Person:

Mitchell, Patrick K.

Whole genome sequencing of 616 asymptomatically carried pneumococci was used to study the impact of the 7-valent pneumococcal conjugate vaccine. Comparison of closely related isolates revealed the role of transformation in facilitating capsule switching to non-vaccine serotypes and the emergence of drug resistance. However, such recombination was found to occur at significantly different rates across the species, and the evolution of the population was primarily driven by changes in the frequency of distinct genotypes extant pre-vaccine. These alterations resulted in little overall effect on accessory genome composition at the population level, contrasting with the fall in pneumococcal disease rates after the vaccine’s introduction.

The introduction of pneumococcal conjugate vaccines (PCVs) in the early years of the 21st century have led to significant changes in pneumococcal epidemiology. Using transmission modeling and genomics based approaches, this dissertation evaluates alterations to the pneumococcal population through the PCV era. Chapter 1 presents a transmission model designed to examine factors that may influence the potential of a previously rare antibiotic resistant lineages to emerge following the introduction of a vaccine targeting more common resistant types, finding that such emergence is more likely in settings with high antibiotic use, high carriage burden, and frequent multiple carriage. Chapter 2 examines the population genomics of pediatric pneumococcal carriage before and after the introduction of PCV-13, finding that the non-vaccine type population composition experienced changes immediately following vaccine introduction but moved back towards its pre-vaccination state over time. Additionally, there is evidence that serotype 3, which is included in PCV-13, has persisted following vaccine introduction, though there are genetic differences between the pre- and post-vaccination population of this serotype. Chapter 3 compares isolates of a single non-vaccine serotype, 33F, collected from carriage and invasive disease, finding evidence that the invasive capacity of this serotype may have declined following the introduction of PCV-13 and that very closely related pairs isolates are disproportionately likely to both be from either carriage or disease. Together, these projects contribute to our understanding of how the pneumococcal population has and will continue to change as PCV use expands.

Pneumococcal conjugate vaccines target the limited subset of the more than 90 known serotypes of Streptococcus pneumoniae responsible for the greatest burden of pneumococcal disease and antibiotic resistance. Following the introduction of these vaccines, serotypes not targeted were able to expand and resistance became more common within these types. Here we use a stochastic dynamic model of pediatric pneumococcal carriage to evaluate potential influences on the emergence of new resistant lineages following the introduction of a vaccine targeting more common resistant types. Antibiotic pressure was the strongest driver, with no emergence at low levels and universal emergence at high levels. At intermediate levels of antibiotic pressure, higher carriage burden and a greater degree of dual carriage promoted emergence. This may have implications for current plans to introduce childhood pneumococcal vaccination in several high-burden countries.