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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
28th October 2014
Streptococcus pneumoniae disease and
control
Developing a model of
pneumococcal population structure
Simulating vaccination
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Nasopharynx
Streptococcus pneumoniae• Gram Positive• Carried in nasopharynx• Invasive infections: pneumonia, meningitis, sepsis• 1.6 million deaths annually
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
capsule
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Vaccine Induced Strain Replacement
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Miller et al. (2011) Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination inEngland 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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:> Immunological competition> Ecological competition
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:> Immunological competition> Ecological competition
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:> Immunological competition> Ecological competition
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:> Immunological competition> Ecological competition
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:> Immunological competition> Ecological competition
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Antigens
Virulence
Metabolism
Antigens
Virulence
MetabolismCapsule
Pili (type I and II)Pneumolysin variants
CarbohydrateAmino acid
LipidNucleotideTransport
Antigens
Virulence
MetabolismCapsule
Pili (type I and II)Pneumolysin variants
CarbohydrateAmino acid
LipidNucleotideTransport
Antigenic Type (AT)
Metabolic Type (MT)
Virulence Type (VT)
a Antigenic Type (AT)
Antigens
Virulence
Metabolism
Pili (type I and II)Pneumolysin variants
CarbohydrateAmino acid
LipidNucleotideTransport
a,b,c
Immunological competition
+ -Cost
Ecological competition
1, 2, 3
1>2>3
Ecologicalcompetition
Antigenic Type (AT)
Metabolic Type (MT)
Virulence Type (VT)
a Antigenic Type (AT)
a
a1+
+
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
a1+
a1-
b3-
b2-
a2-c1-
b1-
b3+
a3+c3+
c2+
b2+
a2+
c1+
b1+c3-
c2-a3-
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
a1
b2
c3
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
a1
b2
c3
Multi locus sequence typing (MLST)
Sequence type (ST)
ST
Sero
type
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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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
IsolatesAllele numbers
Locus 2Locus 3Locus 4
Croucher et al. (2013). Population genomics of post-vaccine changes in pneumococcal epidemiology. Nature Genetics.
www.pubmlst.orgJolley & Maiden (2010). BIGSdb: Scalable analysis of bacterial genome variation at the population level. BMC Bioinformatics 11:595
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Vaccination
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
A B C
2 3
Vaccination could lead to increases in transmissibility and virulence
_ _
Vaccine Induced Metabolic Shift
Antigenic type
Metabolic type
Virulence type
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Metabolic Shift in S. pneumoniae at the genomic level
19A (ST199)
19F(ST320) 19A
Vaccination
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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: 28. 155.
Increase in Type I pili among NVT strains (9% -> 30%)Role of ecological competition?
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
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 | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Acknowledgements
Professor Sunetra GuptaDr Bridget PenmanDr Caroline BuckeeProfessor Martin Maiden
INI, Cambridge | 28th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Princeton University | 10th October 2014 | eleanor.watkins@zoo.ox.ac.uk
Effects of Cross-Immunity
Vaccination
Weak vaccine-induced cross-immunity
No vaccine-induced cross-immunity
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