Vaccination elicits HIV broadly neutralizing antibodies in primates.
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Steichen Jon M, Madden Patrick J, Flynn Claudia T, Phulera Swastik, Shil Monolina, Kalyuzhniy Oleksandr, Liguori Alessia, Kifude Carolyne, Sewall Leigh M, Cottrell Christopher A, Ma Krystal M, Baboo Sabyasachi, Diedrich Jolene K, McKenney Katherine, deCamp Allan C, Carnathan Diane G, Phung Ivy, Ramezani-Rad Parham, Marina-Zárate Ester, Freeman Brian, Xie Zhenfei, Lee Jeong Hyun, Sincomb Troy, Phelps Nicole, Lu Danny, Goodwin Diana, Tingle Ryan, Adachi Yumiko, Alavi Nushin, Tran Jenny, Tran Andy S, Nascimento Alyne, Sovie Catherine, Bader Daniel L V, Voic Hannah, Zhou Xiaoya, Pixton Grace, Walsh Agnes, Melo Mariane B, Schiffner Torben, Batista Facundo D, Burton Dennis R, Irvine Darrell J, Paulson James C, Yates John R, Ozorowski Gabriel, Ward Andrew B, Silvestri Guido, Crotty Shane, Schief William R
Аннотация
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 predetermined 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 preclinical18-34 studies, it faces many immunological challenges and, to date, has not succeeded in generating bnAbs in humans or non-transgenic animals. Here we report testing of an adjuvanted protein germline-targeting vaccine in outbred non-human primates. The vaccine generated bnAb-class memory B cells and sera capable of neutralizing diverse HIV clinical isolates. bnAb lineages were generated in at least 50% of animals, achieving up to 67% neutralization breadth compared with 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 one instance reached titres 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.