1. Malaria Cycle (Hviid, 2004) (Marsh et al, 2004)

2. Variant Surface Antigens (VSA) ➲ Parasite proteins expressed by iRBCs. ➲ Each parasite has a repertoire of ~60 var genes for PfEMP1, where each iRBC expresses one type. ➲ PfEMP1 regulates the adhesion properties. ➲ Major target for the adaptive immune system.

3. VSA_SM (Severe Malaria) ➲ An antigenically conserved group, in time and space, associated with severe disease. ➲ Positively selected in naive hosts. ➲ Each parasite seems to contain VSA_SM. (Bull et al, 2000)

4. Research questions Why is VSA_SM antigenically conserved? Why does every parasite contain VSA_SM?

5. Within-host dynamics ➲ After release of the merozoites by the liver, the whole repertoire of VSAs are expressed. ➲ In a few days, all the iRBCs tend to express the same VSA. ➲ During infection, the iRBCs can clonally switch to express a different VSA (switching matrix)

6. Between-host dynamics ➲ Vector transmission ➲ High transmissibility ➲ High diversity ➲ Multiple infections during lifetime (SIS)

7. Model ➲ Upon infection by a parasite, the strongest VSA for which there is no immunity will be expressed ➲ After clearance, the host has build up immunity against the expressed VSA ➲ SIR-model with homogeneous mixing ➲ Equilibrium analysis VSAs: 1, 2, 3, 4,... Parasites: {1,2}, {1,3}, {2,3},... Stronger VSA: 1 > 2 > 3 > 4 >... Within-host Between-host

8. Flow diagram

9. Results (2 loci) 5 VSA, 2 loci

10. Results (2 loci)

11. Results (1 locus) 5 VSA, 1 locus

12. Frequency VSA_SM (VSA 1) Variable # VSA, 2 loci

13. Results (superinfection and scaled mu) 5 vsa, 2 loci, superinfection, high birth/death rate

14. Extensions ➲ Superinfection. ➲ VSA dependent disease dynamics. ➲ Cross-immunty between the VSAs. ➲ Immunity based on number of infections. ➲ Recombination in the parasite. ➲ VSA_UM without adaptive immunity

15. Conclusions ➲ (Very much work in progress) ➲ In the basic model, it cannot be explained why each parasite should contain some VSA_SM. The conservedness could be explained by its lower prevalence. ➲ Extensions could show that each parasite contains some VSA_SM, but its conservedness is harder to explain. ➲ Epidemiological data on VSA expression is needed