| Shrnutí: | The pneumococcus is a leading pathogen infecting children and adults. Safe, effective vaccines exist and they work by inducing antibodies to the polysaccharide capsule (unique for each serotype) that surrounds the cell; however, current vaccines are limited by the fact that only a few of the nearly 100 antigenically-distinct serotypes are included in the formulations. Within the serotypes, serogroup 6 pneumococci are a frequent cause of serious disease and a common coloniser of the nasopharynx in children. Serotype 6E was first reported in 2004 but was thought to be rare; however, we and others have detected serotype 6E among recent pneumococcal collections. Therefore, we analysed a diverse dataset of ∼1000 serogroup 6 genomes, assessed the prevalence and distribution of serotype 6E, analysed the genetic diversity among serogroup 6 pneumococci and investigated whether pneumococcal conjugate vaccine (PCV)-induced serotype 6A and 6B antibodies mediated the killing of serotype 6E pneumococci. We found that 43% of all genomes were serotype 6E and they were recovered worldwide from healthy children and patients of all ages with pneumococcal disease. Four genetic lineages, three of which were multidrug-resistant, described ∼90% of the serotype 6E pneumococci. Serological assays demonstrated that vaccine-induced serotype 6B antibodies were able to elicit killing of serotype 6E pneumococci. We also revealed three major genetic clusters of serotype 6A capsular sequences, discovered a new hybrid 6C/6E serotype, and identified 44 examples of serotype switching. Therefore, while vaccines appear to offer protection against serotype 6E, genetic variants may reduce vaccine efficacy in the longer term due to the emergence of serotypes that can evade vaccine-induced immunity. IMPORTANCE: A key virulence factor for the pneumococcus is the polysaccharide capsule, which is also the target for vaccine-mediated protection. Within serogroup 6 there are eight different types, the most common of which were thought to be serotypes 6A, 6B and 6C. Our study characterised ~1000 serogroup 6 pneumococcal genomes and the data showed that serotype 6E, previously thought to be rare, was the predominant serotype. Earlier detection of serotype 6E pneumococci was obscured because they cross-react to the serotype 6B antisera used in the traditional serotyping assay, and it was only by inspection of the capsular locus sequences that the high prevalence and global distribution of serotype 6E was realised. Fortunately, vaccine-induced antibodies elicited killing of serotype 6E pneumococci; however, we also revealed considerable nucleotide sequence variation among serogroup 6 and thus ongoing genome sequence-based surveillance is essential.
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