sciimmunol.adu8878
- Citations
- 3
- Primary Topic
- HIV Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 3.11