Correlates of protection to influenza virus, where do we go from here?

Influenza vaccination is the cornerstone of prophylaxis. The regulatory authorities currently annually license vaccines based on serum antibodies directed toward the major surface glycoprotein haemagglutinin (HA). The most commonly used serological test, the haemagglutination inhibition (HI) assay utilizes red blood cells, which show considerable biological variation. There is a need for validated, standardized assays to reduce laboratory variation steps that are currently being taken by the regulatory agencies. Here we examine the historical evidence for defining the HI titer >= 40 as a surrogate correlate of protection and examine alternative assays. Moreover, the immune response to influenza is multifacated and there are probably multiple correlates of protection. We conclude there is a need for detailed immunological analysis including kinetic studies and head to head comparison of vaccines by a range of immunological assays to further define correlates of protection.