Genomics Reveals the Worldwide Distribution of Multidrug-Resistant Serotype 6E Pneumococci

Abstract

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 common colonizers 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 analyzed a diverse data set of ∼1,000 serogroup 6 genomes, assessed the prevalence and distribution of serotype 6E, analyzed the genetic diversity among serogroup 6 pneumococci, and investigated whether pneumococcal conjugate vaccine-induced serotype 6A and 6B antibodies mediate the killing of serotype 6E pneumococci. We found that 43% of all genomes were of 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 because of the emergence of serotypes that can evade vaccine-induced immunity.

Pneumococcus with the “6E” cps Locus Produces Serotype 6B Capsular Polysaccharide

“…Taken together, the data show that putative "serotype 6E" is identical to serotype 6B in serologic properties (10) and in chemical structure (this study). Thus, it should be described as a genetic variant of serotype 6B and expressed as serotype 6B with class 2 cps locus.…”

“…Thus, serotypes "6E" and 6B produce PSs with identical chemical structures and are expected to have identical serologic properties. Indeed, no serologic differences between serotypes 6B and "6E" have been detected (10).…”

“…Recently, several serotype 6B reference strains from the Pneumococcal Molecular Epidemiology Network collection were found to have "serotype 6E" genetic loci (10). Furthermore, SPEC6B, which is used as the serotype 6B reference target strain for the multiplexed opsonophagocytosis assay (MOPA) (11), was found to have the genetic features of "serotype 6E" (unpublished information).…”

“…Although the authors of this study concluded that "serologic and biochemical characterization" is needed to confirm it as a new serotype (6), the putative serotype 6E is being increasingly treated as a distinct serotype in publications describing its discovery in all parts of the world (5, 7-10) and its association with antibiotic resistance (7,10). Consequently, a recent study stated that there is an urgent need to determine the structure of capsular polysaccharide from the putative serotype 6E (10).…”

From Immunologically Archaic to Neoteric Glycovaccines

“…In Germany, the meningitis serotype distribution changed to non-PCV13 types and went along with a reduction in antibiotic resistant isolates. On the other hand, resistant pneumococci are increasingly isolated world-wide [54,55,56]. …”