Download 20141028120012151-236301

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
Developing a
model of
pneumococcal
population
structure
Streptococcus
pneumoniae
disease and
control
INI, Cambridge
|
28th October 2014
Simulating
vaccination
|
[email protected]
Streptococcus pneumoniae
• Gram Positive
• Carried in nasopharynx
• Invasive infections: pneumonia, meningitis, sepsis
• 1.6 million deaths annually
Nasopharynx
INI, Cambridge
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28th October 2014
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capsule
INI, Cambridge
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28th October 2014
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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
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28th October 2014
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[email protected]
Vaccine Induced Strain Replacement
INI, Cambridge
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28th October 2014
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[email protected]
Vaccine Induced Strain Replacement
PCV7
All disease
Non vaccine type disease
Vaccine type disease
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.
INI, Cambridge
|
28th October 2014
|
[email protected]
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
|
[email protected]
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:
> Immunological competition
> Ecological competition
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571
Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
INI, Cambridge
|
28th October 2014
|
[email protected]
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:
> Immunological competition
> Ecological competition
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571
Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
INI, Cambridge
|
28th October 2014
|
[email protected]
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:
> Immunological competition
> Ecological competition
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571
Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
INI, Cambridge
|
28th October 2014
|
[email protected]
Vaccine Induced Strain Replacement
Previous frameworks:
• Strong competition between strains
• Vaccination releases competition
• Inter-strain competitive interactions:
> Immunological competition
> Ecological competition
Lipsitch (1998) Vaccination against colonizing bacteria with multiple serotypes. PNAS. 94 6571
Cobey & Lipsitch (2012) Niche and Neutral Effects of Acquired Immunity Permit Coexistence of Pneumococcal Serotypes. Science 335: 1576.
INI, Cambridge
|
28th October 2014
|
[email protected]
Antigens
Metabolism
Virulence
Antigens
Metabolism
Capsule
Carbohydrate
Amino acid
Lipid
Nucleotide
Transport
Virulence
Pili (type I and II)
Pneumolysin variants
Antigens
Metabolism
Carbohydrate
Amino acid
Lipid
Nucleotide
Transport
Capsule
a
Antigenic Type (AT)
Antigenic Type (AT)
Metabolic Type (MT)
Virulence Type (VT)
Virulence
Pili (type I and II)
Pneumolysin variants
Antigens
Metabolism
1, 2, 3
Carbohydrate
Amino acid
1>2>3
Lipid
Nucleotide
Ecological
Transport
competition
a,b,c
a
Antigenic Type (AT)
Antigenic Type (AT)
Metabolic Type (MT)
Virulence Type (VT)
Virulence
+-
Pili (type I and II)
Pneumolysin
Costvariants
Ecological competition
Immunological
competition
a
a1+
+
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28th October 2014
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b2-
b3+
b3-
a3-
a2-
c2c2+
c1-
c1+
a1+
a2+
a3+
c3+
a1c3-
b2+
INI, Cambridge
|
b1+
28th October 2014
b1-
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c3
b2
a1
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28th October 2014
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c3 b2 ST typing (MLST)
Multi locus sequence
a1+
Serotype
• Non-overlapping combinations
of antigenic and metabolic types
• Only a minority of strains cause
invasive disease, associated with
the fittest metabolic types.
Bruggemann et al. (2003). Clonal Relationships between Invasive and Carriage Streptococcus pneumoniae and Serotype- and Clone-Specific
Sequence type (ST)
Differences in Invasive Disease Potential. JID. 187:1424.
INI, Cambridge
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28th October 2014
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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)
Allele numbers
Isolates
Locus 1
Locus 2
Locus 3
Locus 4
www.pubmlst.org
Jolley
& Maiden
(2010).Population
BIGSdb: Scalable
analysis
of bacterialchanges
genomeinvariation
at the population
level.
BMC Bioinformatics
11:595
Croucher
et al. (2013).
genomics
of post-vaccine
pneumococcal
epidemiology.
Nature
Genetics.
INI, Cambridge
|
28th October 2014
|
[email protected]
INI, Cambridge
|
28th October 2014
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Vaccination
INI, Cambridge
|
28th October 2014
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Vaccine Induced Metabolic Shift
A
B
C
Antigenic type
2
3
Metabolic type
_
_
Virulence type
Vaccination could lead to increases in transmissibility and virulence
INI, Cambridge
|
28th October 2014
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Metabolic Shift in S. pneumoniae: Serotype 19A
United States
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.
INI, Cambridge
|
28th October 2014
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Metabolic Shift in S. pneumoniae at the genomic level
19A
(ST199)
19F
(ST320)
19A
Vaccination
INI, Cambridge
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28th October 2014
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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
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Virulence Shift in S. pneumoniae
Type I Pili
Increase in Type I pili among NVT strains (9% -> 30%)
Role of ecological competition?
Regev-Yochay et al (2010) Re-emergence of the Type I Pilus among Steptococcus pneumoniae isolates in Massachusetts, USA.
Vaccine. 5: 28. 155.
INI, Cambridge
|
28th October 2014
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[email protected]
Virulence Shift in S. pneumoniae
Type II Pili
Increase in Type II pili among 19A strains (1.5% -> 40%)
Zahner et al (2010) Increase in Pilus Islet 2–encoded Pili among Streptococcus pneumoniae Isolates, Atlanta, Georgia, USA. Emerging
Infectious Diseases. 16: 155.
INI, Cambridge
|
28th October 2014
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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.
c
•
Vaccination can lead to the emergence of the fittest
metabolic type and high virulence trait with a nonvaccine serotype.
•
Vaccine-induced metabolic shift can be observed at
the whole genome level.
•
Rapid increases have been observed in pilins in
non-vaccine serotypes.
INI, Cambridge
|
28th October 2014
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[email protected]
Acknowledgements
Professor Sunetra Gupta
Dr Bridget Penman
Dr Caroline Buckee
Professor Martin Maiden
INI, Cambridge
|
28th October 2014
|
[email protected]
Effects of Cross-Immunity
Vaccination
No vaccine-induced
cross-immunity
Weak vaccine-induced crossimmunity
Princeton University
|
10th October 2014
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[email protected]