Despite use of influenza vaccines for more than 65 y, influenza and its complications are a major cause of morbidity and mortality worldwide. Most deaths during influenza virus infections are due to underlying co-morbidities or secondary bacterial pneumonia. The measures of immune response currently used for licensure of influenza vaccines are relevant mainly for protection from viral infection in healthy adults. Development of new or improved influenza vaccines will require a definition of novel, and specific correlates of protection. These correlates should associate immune responses with outcomes that are relevant to specific risk groups, such as asthma exacerbation, hospitalization or disruptions to care or daily activities. Assessment of vaccine effectiveness for both viral and bacterial vaccines should include measures of impact on secondary bacterial pneumonia.