Science. 2022 Dec 02; 378(6623):eadd6502.

PubMed ID: 36454825

Vaccination induces HIV broadly neutralizing antibody precursors in humans

Leggat DJ, Cohen KW, Willis JR, Fulp WJ, deCamp AC, Kalyuzhniy O, Cottrell CA, Menis S, Finak G, Ballweber-Fleming L, Srikanth A, Plyler JR, Schiffner T, Liguori A, Rahaman F, Lombardo A, Philiponis V, Whaley RE, Seese A, Brand J, Ruppel AM, Hoyland W, Yates NL, Williams LD, Greene K, Gao H, Mahoney CR, Corcoran MM, Cagigi A, Taylor A, Brown DM, Ambrozak DR, Sincomb T, Hu X, Tingle R, Georgeson E, Eskandarzadeh S, Alavi N, Lu D, Mullen T-M, Kubitz M, Groschel B, Maenza J, Kolokythas O, Khati N, Bethony J, Crotty S, Roederer M, Karlsson Hedestam GB, Tomaras GD, Montefiori D, Diemert D, Koup RA, Laufer DS, McElrath MJ, McDermott AB, Schief WR

Broadly neutralizing antibodies (bnAbs) can protect against HIV infection but have not been induced by human vaccination. A key barrier to bnAb induction is vaccine priming of rare bnAb-precursor B cells. In a randomized, double-blind, placebo-controlled phase 1 clinical trial, the HIV vaccine-priming candidate eOD-GT8 60mer adjuvanted with AS01B had a favorable safety profile and induced VRC01-class bnAb precursors in 97% of vaccine recipients with median frequencies reaching 0.1% among immunoglobulin G B cells in blood. bnAb precursors shared properties with bnAbs and gained somatic hypermutation and affinity with the boost. The results establish clinical proof of concept for germline-targeting vaccine priming, support development of boosting regimens to induce bnAbs, and encourage application of the germline-targeting strategy to other targets in HIV and other pathogens.