Functional, immunogenetic, and structural convergence in influenza immunity between humans and macaques

Abstract

Human B cell immunity to the influenza hemagglutinin (HA) stem, a universal vaccine target, is often stereotyped and immunogenetically restricted, posing hurdles to study outside of humans. Here, we show that cynomolgus macaques vaccinated with an HA stem immunogen elicit humanlike public B cell lineages targeting two major conserved sites of vulnerability, the central stem and anchor epitopes. Central stem antibodies were predominantly derived from V_H1-138, the macaque homolog of human V_H1-69, a V_H gene preferentially used in human central stem broadly neutralizing antibodies (bnAbs). Similarly, macaques produced anchor bnAbs containing the canonical NWP motif. Both bnAb lineages were functionally and structurally analogous to their human counterparts, with recognition mediated largely by germline-encoded structural motifs. These findings indicate that the macaque immunoglobulin repertoire can support humanlike public bnAb responses to influenza HA, highlighting the value of the macaque model for translational vaccinology. Moreover, this underscores the utility of homologous germline-encoded immunity, suggesting that immune repertoires of macaques and humans have been similarly shaped during evolution.