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, Francesylvain.gandon@mpl.ird.fr

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

Perfect Vaccines(Jenner, 1796)

Naïve host Immune host

Vaccine

Vaccines Epidemiology

Evolution Both

Imperfect Vaccines

Vaccine

Naïve host Semi-Immune host

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

Acknowledgments

Margaret MACKINNON

Sean NEE

Andrew READ

Jean-Baptiste ANDRÉ

Troy DAY