Global emergence and population dynamics of divergent serotype 3 CC180 pneumococci

Abstract

Streptococcus pneumoniae serotype 3 remains a significant cause of morbidity and mortality worldwide, despite inclusion in the 13-valent pneumococcal conjugate vaccine (PCV13). Serotype 3 increased in carriage since the implementation of PCV13 in the United States, while invasive disease rates remain unchanged. We investigated the persistence of serotype 3 in carriage and disease, through genomic analyses of a global sample of 301 serotype 3 isolates of the Netherlands 3 -31 (PMEN31) clone CC180, combined with associated patient data and PCV utilization among countries of isolate collection. We assessed phenotypic variation between dominant clades in capsule charge (zeta potential), capsular polysaccharide shedding, and susceptibility to opsonophagocytic killing, which have previously been associated with carriage duration, invasiveness, and vaccine escape. We identify a recent shift in the CC180 population attributed to a lineage termed Clade II, which was estimated by Bayesian coalescent analysis to have first appeared in 1968 [95% HPD: 1939 -1989] and increased in prevalence and effective population size thereafter. Clade II isolates are divergent from the pre-PCV13 serotype 3 population in non-capsular antigenic composition, competence, and antibiotic susceptibility, the last resulting from the acquisition of a Tn916-like conjugative transposon. Differences in recombination rates among clades correlated with variations in the ATP-binding subunit of Clp protease as well as amino acid substitutions in the comCDE operon. Opsonophagocytic killing assays elucidated the low observed efficacy of PCV13 against serotype 3. Variation in PCV13 use among sampled countries was not independently correlated with the CC180 population shift; therefore, genotypic and phenotypic differences in protein antigens and, in particular, antibiotic resistance may have contributed to the increase of Clade II. Our analysis emphasizes the need for routine, representative sampling of isolates from disperse geographic regions, including historically under-sampled areas. We also highlight the value of genomics in resolving antigenic and epidemiological variations within a serotype, which may have implications for future vaccine development. Author SummaryStreptococcus pneumoniae is a leading cause of bacterial pneumoniae, meningitis, and otitis media. Despite inclusion in the most recent pneumococcal conjugate vaccine, PCV13, serotype 3 remains epidemiologically important globally. We investigated the persistence of serotype 3 using whole-genome sequencing data form 301 isolates collected among 24 countries from 1993-2014. Through phylogenetic analysis, we identified three distinct lineages within a single clonal complex, CC180, and found one has recently emerged and grown in prevalence. We then compared genomic difference among lineages as well as variations in pneumococcal vaccine use among sampled countries. We found that the recently emerged lineage, termed Clade II, has a higher prevalence of antibiotic resistance compared to other lin...

Effectiveness of 13-Valent Pneumococcal Conjugate Vaccine Against Invasive Disease Caused by Serotype 3 in Children: A Systematic Review and Meta-analysis of Observational Studies

“…A coherent hypothesis for PCV13 impact on serotype 3 should take into account all of these data: substantial direct protection; evidence of overall reductions in population-based incidence in the early, but not later, years following introduction; and lower protection afforded by PCV13 against serotype 3 relative to other vaccine serotypes. A recent study has also suggested that there has been a genetic shift from a relatively low to a relatively high antibiotic-resistant serotype 3 clade that was not driven by PCV13 use [43]. One possible explanation that incorporates these observations is that PCV13 provides direct protection against disease and, to a lower extent, carriage.…”

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“…Serotype 3 also causes considerable disease burden [11,27] being the most common overall cause of pneumonia in the USA [34], is highly invasive [28] and is associated with increased mortality [29]. Distinct lineages exist within serotype 3 clonal complex 180, and recent clade distributions shift has led to the emergence and expansion of clade II [35,36], which now represents 50% serotype 3 IPD in the UK [37]. We could not determine serotype 3 clade grouping in this analysis, but clade II emergence may, at least in part, explain serotype 3 disease persistence.…”

Intracellular survival of Streptococcus pneumoniae in human alveolar macrophages is augmented with HIV infection

“…A major strength of this work is the use of a locally-relevant and globally-important invasive pneumococcal ST3. ST3 is among the commonest pneumococcal carriage serotypes in Malawi ( 7 ) and is also a global concern due to the persistent ST3 disease ( 7 , 10 , 11 ). Pneumococcal ST3 is biochemically different from the other serotypes, having a large thick polysaccharide capsule, surrounded by a slime layer, which gives it a characteristic mucoid appearance when grown on blood agar plates ( 46 , 47 ).…”

“…Globally, pneumococcus serotype 3 (ST3) is of major concern, since effectiveness of the pneumococcal conjugate vaccines (PCV) against it remain uncertain. Specifically, there is limited reduction in ST3 disease compared to the other vaccine serotypes in the era of PCV ( 7 , 10 , 11 ).…”