impact of immunization with different pertussis vaccines on selection of escape mutants and...
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ESCAIDE 2015
Nicole Guiso
Institut Pasteur
Impact of immunisation with different subunit pertussisvaccines on selection of escape B. pertussis isolates
and reduction in vaccine effectiveness
ESCAIDE 2015
Bordetella pertussis
The agent of whooping cough was identified inParis, in 1900 by Jules BordetIt was only isolated in Brussels in 1906 by JulesBordet and Octave Gengou, because of thedevelopment of a special medium
Octave Gengou etJules Bordet
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Bordetella parapertussis
Isolated in 1938 The prevalence is lower thanthat of B. pertussis ……..but beware of this « cousin » secreting a black pigment……
Eldering and Kendricks, J. Bact 1938
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Whooping cough: disease due to Gram negativebacteria……..but after many years of research noidentification of a toxin
Bordetella pertussis toxins and adhesinsduring the pre-vaccine era
Pertussis whole-cell (Pw) vaccine composed of heat killed bacteria!
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Pertussis whole-cell vaccinesPrimary-vaccination : 3-4-5 monthsBooster : 24 months
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Pw
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Pertussis is a cyclical diseaseevery 3-5 years
Pw vaccines were efficacious but were they all efficacious and effective?
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Same vaccine strains ? YesSame vaccine ? No
Pertussis whole cell vaccines
Problem N°1Pw vaccines are very difficult to produce in a
reproducible manner……….why?
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Bordetella pertussis and pertussis whole-cell vaccinesWhole genome sequencing allowed the understanding of instability:
presence of hundreds of mobiles elements called Insertion Sequences or IS on the chromosome of the bacteria
Major problem for the production of Pw vaccine or detoxified Pw vaccine or attenuated live vaccine
Parkhill et al, Nature, 2003
Pw vaccines are efficacious but difficult to produce in a reproducible
manner: efficacy varied from 30 to 95% in the 90’s!
…….epidemiology varies according to countries
ESCAIDE 2015 Waning of naturally or vaccine acquired immunity
Naturally-acquired immunity is not life-long andpertussis is not only a pediatric disease
Exact duration of naturally acquired immunity is undetermined and varies depending on the herdimmunity and the level of circulation of thebacteria…..between 8 to 15 years
Protective immunity provided by Pw vaccine appears topersist for at least 8-10 years (four doses)
Grimprel et al, CDLI, 1997 ; Guiso et al., Vaccine, ,2007
Problem N°2:
Pertussis immunity is not long lasting and vaccine boosters are needed…………..but Pw vaccines are reactogenic
A new vaccine is needed!
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Bordetella pertussis
Adhesins Toxins
FHA or FilamentousHemagglutinin
PTX or Pertussistoxin
PRN or Pertactin AC-Hly or AdenylateCyclase -Hemolysin
FIM or Fimbrialproteins
TCT or Trachealcytotoxin
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Development of many different Pa vaccines!All Pa vaccines contain detoxified PT either alone* PT: Pa-1 or with* one adhesin (FHA): Pa-2* two adhesins (FHA+PRN): Pa-3 * four adhesins (FHA+PRN+FIM2+FIM3): Pa-5
Pertussis subunit or acellular vaccines
easier to produce in a reproducible manner
better tolerated by infants
efficacious
Several trials between 1986 and 1995
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Impact of Pa vaccines in Sweden
No difference between vaccines
Pa
Pertussis is still a cyclical diseaseevery 3-5 years
ESCAIDE 2015 French Hospital-based surveillance: RENACOQ
Clinical Surveillance43 pediatric hospitals and the NCR since 1996coordinated by the Ministery of Health (InVS)
Biological SurveillanceCulture
PCR
Surveillance introduced to analyse the impact of the change in the vaccine strategy:
1998: Introduction of an adolescent booster with Pa2002: Pa for primary and boosters, no more Pw2004: Introduction of the cocooning strategy2008: Introduction of a booster at 25 yearsof age plus the Cocooning strategy plus
What is the impact of the vaccine strategyon the duration of vaccine induced-protection but also
on the agents of the disease?
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Booster 2 (Ados)
Booster 3 (Adults)
Primary-vaccination : 2,3,4 monthBooster 1: 16-18 month
PaPw Pw/Pa
Tubiana et al, Ped Infect Dis, 2015
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Duration of protection of Pw and Pa vaccines
2002-2006: two studies in France
2008
Similar duration of protection induced by the Pw vaccine and the Pa-3 vaccine
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2012-2013 in United States
and in Australia:……….decrease of the efficacy of the Pa vaccines in use
Pa vaccines and duration of protection
JID, 2014
Sheridan et al, JAMA 2012
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French Hospital-based surveillance: 1996-2013
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B. parapertussis
B. pertussis
Nov
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French Hospital-based surveillance: 1996-2015Microbiological data
Increase in the proportion of B. pertussis isolates non producing a vaccine antigen, mostly PRN
Future Microbiol. 2014
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Pertactin-deficient Bordetella pertussis
1,18% 1,38%2,63%
4,79%
11,76%13,90%
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B. parapertussis
B. pertussis
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Small increase of B. parapertussis
French Hospital-based surveillance: 1996-2015Microbiological data
All B. parapertussis isolates circulatingsince 2007 are not producing PRN!
Increase in the proportion of B. pertussis isolates non producing a vaccine antigen, mostly PRN
Future Microbiol. 2014
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Five different couples of PRN+/PRN-
Do PRN-deficient B. pertussis isolates present a selective advantage in a Pa-immunized background?
Yes using the murine model
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Circulate in regions where Pa vaccines were introducedbetween 10 to 17 years ago:
Australia, Europe, Japan, United States
However, their proportion is varying : (2% à 70%) Why ?
PRN-deficient Bordetella pertussis
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Is the increase in the circulation of PRN-deficient B. pertussis due to the use of Pa
vaccines ? - no PRN- isolates in Denmark using a vaccine non
containing PRN but only few isolates collectedZedeman et al, Eurosurveillance, 2015
- No comparison with isolates circulating in regions usingonly Pw vaccines
Isolates need to be collected in different regions
ESCAIDE 2015 Is the increase of PRN-deficient B. pertussislinked to vaccine coverage?
Suppression of the 16-18 months booster in Australia
Lower vaccine coverage in the western part of US
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Is the circulation of these PRN-deficient B. pertussis a transient phenomenon during the last huge epidemic cycle observed in 2012-2013 around the world
as it was observed in the late 1990s ?
the proportion of PRN-deficient isolates seems to decrease in Japan suggesting it was linked to the pertussis cycle
Myaki et al, PlosOne, 2013
Is the increase in the proportion of the B. pertussis and B. parapertussis PRN-deficient isolates the pursuit of the adaptation of the two species to their human host?
Pa vaccines are not supposed to induce a protective immunity against B. parapertussis which is rather in favor of an adaptation of both species to their human hosts
Guiso and Hegerle expert Rev of Vaccines, 2015
To answer all the questions raised above it is urgent to have an approach to
whooping cough problems integrating not only the vaccine composition and the
vaccine strategies used but also the biological surveillance of the disease, the
vaccine coverage and the characteristics of the circulating B. pertussis and B.
parapertussis populations
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Age at first dose: as early as possible (6-8 weeks)
Any change in schedule and strategy should be informed by data
Countries should try to reach the highest coverage possible with the current vaccination strategy and to implement disease surveillance
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Thank you for
your attention