Deep Mining of the Human Antibody Repertoire Identifies Frequent and Immunogenetically Diverse CDRH3 Topologies Targetable by Vaccination

Many vaccination strategies against highly variable pathogens such as HIV-1 aim to elicit broadly neutralizing antibodies (bnAbs) with particular immunogenetic or structural features. The V2 apex of the HIV-1 Env protein is a promising target for a class of bnAbs that contain conserved structural motifs in the heavy chain complementarity determining region 3 (CDRH3). Here, we show that these structural motifs are targetable by vaccination by characterizing V2 apex ‘axe-like’ CDRH3s in the human repertoire and developing new immunogens capable of selectively engaging them. We determined the frequency and diversity of axe-like CDHR3s in healthy human donors using a series of structural informatics approaches finding these precursors in 86.5% of donors. Axe-targeting immunogens based on the HIV-1 Env Q23.17 were developed and bound axe-like precursors in cryo-EM structures, induced V2 apex-specific antibody responses in humanized mice, and induced axe-like heterologous neutralizing antibodies in rhesus macaques. These results unveil a new structure-guided immunoinformatic vaccine design paradigm that can be employed to elicit immunogenetically diverse yet structurally conserved classes of antibodies.