Germline-targeting vaccine elicits HIV broadly neutralizing antibodies in nonhuman primates 2303354

Abstract Introduction HIV vaccine development has been exceptionally challenging, for myriad reasons. Nevertheless, protective HIV broadly neutralizing antibodies (bnAbs) exist and have been proposed as templates for vaccine development. Germline-targeting is a conceptually radical approach to vaccine design, aiming to prime rare bnAb-precursor B cells possessing pre-determined human genetic sequence motifs, and then guide B cell affinity maturation to potent bnAb evolution with heterologous booster vaccines. While the approach has shown promise, it faces many novel immunological challenges, commonly thought to be insurmountable in aggregate. To date, germline-targeting has not succeeded in generating bnAbs in nontransgenic animals. Methods Here, we report a germline-targeting vaccine tested in outbred nonhuman primates that successfully generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates. Results Neutralizing Ab clones were generated in ≥ 50% of animals, achieving a remarkable aggregate 62% neutralization breadth compared to the reference bnAb. 200 different bnAb-class clonal families were primed. The vaccine generated large and diverse bnAb-class clonal lineages, including multiple lineages containing > 1,000 memory cells. Furthermore, serum bnAb activity developed in 44% of animals; in the most striking instance serum bnAb breadth reached 84% that of BG18. Conclusion These results demonstrate that germline-targeting vaccines can reproducibly elicit prespecified classes of bnAbs through the priming and maturation of rare precursor B cells under endogenous conditions. Simultaneously, these results also demonstrate fundamental immunological findings, including demonstration that exceptionally rare B cells can be primed and recruited into germinal centers, competitive within germinal centers, affinity matured for extended periods, differentiated into memory B cells, boosted repeatedly with new immunogens, and differentiated into large numbers of bnAb plasma cells. Funding Source NIH NIAID CHAVD UM1 AI144462 Topic Categories Vaccines and Immunotherapy (VAC)