Combined HIV vaccines can act in concert to achieve diverse antibody priming

Researchers at La Jolla Institute for Immunology, Scripps Research, and the Ragon Institute of MGH, MIT, and Harvard report coordinated studies showing that several HIV germline-targeting immunogens can be delivered together to activate multiple broadly neutralizing antibody precursors.

HIV vaccine design faces the challenge that B cells capable of maturing into broadly neutralizing antibodies (bnAb) are exceptionally rare and poorly stimulated by standard antigens. Most immune responses concentrate on variable parts of the viral envelope rather than the conserved regions that would enable cross-strain protection from HIV.

Germline-targeting immunogens have been developed to engage those rare naive B cells directly, but until now, each construct was tested in isolation, leaving open whether several could be given at once without interference. In paired studies published in Science Immunology, investigators tested that question across two models using different vaccine formats.

In the study “Simultaneous induction of multiple classes of broadly neutralizing antibody precursors by combination germline-targeting immunization in nonhuman primates,” researchers led by Henry Sutton extended the approach to rhesus macaques. Thirty-six animals at the Wisconsin National Primate Research Center received escalating doses of three engineered envelope proteins.

Memory B cells specific to each immunogen appeared in all relevant animals by eight weeks after the boost. Transient competition between responses surfaced briefly when all three immunogens were co-administered but subsided over time, leaving comparable somatic mutation levels and neutralization strength to single-immunogen controls.

In the companion study “Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models,” researchers led by Zhenfei Xie designed both protein and mRNA–lipid nanoparticle vaccines carrying up to four HIV envelope immunogens.

Mouse models bore human-sequence B-cell receptors corresponding to distinct bnAb classes. Concurrent protein immunizations activated some precursors weakly and unevenly, whereas mRNA-LNP vaccination produced concurrent activation of four classes of bnAb precursor lineages.

The mRNA platform’s membrane-anchored expression of trimers appeared to favor even participation of multiple B-cell populations, suggesting that vaccine format strongly shapes lineage competition.

Researchers conclude that simultaneous priming across several epitopes is biologically feasible in both small-animal and primate models. These paired findings establish a conceptual foundation for multicomponent germline-targeting vaccines that may streamline HIV immunization schedules while preserving the precision needed to launch multiple bnAb lineages at once.

By Justin Jackson

More information: Henry J. Sutton et al, Simultaneous induction of multiple classes of broadly neutralizing antibody precursors by combination germline-targeting immunization in nonhuman primates, Science Immunology (2025). DOI: 10.1126/sciimmunol.adu8878

Zhenfei Xie et al, Simultaneous priming of HIV broadly neutralizing antibody precursors to multiple epitopes by germline-targeting mRNA-LNP immunogens in mouse models, Science Immunology (2025). DOI: 10.1126/sciimmunol.adu7961