Over the past 15 years, a number of novel vaccines (e.g., GARDASIL®, PrevnarT) have been licensed which help protect against multiple disease-specific serotypes. In some cases, "second generation" versions of these vaccines have already been licensed (e.g., GARDASIL®9, Prevnar 13T) which expand the serotype coverage of the first generation vaccines. With the introduction of "future generation" vaccines, one loses the ability to compare to the original "efficacy-based" vaccine and potentially allows for drift in effectiveness. In addition, with the continuing expansion on the number of serotypes included in the vaccines, the hurdles for showing non-inferiority to previous generations for all serotypes becomes increasingly difficult. This paradigm in vaccine development will be discussed along with the implications on study design, power calculations, choice of statistical criteria, and choice of hypotheses for future generation vaccines.