SUMMARY: The failures of current vaccines to prevent the ongoing transmission of Bordetella pertussis is the central problem behind its resurgence and listing by both CDC and NIH as a priority re- emerging pathogen. Clinical studies and baboon experiments have confirmed that current acellular vaccines protect against disease but fail to prevent colonization, shedding and transmission of B. pertussis. Unfortunately, these experimental systems are not practical, or even available, for the necessary research to develop improved vaccines that can prevent colonization, shedding and transmission. We recently discovered and have overcome prior obstacles to allowing B. pertussis to efficiently colonize mice which has allowed us to develop assays for colonization, shedding and transmission between mice. We have also developed innovative outer membrane vesicle (OMV)- based vaccines and shown that they limit colonization, a substantial improvement over current vaccines. Here we will use our newly developed assays to define the effects of current and our novel vaccines on the ability of B. pertussis to efficiently colonize animals, be shed into their environment and transmit to new hosts. We will then define and compare the systemic immune responses associated with protection from disease with the mucosal immune responses associated with blocking colonization, shedding and transmission. Together these experiments will demonstrate the use of these new assays that are likely to revolutionize approaches to develop and test new vaccines and treatments. They are also likely to validate the improved efficacy of OMV-based vaccines and present evidence that such new vaccines can overcome the major failure of current vaccines by blocking its transmission, providing hope that we could actually eradicate this NIH and CDC priority agent.