Influenza Vaccine Effectiveness: Defining the H3N2 Problem.

Observational studies have consistently shown that influenza vaccine effectiveness (VE) is lower for H3N2 relative to H1N1pdm09 and type B, and this is not entirely explained by antigenic match. The triad of virus, vaccine, and host immunity provides a framework to examine contributing factors. Antigenic evolution facilitates H3N2 immune escape, and increasing glycosylation of the hemagglutinin shields antigenic sites from antibody binding. Egg passage adaptation of vaccine viruses generates mutations that alter glycosylation, impair the neutralizing antibody response, and reduce VE. Complex host immune factors may also influence H3N2 VE, including early childhood imprinting and repeated vaccination, but their role is uncertain. Of the triad of contributing factors, only changes to the vaccine are readily achievable. However, it is unclear whether current licensed non-egg-based vaccines generate superior protection against H3N2. The optimal strategy remains to be defined, but newer vaccine technology platforms offer great potential.