The foundation for any vaccine immunogenicity trial is the identification of appropriate correlates for protection and the measurement of these quantities with well-designed bioassays. An important requirement for developing bioassay protocols is the standardization of each procedure, so it is performed in a uniform manner within a facility and, in the case of multicenter trials, across laboratories. It is also crucial to recognize that the selection and use of techniques used to quantify assay endpoints (e.g., antibody concentration) will affect their accuracy and precision and these methods must also be defined and uniformly applied within and across laboratories. This paper discusses a number of methodological issues related to bioassay design and analysis that would ultimately lead to highly accurate assay endpoint determinations with minimum variance that would be comparable across laboratories. Guidelines are presented for the development of bioassay and data analysis protocols. Strengthening vaccine immunogenicity trial protocols will ensure that these quantities are estimated with the greatest degree of reliability and facilitate the subsequent evaluation of new vaccine formulations. Following these guidelines will give other researchers as well as regulatory authorities more confidence in evaluating and comparing the differences in immunogenicity levels elicited by new and developing vaccines.