Multivalent pneumococcal vaccines can increase the transmissibility and virulence of non-vaccine strains Eleanor Watkins, Caroline Buckee, Bridget Penman,

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Presentation transcript:

Multivalent pneumococcal vaccines can increase the transmissibility and virulence of non-vaccine strains Eleanor Watkins, Caroline Buckee, Bridget Penman, Martin Maiden, Sunetra Gupta Methods for Mathematical and Empirical Analysis of Microbial Communities Isaac Newton Institute for Mathematical Sciences, Cambridge 28 th October 2014

Streptococcus pneumoniae disease and control Developing a model of pneumococcal population structure Simulating vaccination INI, Cambridge | 28 th October 2014 |

Nasopharynx Streptococcus pneumoniae Gram Positive Carried in nasopharynx Invasive infections: pneumonia, meningitis, sepsis 1.6 million deaths annually INI, Cambridge | 28 th October 2014 |

capsule INI, Cambridge | 28 th October 2014 |

Serotypes and Vaccines >95 capsule types only ~15 cause most disease globally Design a vaccine which targets the most virulent serotypes Heptavalent Pneumococcal Conjugate Vaccine (PCV7) 4, 6B, 9V, 14, 18C, 19F, and 23F INI, Cambridge | 28 th October 2014 |

Vaccine Induced Strain Replacement INI, Cambridge | 28 th October 2014 |

Miller et al. (2011) Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis. Vaccine Induced Strain Replacement All disease Vaccine type disease Non vaccine type disease PCV7 INI, Cambridge | 28 th October 2014 |

Vaccine Induced Strain Replacement Previous frameworks: Strong competition between strains Vaccination releases competition Inter-strain competitive interactions: >Immunological competition >Ecological competition INI, Cambridge | 28 th October 2014 |

Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: Vaccine Induced Strain Replacement Previous frameworks: Strong competition between strains Vaccination releases competition Inter-strain competitive interactions: >Immunological competition >Ecological competition INI, Cambridge | 28 th October 2014 |

Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: Vaccine Induced Strain Replacement Previous frameworks: Strong competition between strains Vaccination releases competition Inter-strain competitive interactions: >Immunological competition >Ecological competition INI, Cambridge | 28 th October 2014 |

Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: Vaccine Induced Strain Replacement Previous frameworks: Strong competition between strains Vaccination releases competition Inter-strain competitive interactions: >Immunological competition >Ecological competition INI, Cambridge | 28 th October 2014 |

Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: Vaccine Induced Strain Replacement Previous frameworks: Strong competition between strains Vaccination releases competition Inter-strain competitive interactions: >Immunological competition >Ecological competition INI, Cambridge | 28 th October 2014 |

Antigens Virulence Metabolism

Antigens Virulence Metabolism Capsule Pili (type I and II) Pneumolysin variants Carbohydrate Amino acid Lipid Nucleotide Transport

Antigens Virulence Metabolism Capsule Pili (type I and II) Pneumolysin variants Carbohydrate Amino acid Lipid Nucleotide Transport Antigenic Type (AT) Metabolic Type (MT) Virulence Type (VT) a Antigenic Type (AT)

Antigens Virulence Metabolism Pili (type I and II) Pneumolysin variants Carbohydrate Amino acid Lipid Nucleotide Transport a,b,c Immunological competition + - Cost Ecological competition 1, 2, 3 1>2>3 Ecological competition Antigenic Type (AT) Metabolic Type (MT) Virulence Type (VT) a Antigenic Type (AT)

a a1+ + INI, Cambridge | 28 th October 2014 |

a1+ a1- b3- b2- a2- c1- b1- b3+ a3+ c3+ c2+ b2+ a2+ c1+ b1+ c3- c2- a3- INI, Cambridge | 28 th October 2014 |

a1 b2 c3 INI, Cambridge | 28 th October 2014 |

a1 b2 c3 Multi locus sequence typing (MLST) Sequence type (ST) ST Serotype Bruggemann et al. (2003). Clonal Relationships between Invasive and Carriage Streptococcus pneumoniae and Serotype- and Clone-Specific Differences in Invasive Disease Potential. JID. 187:1424. Non-overlapping combinations of antigenic and metabolic types Only a minority of strains cause invasive disease, associated with the fittest metabolic types INI, Cambridge | 28 th October 2014 |

Metabolic Analysis of Pneumococcal Genomes 616 pneumococcal genomes from Massachussetts Identified all loci involved with metabolism and transport (890 in total) Analysed allelic diversity of each metabolic/transport locus (Genome Comparator) Locus 1 Isolates Allele numbers Locus 2 Locus 3 Locus 4 Croucher et al. (2013). Population genomics of post-vaccine changes in pneumococcal epidemiology. Nature Genetics. Jolley & Maiden (2010). BIGSdb: Scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 11:595 INI, Cambridge | 28 th October 2014 |

Vaccination INI, Cambridge | 28 th October 2014 |

AB C 2 3 Vaccination could lead to increases in transmissibility and virulence _ _ Vaccine Induced Metabolic Shift Antigenic type Metabolic type Virulence type INI, Cambridge | 28 th October 2014 |

Metabolic Shift in S. pneumoniae: Serotype 19A Vaccine serotype 4 Vaccine serotype 19F Non vaccine serotype 19A Beall et al (2010) Shifting Genetic Structure of Invasive Serotype 19A Pneumococci in the United States. JID. 203:1360. United States INI, Cambridge | 28 th October 2014 |

Metabolic Shift in S. pneumoniae at the genomic level 19A (ST199) 19F (ST320) 19A Vaccination INI, Cambridge | 28 th October 2014 |

Virulence Shift in S. pneumoniae Type I and II Pili Mediate adhesion to host cells Present in 30% (TI) and 16% (TII) of invasive pneumococci Bind to host extra-cellular matrix Interference between piliated strains and Staphylococcus aureus Regev-Yochay et al (2009) The pneumococcal pilus predicts the absence of Staphylococcus aureus co-colonization in pneumococcal carriers. Clin. Inf. Dis. 15: 760. INI, Cambridge | 28 th October 2014 |

Virulence Shift in S. pneumoniae Type I Pili Regev-Yochay et al (2010) Re-emergence of the Type I Pilus among Steptococcus pneumoniae isolates in Massachusetts, USA. Vaccine. 5: Increase in Type I pili among NVT strains (9% -> 30%) Role of ecological competition? INI, Cambridge | 28 th October 2014 |

Virulence Shift in S. pneumoniae Type II Pili Zahner et al (2010) Increase in Pilus Islet 2–encoded Pili among Streptococcus pneumoniae Isolates, Atlanta, Georgia, USA. Emerging Infectious Diseases. 16: 155. Increase in Type II pili among 19A strains (1.5% -> 40%) INI, Cambridge | 28 th October 2014 |

Summary Multilocus models allow us to examine different types of competition acting on different loci. Model predicts non-overlapping associations between antigenic and metabolic types, with a minority causing disease. Vaccination can lead to the emergence of the fittest metabolic type and high virulence trait with a non- vaccine serotype. Vaccine-induced metabolic shift can be observed at the whole genome level. Rapid increases have been observed in pilins in non-vaccine serotypes. c INI, Cambridge | 28 th October 2014 |

Acknowledgements Professor Sunetra Gupta Dr Bridget Penman Dr Caroline Buckee Professor Martin Maiden INI, Cambridge | 28 th October 2014 |

Princeton University| 10 th October 2014 | Effects of Cross-Immunity Vaccination Weak vaccine-induced cross- immunity No vaccine-induced cross-immunity