Science. 2019 Dec 6; 366(6470):NA.

PubMed ID: 31672916

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses

Steichen JM, Lin YC, Havenar-Daughton C, Pecetta S, Ozorowski G, Willis JR, Toy L, Sok D, Liguori A, Kratochvil S, Torres JL, Kalyuzhniy O, Melzi E, Kulp DW, Raemisch S, Hu X, Bernard SM, Georgeson E, Phelps N, Adachi Y, Kubitz M, Landais E, Umotoy J, Robinson A, Briney B, Wilson IA, Burton DR, Ward AB, Crotty S, Batista FD, Schief WR

Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.