HIV Vaccine Design to Target Germline Precursors of Glycan-Dependent Broadly Neutralizing Antibodies

Broadly neutralizing antibodies (bnAbs) against the N332 supersite of the HIV envelope (Env) trimer are the most common bnAbs induced during infection, making them promising leads for vaccine design. Wild-type Env glycoproteins lack detectable affinity for supersite-bnAb germline precursors and are therefore unsuitable immunogens to prime supersite-bnAb responses. We employed mammalian cell surface display to design stabilized Env trimers with affinity for germline-reverted precursors of PGT121-class supersite bnAbs. The trimers maintained native-like antigenicity and structure, activated PGT121 inferred-germline B cells ex vivo when multimerized on liposomes, and primed PGT121-like responses in PGT121 inferred-germline knockin mice. Design intermediates have levels of epitope modification between wild-type and germline-targeting trimers; their mutation gradient suggests sequential immunization to induce bnAbs, in which the germline-targeting prime is followed by progressively less-mutated design intermediates and, lastly, with native trimers. The vaccine design strategies described could be utilized to target other epitopes on HIV or other pathogens. •Developed mammalian cell display to design germline-targeting native-like trimers•Germline-targeting trimers retain native-like antigenicity and structure•Germline-targeting trimers prime glycan-dependent HIV bnAb responses in knockin mice•Designed boosting schemes intended to induce bnAbs Elicitation of broadly neutralizing antibodies (bnAbs) is a critical HIV vaccine goal. Steichen et al. have developed immunogens that prime germline-precursor B cells for the bnAb PGT121 and can therefore initiate bnAb induction. The authors have also designed boosting immunogens to shepherd the antibody maturation to develop bnAbs.