For over 10 years, the test-negative case-control design is used for a timely and reliable estimation of seasonal influenza vaccine performance. Influenza vaccine effectiveness (VE) varies significantly by influenza type and subtype. Therefore, the calculation of type/subtype specific VE estimates is essential, as the calculation of an overall protective effect could be misleading if several types are circulating. Besides viral factors, also host and environmental factors influence the protective effect of influenza vaccines considerably. Rising evidence suggests that repeated vaccination using the identical vaccine in successive seasons combined with the circulation of relevant drift variants negatively interferes with the protection provided by the vaccine. For a better understanding of factors influencing VE, it is important to combine genetic, antigenic, epidemiologic and clinical data with agent-host factors for optimizing VE estimates.