title: Evidence for soft selective sweeps in the evolution of pneumococcal multidrug resistance and vaccine escape.
abstract: The multidrug-resistant Streptococcus pneumoniae Taiwan(19F)-14, or PMEN14, clone was first observed with a 19F serotype, which is targeted by the heptavalent polysaccharide conjugate vaccine (PCV7). However, "vaccine escape" PMEN14 isolates with a 19A serotype became an increasingly important cause of disease post-PCV7. Whole genome sequencing was used to characterize the recent evolution of 173 pneumococci of, or related to, PMEN14. This suggested that PMEN14 is a single lineage that originated in the late 1980s in parallel with the acquisition of multiple resistances by close relatives. One of the four detected serotype switches to 19A generated representatives of the sequence type (ST) 320 isolates that have been highly successful post-PCV7. A second produced an ST236 19A genotype with reduced resistance to β-lactams owing to alteration of pbp1a and pbp2x sequences through the same recombination that caused the change in serotype. A third, which generated a mosaic capsule biosynthesis locus, resulted in serotype 19A ST271 isolates. The rapid diversification through homologous recombination seen in the global collection was similarly observed in the absence of vaccination in a set of isolates from the Maela refugee camp in Thailand, a collection that also allowed variation to be observed within carriage through longitudinal sampling. This suggests that some pneumococcal genotypes generate a pool of standing variation that is sufficiently extensive to result in "soft" selective sweeps: The emergence of multiple mutants in parallel upon a change in selection pressure, such as vaccine introduction. The subsequent competition between these mutants makes this phenomenon difficult to detect without deep sampling of individual lineages.
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, MassachusettsPathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Croucher
authors.affiliation: Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Claire
authors.initials: C
authors.lastname: Chewapreecha
authors.affiliation: Center for Communicable Disease Dynamics, Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts.
authors.forename: William P
authors.initials: WP
authors.lastname: Hanage
authors.affiliation: Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Simon R
authors.initials: SR
authors.lastname: Harris
authors.affiliation: Respiratory Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Lesley
authors.initials: L
authors.lastname: McGee
authors.affiliation: Institute for Medical Microbiology, National Reference Center for Streptococci, University Hospital, RWTH Aachen, Aachen, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: van der Linden
authors.affiliation: Samsung Medical Centre, Sungkyunkwan University School of Medicine and Asia Pacific Foundation for Infectious Disease, Seoul, South Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Song
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, South Korea.
authors.forename: Kwan Soo
authors.initials: KS
authors.lastname: Ko
authors.affiliation: Laboratory of Molecular Genetics, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, PortugalLaboratory of Microbiology, The Rockefeller University, New York, New York.
authors.forename: Herminia
authors.initials: H
authors.lastname: de Lencastre
authors.affiliation: Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, ThailandMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandCentre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, United Kingdom.
authors.forename: Claudia
authors.initials: C
authors.lastname: Turner
authors.affiliation: Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Yang
authors.affiliation: Laboratory of Molecular Genetics, Instituto de Tecnologia Química e Biológica, Universidade Nova de Lisboa, Oeiras, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sá-Leão
authors.affiliation: Respiratory Diseases Branch, Centers for Disease Control and Prevention, Atlanta, Georgia.
authors.forename: Bernard
authors.initials: B
authors.lastname: Beall
authors.affiliation: Hubert Department of Global Health, Rollins School of Public Health and Division of Infectious Diseases, School of Medicine, Emory UniversityCentre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Gauteng, South Africa.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Klugman
authors.affiliation: Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Julian
authors.initials: J
authors.lastname: Parkhill
authors.affiliation: Shoklo Malaria Research Unit, Mahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Mae Sot, ThailandMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandCentre for Tropical Medicine, Nuffield Department of Medicine, University of Oxford, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Turner
authors.affiliation: Pathogen Genomics, The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United KingdomDepartment of Medicine, University of Cambridge, Addenbrooke's Hospital, United Kingdom sdb@sanger.ac.uk.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Bentley
mesh_terms: D002874:Chromosome Mapping; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019143:Evolution, Molecular; D006801:Humans; D010802:Phylogeny; D022242:Pneumococcal Vaccines; D011995:Recombination, Genetic; D012641:Selection, Genetic; D013296:Streptococcus pneumoniae / Q000235:genetics* / Q000276:immunology*
chemical_list: D022242:Pneumococcal Vaccines
keywords: antibiotic resistance; bacterial evolution; phylogenomics; recombination; selective sweeps; vaccine escape