Over the past 15 years, a number of novel vaccines (e.g., GARDASIL™, Prevnar™) 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., Prevnar 13™) 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 will be increasingly difficult. Indeed, current WHO recommendations for the development of pneumococcal conjugate vaccines state that non-inferiority on all common serotypes may not be required for licensure (which occurred in the licensing of Prevnar 13™). In this roundtable, this paradigm will be discussed along with the implications on study design, power calculations, choice of non-inferiority margins, and choice of hypotheses for future generation vaccines.