Henry J. Sutton, M. Krystal, Jon M. Steichen, Torben Schiffner, Tasha K. Altheide, Alessia Liguori, Danny Lu, Michael Kubitz, Erik Georgeson, Nicole Phelps, Ryan Tingle, Nushin Alavi, Elana Ben‐Akiva, Xiaoya Zhou, Carolyne Kifude, Claudia T. Flynn, Eva G. Rakasz, Darrell J. Irvine, William R. Schief, Shane Crotty
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.