BackgroundDespite use of highly effective conjugate vaccines, invasive pneumococcal disease (IPD) remains a leading cause of morbidity and mortality and disproportionately affects Indigenous populations. Although included in the 13-valent pneumococcal conjugate vaccine (PCV13), which was introduced in 2010, serotype 3 (ST3) continues to cause disease among Indigenous communities in the Southwest US. In the Navajo Nation, ST3 IPD incidence increased among adults (3.8/100,000 in 2001-2009 and 6.2/100,000 in 2011-2019); in children the disease persisted although the rates dropped from 5.8/100,000 to 2.3/100,000.MethodsWe analyzed the genomic epidemiology of ST3 isolates collected from 129 adults and 63 children with pneumococcal carriage (n=61) or IPD (n=131) from 2001–2018 of the Navajo Nation. Using whole-genome sequencing data, we determined clade membership and assessed changes in ST3 population structure over time.ResultsThe ST3 population structure was characterized by three dominant subpopulations:clade II(n=90, 46.9%) andclade Iα(n=59, 30.7%), which fall into Clonal Complex (CC) 180, and a non-CC180 clade (n=43, 22.4%). The proportion ofclade II-associated IPD cases increased significantly from 2001-2010 to 2011-2018 among adults (23.1% to 71.8%; p<0.001) but not in children (27.3% to 33.3%; p=0.84). Over the same period, the proportion ofclade II-associated carriage increased; this was statistically significant among children (23.3% to 52.6%; p=0.04) but not adults (0% to 50.0%, p=0.08).ConclusionsIn this setting with persistent ST3 IPD and carriage,clade IIhas increased since 2010. Genomic changes may be contributing to the observed trends in ST3 carriage and disease over time.