pathogen adaptation under imperfect vaccination: implications for pertussis michiel van boven 1,...
Post on 20-Dec-2015
223 views
TRANSCRIPT
![Page 1: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/1.jpg)
Pathogen adaptation under imperfect vaccination: implications for pertussis
Michiel van Boven1, Frits Mooi2,3, Hester de Melker3
Joop Schellekens3 & Mirjam Kretzschmar3
1Wageningen University/Utrecht University2Utrecht University/Academic Hospital Utrecht
3National Institute of Public Health & the Environment
![Page 2: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/2.jpg)
Pertussis, basic facts gram-negative bacterium first described: 1540 ! first isolated: 1906 by Bordet and Gengou main species in the genus Bordetella: B. pertussis,
B. parapertussis, and B. bronchiseptica B. pertussis and B. parapertussis : mostly human B. bronchiseptica : dogs, pigs, sheep Bp and Bpp : limited survival outside the host Bb : prolonged starvation resistance Bp and Bpp infections: severe in unvaccinated infants,
usually mild in adolescents and adults
![Page 3: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/3.jpg)
Pertussis vaccination
before 1940: a leading cause of infant death nowadays: very low mortality rates in developed countries Dutch vaccination program: started in 1953 vaccine: killed whole-cell (Tohama) vaccination coverage: ~96% up to 2002: vaccination at age 3,4,5, and 11 months since 2002: vaccination at age 2,3,4, and 10 months since 2002: booster with subunit vaccine at 4 years 2006: replacement of whole-cell vaccine by subunit vaccine subunit vaccines: 1-5 components (e.g., ptx, pertactin, fha)
![Page 4: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/4.jpg)
Pertussis trend in the Netherlands
date1/1990 1/1992 1/1994 1/1996 1/1998 1/2000 1/2002
num
ber of
cas
es (m
onth-1
)
0
200
400
600
800
1000
![Page 5: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/5.jpg)
Age distribution of cases before and after 1996
![Page 6: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/6.jpg)
Distribution of cases by vaccination status
![Page 7: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/7.jpg)
Virulence genes of B. pertussis
![Page 8: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/8.jpg)
Phase modulation in the bordetellae
![Page 9: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/9.jpg)
Questions
What is the contribution of circulation in unvaccinated infants to the overall circulation of pertussis?
How does the infection incidence depend on period of immunity after vaccination or infection?
How will the pathogen population evolve in response to vaccination?
![Page 10: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/10.jpg)
Model structure
Central idea: there is a difference between infection in immunologically naïve individuals (‘primary infection’) and infection in individuals whose immune system has been primed (‘secondary infection’)
S
V
S I R
I
1
1
22
g1h
gVh
p
1-p
g2h
V
![Page 11: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/11.jpg)
Model parameters
![Page 12: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/12.jpg)
herd immunity cannot always be achieved (McLean and others)
the reproduction ratio increases with p if
for the default parameter values, Rp increases with p if
secondary infections are 7% more transmissible than primary infections
Population dynamical analysis: invasion
V
V
σμσ
gfgf
11
22
μα
gfμσ
σp
μαgf
RV
V
2
22
1
11p p-1
![Page 13: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/13.jpg)
Population dynamical analysis: endemicity
![Page 14: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/14.jpg)
Evolutionary adaptation
Adaptation of B. pertussis to vaccination occurs in two ways:
(1) the pathogen population may evolve to become polymorphic (2) the pathogen may evolve higher or lower levels of virulence gene expression
![Page 15: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/15.jpg)
Scenarios
1. B. pertussis can increase (or decrease) its efficiency in immunologically naïve individuals by increasing (decreasing) the expression of virulence genes. On the other hand, increased expression of virulence genes results in a stronger immune response in primed individuals.
2. B. pertussis can evolve to circumvent the immunity induced by vaccination. However, strains that circumvent the vaccination induced immune response have reduced fitness.
![Page 16: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/16.jpg)
fitness measure: the growth rate λ(y,x) of a mutant strain characterized by a variable y in a resident pathogen population characterized by a variable x
the selection gradient:
ESS condition:
maximum condition:
convergence condition:
Evolutionary invasion analysis
![Page 17: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/17.jpg)
1. virulence gene expression
112
11
1
2
11fVgfS
fSdfdf
Vff
In the first example, the parameters f1 and f2 are
molded by selection. For this scenario, the ESS condition reads
![Page 18: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/18.jpg)
1. virulence gene expression
![Page 19: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/19.jpg)
trade-off: 212250
1250 ff
1. virulence gene expression
![Page 20: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/20.jpg)
2. immune evasion
pghgσμ
μfgVf
dgαd
VVVV
ggVVV
22
In this example, the parameters σV and α are
supposed to be molded by selection, and the ESS condition reads
![Page 21: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/21.jpg)
2. immune evasion
Suppose that a resident strain is present that cannot
infect individuals in class V (gv=0) The infectious period of the resident strain is days. A mutant strain that is fully able to infect individuals in
class V (i.e. g’v=0) can invade if its infectious period
is not shorter than days. If the period of protection after vaccination is ten years (instead of five), the mutant can invade the infectious period is not shorter than days.
6.143651 μα
1.13365Δ
1 αμα
9.11365Δ
1 αμα
![Page 22: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/22.jpg)
Pathogen adaptation: summary of results
For realistic parameter values primary susceptibles constitute only a small fraction of the population, while secondary susceptibles abound. Consequently, pertussis circulation depends mainly on (unnoticed) infections in children, adolescents and adults.
The pathogen is more likely to adapt to efficiently exploit secondary susceptibles than to efficiently exploit primary susceptibles.
Pertussis strains that evade the immunity induced by vaccination can only invade if they incur no or a modest fitness cost.
![Page 23: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/23.jpg)
Tests and open questions
How long does immunity, against infection and against disease, last after infection and vaccination?
Are there systematic differences between strains found in countries with high vaccination coverage and strains found in countries with low vaccination coverage?
![Page 24: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/24.jpg)
Michiel van Boven1, Don Klinkenberg1, Franjo Weissing2, Hans Heesterbeek1
1Faculty of Veterinary Medicine, Utrecht University
2Theoretical Biology, University of Groningen
The optimal amount of antiviral control
![Page 25: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/25.jpg)
Main question: What is the optimal
amount
of costly (i.e. potentially lethal)
antiviral
therapy when faced with a virulent
pathogen that can kill the host?
![Page 26: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/26.jpg)
the public health officer: maximize the
performance of the population
the individual: maximize your own
performance
given the actions of those around you
Two perspectives
![Page 27: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/27.jpg)
life expectancy, L(y,x)
probability to be alive after T years, L(y,x,T)
perceived risk, L(y, I(x), V(x))
Objective functions
![Page 28: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/28.jpg)
Model structure
μ : background mortality ρ : recovery rate
γ : antivirals induced mortality ν : antiviral control rate
α : infection induced mortality σ: non-compliance rate
: force of infection
![Page 29: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/29.jpg)
1. Life expectancy at the endemic equilibrium
pathogen absent:
no antiviral control:
no individual differences:
rare type νy in a resident population νx :
![Page 30: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/30.jpg)
Endemic pathogens, life expectancy as objective function
![Page 31: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/31.jpg)
Endemic pathogens, life expectancy as objective function
![Page 32: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/32.jpg)
Endemic pathogens, limited time horizon
![Page 33: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/33.jpg)
Endemic pathogens, limited time horizon
![Page 34: Pathogen adaptation under imperfect vaccination: implications for pertussis Michiel van Boven 1, Frits Mooi 2,3, Hester de Melker 3 Joop Schellekens 3](https://reader035.vdocuments.us/reader035/viewer/2022062421/56649d415503460f94a1b6c6/html5/thumbnails/34.jpg)
Outbreak situations, limited time horizon
?