Immunization by Avian H5 Influenza Hemagglutinin Mutants with Altered Receptor Binding Specificity

TLDR

Influenza virus entry is mediated by the hemagglutinin receptor‑binding domain, and adaptation of avian strains to humans is linked to a shift from α2,3‑ to α2,6‑linked sialic acid recognition. The study aims to identify H5N1 hemagglutinin mutations that alter receptor specificity toward human‑like α2,6‑linked sialic acids or away from avian α2,3‑linked sialic acids. The authors generated receptor‑binding domain mutants of H5N1 HA that either reduce α2,3‑SA binding or enhance α2,6‑SA binding. The engineered HA mutants enabled the creation of vaccines and monoclonal antibodies that neutralize emerging variants, showing that structure‑guided HA specificity alteration can inform preemptive vaccine and therapeutic design against future human‑adapted H5N1 strains.

Abstract

Influenza virus entry is mediated by the receptor binding domain (RBD) of its spike, the hemagglutinin (HA). Adaptation of avian viruses to humans is associated with HA specificity for α2,6- rather than α2,3-linked sialic acid (SA) receptors. Here, we define mutations in influenza A subtype H5N1 (avian) HA that alter its specificity for SA either by decreasing α2,3- or increasing α2,6-SA recognition. RBD mutants were used to develop vaccines and monoclonal antibodies that neutralized new variants. Structure-based modification of HA specificity can guide the development of preemptive vaccines and therapeutic monoclonal antibodies that can be evaluated before the emergence of human-adapted H5N1 strains.