Functional, Immunogenetic, and Structural Convergence in Influenza Immunity between Humans and Macaques

Abstract

Human B cell immunity to the influenza hemagglutinin (HA) stem region, a universal influenza vaccine target, is often stereotyped and immunogenetically restricted, posing challenges for study outside humans. Here, we show that macaques vaccinated with a HA stem immunogen elicit human-like public B cell lineages targeting two major conserved sites of vulnerability, the central stem and anchor epitopes. Central stem antibodies were predominantly derived from VH1-138, the macaque homolog of human VH1-69, a VH-gene preferentially used in human central stem broadly neutralizing antibodies (bnAbs). Similarly, macaques produced anchor bnAbs with the human-like NWP motif. Both bnAb lineages were functionally and structurally analogous to their human counterparts, with recognition mediated largely by germline-encoded motifs. Thus the macaque immunoglobulin repertoire supports human-like public bnAb responses to influenza HA. Moreover, this underscores the utility of homologous germline-encoded immunity, suggesting that immune repertoires of macaques and humans may have been similarly shaped during evolution. HIGHLIGHTS[bullet] Functional human-like public antibody lineages can be elicited to HA stem supersites in macaques. [bullet]Macaque central stem bnAbs are predominantly derived from VH1-138, a VH-gene homologous to human VH1-69. [bullet]The human-like CDR L3 NWP anchor epitope-targeting lineage can be elicited in macaques. [bullet]Central stem and anchor bnAbs from humans and macaques engage their respective epitopes with atomic level similarity.