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Imperfect vaccines, within-host dynamics & parasite evolution Sylvain GANDON Génétique et Évolution des Maladies Infectieuses, UMR CNRS-IRD 2724 IRD, 911.

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Presentation on theme: "Imperfect vaccines, within-host dynamics & parasite evolution Sylvain GANDON Génétique et Évolution des Maladies Infectieuses, UMR CNRS-IRD 2724 IRD, 911."— Presentation transcript:

1 Imperfect vaccines, within-host dynamics & parasite evolution Sylvain GANDON Génétique et Évolution des Maladies Infectieuses, UMR CNRS-IRD 2724 IRD, 911 avenue Agropolis 34394 Montpellier Cedex 5, France sylvain.gandon@mpl.ird.fr DIMACS Workshop on Evolutionary Considerations in Vaccine Use, June 27-29, 2005

2 Myxomatosis evolution Average mortality of naïve rabbits Year Fenner & Fantini (1999) Emergence of rabbit resistance

3 Naive rabbit Resistant rabbit Virulent virus Avirulent virus Myxomatosis evolution From Best & Kerr (2000) ✝

4 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

5 Outline 1. Imperfect vaccines 2. Epidemiological models 3. Evolutionary models - virulence mutants - escape mutants 4. Epidemiology and evolution 5. Conclusion Vaccines EpidemiologyEvolutionBoth

6 Perfect Vaccines (Jenner, 1796) Naïve hostImmune host Vaccine Vaccines EpidemiologyEvolutionBoth

7 Imperfect Vaccines Vaccine Naïve hostSemi-Immune host Vaccines EpidemiologyEvolutionBoth

8 r 1 r 2 r 3 Semi-immunity Host resistance may act at different steps of parasite life cycle Anti - infection Anti - growth Anti - transmission Vaccines EpidemiologyEvolutionBoth

9 Vaccines against malaria gametocytes merozoites sporozoites Life cycle of Plasmodium falciparum Anti-infection : r 1 Anti-growth : r 2 Anti-transmission : r 3 Vaccines RTS,S/ASO2A (Alonso et al. 2004) EpidemiologyEvolutionBoth

10 Vaccine quality: r1r1 Naïve Hosts r3r3 r2r2 Vaccinated Hosts Epidemiological Model p p Vaccines EpidemiologyEvolutionBoth Recovered Hosts Force of infection: Scherer & McLean (2002)

11 Vaccination and eradication Basic reproductive ratio before vaccination,. Vaccination threshold: 012345678910 0 0.2 0.4 0.6 0.8 1 Perfect vaccine Imperfect vaccine (r 1 = r 2 = r 3 =0.3) pcpc Vaccines EpidemiologyEvolutionBoth Eradication

12 Vaccination and transient dynamics Time (years) Vaccines EpidemiologyEvolutionBoth R 0 =11 p c =0.91 Honeymoon period Infected individuals Vaccination start p = 0.5p = 0.3p = 0.95p = 0.88p = 0.7

13 Evolutionary consequences Vaccines Treated host (e.g. vaccinated) Naïve host Escape evolution Parasite fitness Wild type parasite Escape mutant EpidemiologyEvolutionBoth Cost of escape

14 Evolutionary consequences Escape evolution Virulence evolution: Exploitation strategy Virulence:  Transmission:  Vaccines EpidemiologyEvolutionBoth

15 r3r3 r2r2 Virulence,  ESS N Evolution of virulence in a heterogeneous host population Vaccines r2r2 r1r1 EpidemiologyEvolutionBoth WNWN W W ESS V WVWV

16 Results: vaccine quality Different imperfect vaccines with p=0.5 Vaccine efficacy: r 1, r 2, r 3 Anti-growth r 2 ESS virulence Vaccines Anti- Infection r 1 Anti- transmission r 3 EpidemiologyEvolutionBoth

17 010.20.40.60.8 0 0.1 0.2 0.3 0.4 Vaccination coverage, p. pcpc r 1 =0.5, r 2 =0.4 Virulence evolution and eradication ESS virulence r 1 =0.5, r 2 =0.6 pbpb Vaccination coverage, p. 0 0.1 0.2 0.3 0.4 010.20.40.60.8 pcpc Vaccines EpidemiologyEvolutionBoth Results: vaccine quantity

18 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., r 1, r 3 ) may limit virulence evolution. Vaccines EpidemiologyEvolutionBoth

19 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 EpidemiologyEvolutionBoth Conclusion of simple models

20 Within-host dynamics Parasite: Immunity: r r Vaccines EpidemiologyEvolutionBoth André et al. (2003)

21 Within-host dynamics and parasite fitness Parasitemia Time Virulence,  Transmission,  Clearance,  Infection Clearance Parasite growth Host imunity Vaccines    EpidemiologyEvolutionBoth

22 Within-host growth rate, r Mean Transmission Mean Virulence 0510 15 20 0.2 0.4 0.6 0.8 1 05101520 0 2 4 05101520 0.2 0.4 0.6 Mean Clearance Within-host dynamics & vaccination Naïve host Vaccinated host Vaccines    EpidemiologyEvolutionBoth

23 Within-host growth rate, r Mean Transmission Mean Virulence 0510 15 20 0.2 0.4 0.6 0.8 1 05101520 0 2 4 05101520 0.2 0.4 0.6 Mean Clearance    Within-host dynamics & vaccination Vaccines EpidemiologyEvolutionBoth

24 rnrn rvrv 0 2 4 6 8 10 12 Within-host growth rate Parasite fitness, W 01020 Within-host growth rate, r Mean Transmission Mean Virulence 0510 15 20 0.2 0.4 0.6 0.8 1 05101520 0 2 4 05101520 0.2 0.4 0.6 Mean Clearance    Within-host dynamics & vaccination Vaccines    EpidemiologyEvolutionBoth Virulence mutant Wild-type parasite

25 Within-host dynamics & vaccination Vaccines Prevalence of r n and r v EpidemiologyEvolutionBoth 00.20.40.60.81 0 0.5 1 Vaccination coverage 00.20.40.60.81 0 0.1 0.2 0.3 0.4 Mean mortality rate

26 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 EpidemiologyEvolutionBoth

27 Virulence versus escape evolution Parasite fitness Wild type parasite Escape mutant Virulence evolution Escape evolution 0 2 4 6 8 10 12 Within-host growth rate rnrn rvrv Parasite fitness 01020    Virulence mutant Wild-type parasite

28 What are the differences between these mutants? Escape mutants pay the cost on transmission (lower  ): R 0 Virulence mutants pay the cost on virulence (higher  ): R 0 Which evolution is more likely? At epidemiological equilibrium: the mutant with the higher R 0 Away from this equilibrium: the mutant with the higher r Vaccines EpidemiologyEvolutionBoth Virulence versus escape evolution  

29 Vaccines EpidemiologyEvolutionBoth Epidemiology and evolution 3 strains will compete before and after vaccination: - Wild type, WT: , ,  - Escape mutant, E: , ,  - Virulence mutant, V: , ,  R0R0 N R0R0 N R0R0 N, R 0 V V V

30 Vaccines EpidemiologyEvolutionBoth Epidemiology and evolution On naïve hosts: On vaccinated hosts: R0R0 N R0R0 N R0R0 N R0R0 V R0R0 V R0R0 V  WT wins  E wins

31 Vaccines EpidemiologyEvolutionBoth Epidemiology and evolution WT E Time (years) Infected individuals Escape evolution No evolution (no mutation) WT Time (years) Infected individuals Virulence evolution WT V Time (years) Infected individuals Virulence & escape evolution WT E V Time (years) Infected individuals Vaccination start WT E V V E

32 Conclusion The ultimate goal is to merge: Evolution Epidemiology Immunology Different spatial scales Different speeds population cell, individualvery fast fast slow, fast

33 Acknowledgments Margaret MACKINNON Sean NEE Andrew READ Jean-Baptiste ANDRÉ Troy DAY

34

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