Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea

Sofonias K Tessema; Digjaya Utama; Olga Chesnokov; Anthony N Hodder; Clara S Lin; G L Abby Harrison; Jakob S Jespersen; Bent Petersen; Livingstone Tavul; Peter Siba; Dominic Kwiatkowski; Thomas Lavstsen; Diana S Hansen; Andrew V Oleinikov; Ivo Mueller; Alyssa E Barry

doi:10.1128/iai.00485-17

Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea

Sofonias K Tessema, Digjaya Utama, Olga Chesnokov, Anthony N Hodder, Clara S Lin, G L Abby Harrison, Jakob S Jespersen, Bent Petersen, Livingstone Tavul, Peter Siba, Dominic Kwiatkowski, Thomas Lavstsen, Diana S Hansen, Andrew V Oleinikov, Ivo Mueller, Alyssa E Barry

9 Citations (Scopus)

Abstract

Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3PF11_0521, in comparison to four control antigens, including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant. Antibody levels for the group A antigens were strongly associated with age and exposure. Antibody responses to DBLβ3PF11_0521 were associated with a 37% reduced risk of high-density clinical malaria in the follow-up period (adjusted incidence risk ratio [aIRR] = 0.63 [95% confidence interval {CI}, 0.45 to 0.88; P = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI, 0.55 to 1.01; P = 0.06]), while there was no such association for other variants. Children who experienced severe malaria also had significantly lower levels of antibody to DBLβ3PF11_0521 and the other group A domains than those that experienced nonsevere malaria. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster, and were similar to sequences from other areas of endemicity. PfEMP1 variants associated with these DBLβ domains were enriched for DC4 and DC13 head structures implicated in endothelial protein C receptor (EPCR) binding and severe malaria, suggesting conservation of dual binding specificities. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates and as biomarkers for protective immunity against clinical P. falciparum malaria.

Original language	English
Article number	e00485-17
Journal	Infection and Immunity
Volume	86
Issue number	8
Pages (from-to)	1-14
Number of pages	14
ISSN	0019-9567
DOIs	https://doi.org/10.1128/iai.00485-17
Publication status	Published - 1 Aug 2018

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Tessema, S. K., Utama, D., Chesnokov, O., Hodder, A. N., Lin, C. S., Harrison, G. L. A., Jespersen, J. S., Petersen, B., Tavul, L., Siba, P., Kwiatkowski, D., Lavstsen, T., Hansen, D. S., Oleinikov, A. V., Mueller, I., & Barry, A. E. (2018). Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea. Infection and Immunity, 86(8), 1-14. [e00485-17]. https://doi.org/10.1128/iai.00485-17

Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea. / Tessema, Sofonias K; Utama, Digjaya; Chesnokov, Olga et al.

In: Infection and Immunity, Vol. 86, No. 8, e00485-17, 01.08.2018, p. 1-14.

Research output: Contribution to journal › Journal article › Research › peer-review

Tessema, SK, Utama, D, Chesnokov, O, Hodder, AN, Lin, CS, Harrison, GLA, Jespersen, JS , Petersen, B, Tavul, L, Siba, P, Kwiatkowski, D, Lavstsen, T, Hansen, DS, Oleinikov, AV, Mueller, I & Barry, AE 2018, 'Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea', Infection and Immunity, vol. 86, no. 8, e00485-17, pp. 1-14. https://doi.org/10.1128/iai.00485-17

Tessema SK, Utama D, Chesnokov O, Hodder AN, Lin CS, Harrison GLA et al. Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea. Infection and Immunity. 2018 Aug 1;86(8):1-14. e00485-17. doi: 10.1128/iai.00485-17

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title = "Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea",

abstract = "Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3PF11_0521, in comparison to four control antigens, including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant. Antibody levels for the group A antigens were strongly associated with age and exposure. Antibody responses to DBLβ3PF11_0521 were associated with a 37% reduced risk of high-density clinical malaria in the follow-up period (adjusted incidence risk ratio [aIRR] = 0.63 [95% confidence interval {CI}, 0.45 to 0.88; P = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI, 0.55 to 1.01; P = 0.06]), while there was no such association for other variants. Children who experienced severe malaria also had significantly lower levels of antibody to DBLβ3PF11_0521 and the other group A domains than those that experienced nonsevere malaria. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster, and were similar to sequences from other areas of endemicity. PfEMP1 variants associated with these DBLβ domains were enriched for DC4 and DC13 head structures implicated in endothelial protein C receptor (EPCR) binding and severe malaria, suggesting conservation of dual binding specificities. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates and as biomarkers for protective immunity against clinical P. falciparum malaria.",

author = "Tessema, {Sofonias K} and Digjaya Utama and Olga Chesnokov and Hodder, {Anthony N} and Lin, {Clara S} and Harrison, {G L Abby} and Jespersen, {Jakob S} and Bent Petersen and Livingstone Tavul and Peter Siba and Dominic Kwiatkowski and Thomas Lavstsen and Hansen, {Diana S} and Oleinikov, {Andrew V} and Ivo Mueller and Barry, {Alyssa E}",

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T1 - Antibodies to intercellular adhesion molecule 1-binding Plasmodium falciparum erythrocyte membrane protein 1-DBLβ are biomarkers of protective immunity to malaria in a cohort of young children from Papua New Guinea

AU - Tessema, Sofonias K

AU - Utama, Digjaya

AU - Chesnokov, Olga

AU - Hodder, Anthony N

AU - Lin, Clara S

AU - Harrison, G L Abby

AU - Jespersen, Jakob S

AU - Petersen, Bent

AU - Tavul, Livingstone

AU - Siba, Peter

AU - Kwiatkowski, Dominic

AU - Lavstsen, Thomas

AU - Hansen, Diana S

AU - Oleinikov, Andrew V

AU - Mueller, Ivo

AU - Barry, Alyssa E

PY - 2018/8/1

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N2 - Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3PF11_0521, in comparison to four control antigens, including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant. Antibody levels for the group A antigens were strongly associated with age and exposure. Antibody responses to DBLβ3PF11_0521 were associated with a 37% reduced risk of high-density clinical malaria in the follow-up period (adjusted incidence risk ratio [aIRR] = 0.63 [95% confidence interval {CI}, 0.45 to 0.88; P = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI, 0.55 to 1.01; P = 0.06]), while there was no such association for other variants. Children who experienced severe malaria also had significantly lower levels of antibody to DBLβ3PF11_0521 and the other group A domains than those that experienced nonsevere malaria. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster, and were similar to sequences from other areas of endemicity. PfEMP1 variants associated with these DBLβ domains were enriched for DC4 and DC13 head structures implicated in endothelial protein C receptor (EPCR) binding and severe malaria, suggesting conservation of dual binding specificities. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates and as biomarkers for protective immunity against clinical P. falciparum malaria.

AB - Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) mediates parasite sequestration to the cerebral microvasculature via binding of DBLβ domains to intercellular adhesion molecule 1 (ICAM1) and is associated with severe cerebral malaria. In a cohort of 187 young children from Papua New Guinea (PNG), we examined baseline levels of antibody to the ICAM1-binding PfEMP1 domain, DBLβ3PF11_0521, in comparison to four control antigens, including NTS-DBLα and CIDR1 domains from another group A variant and a group B/C variant. Antibody levels for the group A antigens were strongly associated with age and exposure. Antibody responses to DBLβ3PF11_0521 were associated with a 37% reduced risk of high-density clinical malaria in the follow-up period (adjusted incidence risk ratio [aIRR] = 0.63 [95% confidence interval {CI}, 0.45 to 0.88; P = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI, 0.55 to 1.01; P = 0.06]), while there was no such association for other variants. Children who experienced severe malaria also had significantly lower levels of antibody to DBLβ3PF11_0521 and the other group A domains than those that experienced nonsevere malaria. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster, and were similar to sequences from other areas of endemicity. PfEMP1 variants associated with these DBLβ domains were enriched for DC4 and DC13 head structures implicated in endothelial protein C receptor (EPCR) binding and severe malaria, suggesting conservation of dual binding specificities. These results provide further support for the development of specific classes of PfEMP1 as vaccine candidates and as biomarkers for protective immunity against clinical P. falciparum malaria.

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