The unmet need in the elderly: How immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines

► As part of the “inflammaging” process, innate immune processes may not only be ineffective, they may result in harmful inflammatory responses to infection. ► Increased levels of “bGrzB” activity associated with CMV, may be a common thread between immune dysfunction and the risk for cardiovascular complications of influenza. ► The IFN-γ:IL-10 ratio and GrzB activity in influenza-challenged PBMC can be used as biomarkers to firmly establish vaccine-mediated protection/failure. ► Adding specific adjuvants may further enhance vaccine responses even in the face of a suboptimal immune system. ► Reliance on antibody titers as a sole predictor of vaccine efficacy is a major barrier to the development of more effective influenza vaccines, which remains an unmet need.