Abstract
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.
Competing Interest Statement
R.H. and D.W.K. have pending intellectual property interests related to immunogens and approaches discussed in the manuscript. D.W.K. discloses a paid association with Inovio (SRA). D.B.W. has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board series. Remuneration received by D.B.W. includes direct payments and stock or stock options. D.B.W. also discloses the following paid associations with commercial partners: GeneOne (consultant), Geneos (advisory board), AstraZeneca (advisory board, speaker), Inovio (BOD, SRA, Stock), Sanofi (advisory board) and BBI (advisory board).
