Viva la revolución: rethinking influenza A virus antigenic drift

Rapid antigenic evolution of the influenza A virus hemagglutinin has precluded developing vaccines that provide durable protection. The yearly costs of influenza (circa $1011 in the USA alone) easily justify investments in better understanding the interaction of influenza with antibodies and other inducible elements of the immune system that potentially limit or circumvent antigenic variation. Here, I summarize exciting new findings that offer the possibility of a quantum improvement in vaccine efficacy, focusing on studies clearly documenting robust neutralizing antibody responses to the conserved stem region of the hemagglutinin.

► Breakthroughs in basic understanding suggest novel vaccine strategies for inducing broad antibody immunity that circumvents antigenic drift.
► Internal proteins may provide effective targets for vaccines based on NK cell recognition or ADCC.
► A key feature of immune escape may be modulation of HA receptor avidity which triggers epistatic alterations secondarily modulating antigenicity.
► Humans generate neutralizing antibodies that interact with epitopes conserved within and even between hemagglutinin subtypes.