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Population genomics of post-vaccination changes in pneumococcal population structure

Population genomics of post-vaccination changes in pneumococcal population structure. Nicholas Croucher. 4 th September, 2013. Streptococcus pneumoniae. Gram positive bacterium with ‘diplococcal’ morphology Commensal and pathogen

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Population genomics of post-vaccination changes in pneumococcal population structure

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  1. Population genomics of post-vaccination changes in pneumococcal population structure Nicholas Croucher 4th September, 2013

  2. Streptococcus pneumoniae • Gram positive bacterium with ‘diplococcal’ morphology • Commensal and pathogen • Encapsulated with one of >90 polysaccharide capsules (‘serotypes’) • Many serotypes belong to a ‘serogroup’, e.g. 23F, 23A, 23B • Naturally transformable

  3. Introduction of PCV7 • Prevnar 7 valent conjugate polysaccharide vaccine (PCV7) introduced in 2000 • Includes serotypes 4, 6B, 9V, 14, 18C, 19F and 23F Pilishviliet al (2010) JID

  4. The SPARC Collection • Rates of invasive pneumococcal disease in MA fell 69% • The SPARC collection: • Children <8 years old sampled during routine well or sick PCP visits • From 16 communities (2001) or 8 communities (2004 & 2007) • Single colonies isolated from nasopharyngeal swabs • Levels of carriage (sampling of 2,638 children across 3 winters) remained unchanged: • 27% in 2000-2001 • 23% in 2003-2004 • 30% in 2006-2007

  5. Serotypes 2001 Key: Vaccine type 2004 Vaccine type-related Non-vaccine type 2007 Hanageet al (2010) Epidemics

  6. Serotype and invasiveness Yildirimet al (2010) Vaccine

  7. Questions • What mechanisms underlay the changes in the population structure? • Serotype switching v strain replacement • What causes differences in invasiveness? • What substructuring of the population can be detected? • Why are only some strains resistant?

  8. Dataset • Samples were sequenced on IlluminaHiSeq machines as multiplexed libraries • A total of 616 isolates produced sequences that passed all quality control: • 133 isolates from 2001 (75 nt reads) • 203 isolates from 2004 (75 nt reads) • 280 isolates from 2007 (100 nt reads)

  9. Analysis pipeline Assemble de novo with Velvet Predict genes with Glimmer3 and Prodigal All v all comparison of proteins Assign proteins into COGs with COGtriangles

  10. Analysis pipeline Assemble de novo with Velvet 616 genomes Predict genes with Glimmer3 and Prodigal 1.2 million proteins All v all comparison of proteins 1.44x1012 alignments Assign proteins into COGs with COGtriangles 5,442 COGs

  11. COG distribution Frequency No. isolates containing COG

  12. COG distribution ~2,000 genes in a genome ~1,500 genes in ‘core’ genome Rare genes encoding different capsule types, mobile genetic elements, etc Frequency No. isolates containing COG

  13. Population structure

  14. Sequence cluster 2

  15. Sequence cluster 1

  16. Detecting recombination

  17. Detecting recombination

  18. Changes with vaccination

  19. Changes with vaccination

  20. Changes with vaccination

  21. Vaccine-induced bottlenecks SC15: PMEN14 lineage SC5: PMEN3 lineage Ancestral serotype 19F Ancestral serotype: 9V 19A switch 19A switch

  22. Changes with vaccination

  23. Changes with vaccination

  24. Revealing hidden diversity

  25. Emergence of resistance

  26. Beta lactam resistance

  27. Beta lactam resistance

  28. Beta lactam resistance

  29. Beta lactam resistance

  30. Antibiotic resistance Macrolide resistance Tetracycline resistance: tetM ermB mef

  31. Antibiotic resistance Macrolide resistance Tetracycline resistance: tetM ermB mef

  32. Geographic structuring Proportion of pairs from same site within threshold Threshold genetic distance

  33. Geographic structuring Proportion of pairs from same site within threshold Threshold genetic distance

  34. Response to immune selection? Logistic regression coefficient against host age No. strains containing COG

  35. Changes in COG frequency Log10 odds ratio, 2001 v 2007 Prevalence in 2001

  36. Changes in COG frequency Log10 odds ratio, 2001 v 2007 Prevalence in 2001

  37. Conclusions • PCV7 had a big impact on the population’s serotype composition, but this was not reflected across the rest of the genome • Changes were primarily through the emergence of pre-existing low-frequency variants • This means recombination among the population is yet to have impacted on the response to PCV7

  38. Acknowledgements • CCDD • Marc Lipsitch • Bill Hanage • Bernice Sims • Abbie Stevenson • Patrick Mitchell • BU • Stephen Pelton • WTSI • Stephen Bentley • Julian Parkhill • HMS • Jon Finkelstein • Grace Lee Funding: AXA postdoctoral fellowship; NIH and Wellcome Trust

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