Characteristics of epitopes of limited variability on the head of influenza H1 haemagglutinin

It is commonly assumed that all naturally protective targets of immunity in influenza are highly variable. Our theoretical work suggests, by contrast, that influenza evolution is primarily driven by naturally protective immune responses against epitopes of limited variability (ELV). We have identified and characterised at least one such ELV on the head region of the major influenza antigen, haemagglutinin (HA), of H1 influenza, opening up the possibility of a novel method of producing a universal influenza vaccine. Here we demonstrate that the head region of H1 haemagglutinin can be decomposed into a number of discrete variable regions (VRs): ELVs tend to include a limited number of VRs compared to other epitopes either because of the smaller footprint of the associated antibody or because they are centred on VRs that are relatively isolated from the others. We conclude that the variability of an antibody binding site is determined by the number of variable residues included in its footprint rather than the intrinsic entropy of any particular region.