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Imperfect vaccines,within-host dynamics& parasite evolution
Sylvain GANDONGénétique et Évolution des Maladies Infectieuses,
UMR CNRS-IRD 2724IRD, 911 avenue Agropolis
34394 Montpellier Cedex 5, [email protected]
DIMACS Workshop on Evolutionary Considerations in Vaccine Use, June 27-29, 2005
Myxomatosis evolution
60
65
70
75
80
85
90
95
100
1950 1960 1970 1980 1990 2000
Average mortality of naïve rabbits
Year
Fenner & Fantini (1999)
Emergence of rabbit resistance
Naive rabbit Resistant rabbit
Virulent virus
Avirulent virus
Myxomatosis evolutionFrom Best & Kerr (2000)
✝
Myxomatosis evolution
● Virulence can evolve fast (in both directions)
● To understand this evolution we need to:
(1) link within-host dynamics and parasite fitness
(2) include host heterogeneity
Outline
1. Imperfect vaccines2. Epidemiological models3. Evolutionary models
- virulence mutants- escape mutants
4. Epidemiology and evolution5. Conclusion
Vaccines Epidemiology
Evolution Both
r1 r2 r3
Semi-immunityHost resistance may act at different steps of
parasite life cycle
Anti - infection
Anti - growth
Anti - transmission
Vaccines Epidemiology
Evolution Both
Vaccines against malaria
gametocytes
merozoites
sporozoites
Life cycle of Plasmodium falciparum
Anti-infection : r1
Anti-growth : r2
Anti-transmission : r3
Vaccines
RTS,S/ASO2A (Alonso et al. 2004)
Epidemiology
Evolution Both
Vaccine quality: NV hh 1 r1
VVVVVV
VVV
VN
NNNN
NNN
IShdtdI
ShpdtdS
RIdtdR
IhSdtdI
ShpdtdS
)(/
)(/
)(/
)(/
)()1(/
Naïve Hosts
NV 1 r3
NV 1 r2
Vaccinated Hosts
Epidemiological Model
p
p
Vaccines Epidemiology
Evolution Both
Recovered Hosts
VVNNN IIh Force of infection:
Scherer & McLean (2002)
Vaccination and eradication
Basic reproductive ratio before vaccination, .
Vaccination threshold:
0 1 2 3 4 5 6 7 8 9 100
0.2
0.4
0.6
0.8
1
0R
Perfect vaccine
Imperfect vaccine (r1 = r2 = r3 =0.3)
pc
Vaccines Epidemiology
Evolution Both
Eradic
ation
Vaccination and transient dynamics
Time (years)
Vaccines Epidemiology
Evolution Both
R0=11
pc=0.91
0 50 100 150 2000
25
50
75
100
0 50 100 150 2000
25
50
75
100
0 50 100 150 2000
25
50
75
100
0 50 100 150 2000
25
50
75
100
Honeymoon period
0 50 100 150 2000
25
50
75
100
Infected individuals
Vaccination start
p = 0.5p = 0.3p = 0.95p = 0.88p = 0.7
Evolutionary consequences
Vaccines
Treated host (e.g. vaccinated)
Naïve host
• Escape evolutionP
aras
ite
fitn
ess
Wild typeparasite
Escapemutant
Epidemiology
Evolution Both
Cost of escape
Evolutionary consequences
• Escape evolution
• Virulence evolution:
Exploitation strategy
Virulence:
Transmission: Vaccines Epidemiolog
yEvolution Both
VN SSR
11
110
r3
r2
VwNw
Virulence,
ESSN
Evolution of virulence in a heterogeneous host population
Vaccines
r2 r1
Epidemiology
Evolution Both
WN
W
W
ESSV
WV
Results: vaccine qualityDifferent imperfect vaccines with p=0.5
Vaccine efficacy: r1, r2, r3
0 0.2 0.4 0.6 0.8 1
1
2
Anti-growthr2
ESSvirulence
Vaccines
Anti-Infection
r1
Anti-transmission
r3
Epidemiology
Evolution Both
0 10.2 0.4 0.6 0.80
0.1
0.2
0.3
0.4
Vaccination coverage, p.
pc
r1=0.5, r2=0.4
Virulence evolution and eradication
ESSvirulence
r1=0.5, r2=0.6
pb
Vaccination coverage, p.
0
0.1
0.2
0.3
0.4
0 10.2 0.4 0.6 0.8
pc
Vaccines Epidemiology
Evolution Both
Results: vaccine quantity
Conclusion of simple models
Parasite evolution may erode the benefits of vaccination
• Evolution of higher virulence (on naïve hosts)
• Eradication becomes less feasable
However, some vaccines components (i.e., r1, r3) may limit virulence evolution.
Vaccines Epidemiology
Evolution Both
But things are missing from the model:
- within-host dynamics (dynamics of immunity)
- mechanistic description of the vaccine effects
- link between virulence () and transmission ()
- link between virulence () and clearance ()
- heterogeneity among infected hosts through time
…
Vaccines Epidemiology
Evolution Both
Conclusion of simple models
IddI
00 exp 1
kIP P r e
dP d r kI P
Within-host dynamics
Parasite:
Immunity:
r
r
Vaccines Epidemiology
Evolution Both
André et al. (2003)
Within-host dynamicsand parasite fitness
Par
asit
emia
Time
Virulence,
Transmission,
Clearance,
Infection ClearanceClearanceClearance
Parasite growth
Host imunity
Vaccines
W
Epidemiology
Evolution Both
Within-host growth rate, r
Mean Transmission
Mean Virulence
0 5 10 15 20
0.2
0.4
0.6
0.8
1
0 5 10 15 200
2
4
0 5 10 15 20
0.2
0.4
0.6
Mean Clearance
Within-host dynamics & vaccination
Naïve host
Vaccinated host
Vaccines
Epidemiology
Evolution Both
Within-host growth rate, r
Mean Transmission
Mean Virulence
0 5 10 15 20
0.2
0.4
0.6
0.8
1
0 5 10 15 200
2
4
0 5 10 15 20
0.2
0.4
0.6
Mean Clearance
Within-host dynamics & vaccination
Vaccines Epidemiology
Evolution Both
rn rv0
2
4
6
8
10
12
Within-host growth rate
Par
asite
fitn
ess,
W
0 10 20
Within-host growth rate, r
Mean Transmission
Mean Virulence
0 5 10 15 20
0.2
0.4
0.6
0.8
1
0 5 10 15 200
2
4
0 5 10 15 20
0.2
0.4
0.6
Mean Clearance
Within-host dynamics & vaccination
Vaccines
W
Epidemiology
Evolution Both
Virulence mutant
Wild-type parasite
Within-host dynamics & vaccination
Vaccines
Prevalence ofrn and rv
Epidemiology
Evolution Both
0 0.2 0.4 0.6 0.8 10
0.5
1
Vaccination coverage
Vaccination coverage0 0.2 0.4 0.6 0.8 1
0
0.1
0.2
0.3
0.4
Mean mortality rate
Within-host dynamics & vaccination
Vaccines
Main results
● Confirms results of simpler models:vaccination can promote the evolution of higher virulence
● Coexistence of different strains is possible
● Evolutionary bistability emerges easily
● The virulence mutant is a generalist strategy
Epidemiology
Evolution Both
Virulence versus escape evolution
Pa
rasi
te fi
tnes
s
Wild typeparasite
Escapemutant
Virulence evolution Escape evolution
0
2
4
6
8
10
12
Within-host growth ratern rv
Pa
rasi
te fi
tnes
s
0 10 20
W
Virulence mutant
Wild-type parasite
What are the differences between these mutants?Escape mutants pay the cost on transmission (lower ): R0
Virulence mutants pay the cost on virulence (higher ): R0
Which evolution is more likely?At epidemiological equilibrium: the mutant with the higher R0
Away from this equilibrium: the mutant with the higher r
Vaccines Epidemiology
Evolution Both
S
S
Virulence versus escape evolution
S
S
Vaccines Epidemiology
Evolution Both
Epidemiology and evolution
3 strains will compete before and after vaccination:
- Wild type, WT: , ,
- Escape mutant, E: , ,
- Virulence mutant, V: , ,
R0N
R0N
R0N , R0
V
, R0 V
, R0 V
Vaccines Epidemiology
Evolution Both
Epidemiology and evolution
On naïve hosts:
On vaccinated hosts:
R0N R0
N R0N
R0V R0
V R0V
WT wins
E wins
Vaccines Epidemiology
Evolution Both
Epidemiology and evolution
0 50 100 150 200 2500
100
200
300
400
500
600
700
WTE
Time (years)
Infe
cted
ind
ivid
uals
Escape evolution
0 50 100 150 200 2500
100
200
300
400
500
600
700
No evolution(no mutation)
WT
Time (years)
Infe
cted
ind
ivid
uals
0 50 100 150 200 2500
100
200
300
400
500
600
700
Virulence evolution
WT
V
Time (years)
Infe
cted
ind
ivid
uals
0 50 100 150 200 2500
100
200
300
400
500
600
700
Virulence & escape evolution
WT E
V
Time (years)
Infe
cted
ind
ivid
uals
Vaccination start
WT E
WT V
V
WT E
Conclusion
The ultimate goal is to merge:
Evolution
Epidemiology
Immunology
Different spatial scales
Different speeds
population
population
cell, individual very fast
fast
slow, fast