Vaccination elicits HIV broadly neutralizing antibodies in primates

The high antigenic diversity of HIV has been a major obstacle to development of a broadly protective vaccine. Nevertheless, protective HIV broadly neutralizing antibodies (bnAbs) exist and have been proposed as templates for vaccine development1-6. Germline-targeting is a conceptually radical vaccine design approach to elicit bnAbs, aiming to prime rare bnAb-precursor B cells possessing pre-determined human genetic and structural features shared with template bnAbs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous boosters7-11. Although the approach has shown promise in clinical12-17 and pre-clinical18-34 studies, it faces many immunological challenges and, to date, has not succeeded in generating bnAbs in humans or nontransgenic animals. Here, we report an adjuvanted protein germline-targeting vaccine tested in outbred nonhuman primates that generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates. bnAb lineages were generated in ≥50% of animals, achieving up to 67% neutralization breadth compared to the reference bnAb. Vaccine-induced bnAbs exhibited precise structural mimicry of human bnAb interactions with HIV envelope (Env), matching the germline-targeting predictions. Furthermore, serum bnAb activity developed in 44% of animals and in the most striking instance reached titers expected to confer protection against diverse HIV isolates. These results demonstrate proof of principle that germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs to prespecified epitopes under endogenous conditions, supporting further optimization of this approach for HIV vaccine development.