Habib, R.; Solieva, S. O.; Lin, Z. J.; Ghosh, S.; Bayruns, K.; Singh, M.; Agostino, C. J.; Tursi, N. J.; Sowers, K. J.; Huang, J.; Roark, R. S.; Purwar, M.; Park, Y.; Ayyanathan, K.; Li, H.; Carey, J. W.; Kim, A.; Park, J.; McCanna, M. E.; Skelly, A. N.; Chokkalingam, N.; Kriete, S.; Shupin, N.; Huynh, A.; Walker, S.; Laenger, N.; Du, J.; Cui, J.; Hahn, B. H.; Patel, A.; Escolano, A.; Kwong, P. D.; Shapiro, L.; Bowman, G. R.; Shaw, G. M.; Weiner, D. B.; Pallesen, J.; Kulp, D. W.

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.