SignificancePneumococcal disease represents a global health problem, especially for the young, the elderly, and the resource-limited. Disease progression begins with asymptomatic nasopharyngeal bacterial colonization before subsequent dissemination and disease (pneumonia, sepsis, and middle ear infection). Analysis of this transition from colonization to disease provided antigens that were tested in this study for directed vaccination against only the virulent subset of pneumococci. In so doing, a “smart” vaccine was sought that would address this disease broadly, effectively, and selectively.