Evolutionary dynamics of epitopes of limited variability on the head of influenza H1 haemagglutinin

It is commonly assumed that naturally protective targets of immunity in influenza are highly variable. Theoretical work suggests, by contrast, that influenza evolution is primarily driven by naturally protective responses against epitopes of limited variability (ELV). At least one ELV has been identified on the head region of haemagglutinin of H1 influenza, opening up the possibility of producing a universal influenza vaccine. Here, for the first time, we provide a comprehensive catalogue of ELVs within the head region of H1 haemagglutinin and explain how they arise within its apparently high variable landscape. We show 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 others. Thus, 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.