High-resolution genomics identifies pneumococcal diversity and persistence of vaccine types in children with community-acquired pneumonia in the UK and Ireland
Authors: Rodriguez-Ruiz Juan Pablo , Xavier Basil Britto , Stöhr Wolfgang , van Heirstraeten Liesbet , Lammens Christine , Finn Adam , Goossens Herman , Bielicki Julia Anna , Sharland Michael , Malhotra-Kumar Surbhi ,   on behalf of the PERUKI, GAPRUKI and CAP-IT networks, Gibb Diana M. , Lyttle Mark D. , Barratt Sam , Dunn David , Clements Michelle , Sturgeon Kate , Molyneux Elizabeth , Butler Chris C. , Smyth Alan , Prichard Catherine , Peto Tim E. A. , Cousens Simon , Logan Stuart , Bamford Alasdair , Turkova Anna , Goodman Anna L. , Fitzgerald Felicity , Faust Saul N. , Powell Colin , Little Paul S. , Robotham Julie , Wan Mandy , Klein Nigel , Rogers Louise , Vitale Elia , Hawcutt Daniel B. , Rotheram Mathew , Hartshorn Stuart , Jyothish Deepthi , Ross James G. , Patel Poonam , Vergnano Stefania , Morgan Jeff , Nyamugunduru Godfrey , Furness John C. , Holt Susannah J. , Gibbs John , Alcock Anastasia E. , Hall Dani , Cheung Ronny , Murad Arshid , Jerman K. M. , Bird Chris , Baron Tanya K. Z. , Cantle Fleur , Mullen Niall , McCrone Rhona , Robinson Gisela , Starkey Lizzie , O’Riordan Sean , Roland Damian , Bandi Srini , Gough Chris , Gardner Sharryn , Barrett M. J. , Walton Emily K. , Kapur Akshat , Foster Steven J. , Bland R. M. , Bloom Ben , Parikh Ami , Potier Katherine , Gilchrist Judith , West Noreen , Heath Paul T. , Iqbal Yasser , Maconochie Ian K. , Nyirenda Maggie , Keers Sophie , Cathie Katrina , Bayreuther Jane , Herrieven Elizabeth-Jayne L. , Townend Willian 
Published: April 2024

Abstract
Background
Streptococcus pneumoniae is a global cause of community-acquired pneumonia (CAP) and invasive disease in children. The CAP-IT trial (grant No. 13/88/11; https://www.capitstudy.org.uk/) collected nasopharyngeal swabs from children discharged from hospitals with clinically diagnosed CAP, and found no differences in pneumococci susceptibility between higher and lower antibiotic doses and shorter and longer durations of oral amoxicillin treatment. Here, we studied in-depth the genomic epidemiology of pneumococcal (vaccine) serotypes and their antibiotic resistance profiles.

Methods
Three-hundred and ninety pneumococci cultured from 1132 nasopharyngeal swabs from 718 children were whole-genome sequenced (Illumina) and tested for susceptibility to penicillin and amoxicillin. Genome heterogeneity analysis was performed using long-read sequenced isolates (PacBio, n = 10) and publicly available sequences.

Results
Among 390 unique pneumococcal isolates, serotypes 15B/C, 11 A, 15 A and 23B1 were most prevalent (n = 145, 37.2%). PCV13 serotypes 3, 19A, and 19F were also identified (n = 25, 6.4%). STs associated with 19A and 19F demonstrated high genome variability, in contrast to serotype 3 (n = 13, 3.3%) that remained highly stable over a 20-year period. Non-susceptibility to penicillin (n = 61, 15.6%) and amoxicillin (n = 10, 2.6%) was low among the pneumococci analysed here and was independent of treatment dosage and duration. However, all 23B1 isolates (n = 27, 6.9%) were penicillin non-susceptible. This serotype was also identified in ST177, which is historically associated with the PCV13 serotype 19F and penicillin susceptibility, indicating a potential capsule-switch event.

Conclusions
Our data suggest that amoxicillin use does not drive pneumococcal serotype prevalence among children in the UK, and prompts consideration of PCVs with additional serotype coverage that are likely to further decrease CAP in this target population. Genotype 23B1 represents the convergence of a non-vaccine genotype with penicillin non-susceptibility and might provide a persistence strategy for ST types historically associated with vaccine serotypes. This highlights the need for continued genomic surveillance.