Protective immunity against severe malaria is associated with antibodies to a conserved repertoire of PfEMP1 variants

Tessema, S.; Nakajima, R.; Jasinskas, A.; Monk, S.; Lekieffre, L.; Lin, E.; Kiniboro, B.; Proietti, C.; Siba, P. M.; Felgner, P.; Doolan, D. L.; Mueller, I.; Barry, A.

doi:10.1101/472159

bioRxiv · 10.1101/472159

Protective immunity against severe malaria is associated with antibodies to a conserved repertoire of PfEMP1 variants

Tessema, S.·Nakajima, R.·Jasinskas, A.·Monk, S.·Lekieffre, L.·Lin, E.·Kiniboro, B.·Proietti, C.·Siba, P. M.·Felgner, P.·Doolan, D. L.·Mueller, I.·Barry, A.

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Abstract

Extreme diversity of the major surface antigen and virulence determinant of the malaria parasite Plasmodium falciparum, Erythrocyte Membrane Protein-1 (PfEMP1), poses a major barrier to identifying targets of protective immunity. To overcome this problem, we developed a PfEMP1 protein microarray containing 456 DBL domains, which was used to characterize the immunome of a cohort of semi-immune children and to identify variants associated with protective immune responses. Children with high mean antibody levels to DBL group 2 had a 26-36% reduced risk of uncomplicated (clinical) malaria, however only 8 diverse DBL variants were weakly associated with protection from clinical malaria and had low predictive accuracy. On the other hand, children with high mean antibodies to DBL groups 1 and 2 (which are markers for pathogenic \"Type A\" PfEMP1) and elevated antibodies to 85 (18.6%) of individual DBL variants had a 70 -100% reduced risk of severe malaria. Of the top 20 predictive variants for severe disease protection, 17 were strongly associated with protection (86 - 100% reduction in risk of severe malaria) and had high predictive accuracy for severe disease risk. Many variants were conserved and had highly correlated antibody responses, including the three highest-ranking variants, which were linked to EPCR-binding CIDR domains. The results suggest that while immunity to uncomplicated malaria is characterised by antibodies to a diverse repertoire of PfEMP1, immunity to severe malaria requires antibodies to a limited subset of antigenically conserved variants. These findings provide new insights into antimalarial immunity and potential biomarkers for tracking disease risk.

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Tessema, S., Nakajima, R., Jasinskas, A., Monk, S., Lekieffre, L., Lin, E., Kiniboro, B., Proietti, C., Siba, P. M., Felgner, P., Doolan, D. L., Mueller, I., Barry, A.. 2018-11-19. Protective immunity against severe malaria is associated with antibodies to a conserved repertoire of PfEMP1 variants. https://doi.org/10.1101/472159

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