Streptococcus pneumoniae, or pneumococcus, is an important cause of pneumonia, meningitis, and otitis media. Pneumococcus is classified into 92 serotypes, which differ in their nasopharyngeal carriage prevalence and disease incidence. Similar serotype rank orders are found worldwide, and this dissertation sought to understand the host and microbial factors that could affect these stable patterns.

In the first section, I evaluated whether serotype-specific immunity could play a role in protecting against acquisition. For some serotypes, prior colonization with a particular serotype provided specific protection against future acquisition of that same type, and this protection was associated with increased anticapsular antibody concentrations. Next, I evaluated how serotype affects interactions with host innate immune effectors. Using isogenic variants and clinical isolates, I found that serotypes that were more prevalent among carriage isolates tended to be more heavily encapsulated in vitro and were more resistant to non-opsonic killing by neutrophils. Significantly, I identified a novel association between the primary structure of the capsular polysaccharides, degree of encapsulation, and prevalence during both the pre- and post- vaccine eras. Extending these findings to invasive disease, I found that serotypes that were associated with an increased risk of death in bacteremic pneumonia, as determined in a meta-analysis, tended to be more heavily encapsulated in vitro. I then created a statistical model to predict patterns of invasive disease using capsular polysaccharide structure and case-fatality data. The results of this dissertation contribute novel information about the biology and epidemiology of pneumococcal serotypes.