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*

*Corresponding author for this work

    Research output: Contribution to journalJournal articleResearchpeer-review

    126 Downloads (Pure)

    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 antibody levels 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% CI: 0.45-0.88; p = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI: 0.55-1.01; p = 0.06]), whilst there was no such association for other variants. Children who experienced severe malaria also had significantly lower antibody levels to DBLβ3PF11_0521 and the other group A domains than other children. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster and were similar to sequences from other endemic areas. PfEMP1 variants associated with these DBLβ were enriched for DC4 and DC13 head-structures implicated in EPCR-binding and severe malaria, suggesting conservation of dual binding specificity. 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 languageEnglish
    Article numbere00485-17
    JournalInfection and Immunity
    Volume86
    Issue number8
    Number of pages14
    ISSN0019-9567
    DOIs
    Publication statusPublished - 2018

    Keywords

    • DBLβ
    • EPCR
    • ICAM1
    • Papua New Guinea
    • PfEMP1
    • Antibodies
    • Diversity
    • Malaria
    • var genes

    Cite this

    Tessema, Sofonias K ; Utama, Digjaya ; Chesnokov, Olga ; Hodder, Anthony N ; Lin, Clara S ; Harrison, G. L. Abby ; Jespersen, Jakob S ; Petersen, Bent ; Tavul, Livingstone ; Siba, Peter ; Kwiatkowski, Dominic ; Lavstsen, Thomas ; Hansen, Diana S ; Oleinikov, Andrew V ; Mueller, Ivo ; Barry, Alyssa E. / 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. In: Infection and Immunity. 2018 ; Vol. 86, No. 8.
    @article{dfc414d3cdf044e1a905695abefc5f84,
    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 antibody levels 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{\%} CI: 0.45-0.88; p = 0.007]) and a 25{\%} reduction in risk of low-density clinical malaria (aIRR = 0.75 [95{\%} CI: 0.55-1.01; p = 0.06]), whilst there was no such association for other variants. Children who experienced severe malaria also had significantly lower antibody levels to DBLβ3PF11_0521 and the other group A domains than other children. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster and were similar to sequences from other endemic areas. PfEMP1 variants associated with these DBLβ were enriched for DC4 and DC13 head-structures implicated in EPCR-binding and severe malaria, suggesting conservation of dual binding specificity. 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.",
    keywords = "DBLβ, EPCR, ICAM1, Papua New Guinea, PfEMP1, Antibodies, Diversity, Malaria, var genes",
    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}",
    year = "2018",
    doi = "10.1128/IAI.00485-17",
    language = "English",
    volume = "86",
    journal = "Infection and Immunity",
    issn = "0019-9567",
    publisher = "American Society for Microbiology",
    number = "8",

    }

    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. 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; Hodder, Anthony N; Lin, Clara S; Harrison, G. L. Abby; Jespersen, Jakob S; Petersen, Bent; Tavul, Livingstone; Siba, Peter; Kwiatkowski, Dominic; Lavstsen, Thomas; Hansen, Diana S; Oleinikov, Andrew V; Mueller, Ivo; Barry, Alyssa E.

    In: Infection and Immunity, Vol. 86, No. 8, e00485-17, 2018.

    Research output: Contribution to journalJournal articleResearchpeer-review

    TY - JOUR

    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

    Y1 - 2018

    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 antibody levels 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% CI: 0.45-0.88; p = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI: 0.55-1.01; p = 0.06]), whilst there was no such association for other variants. Children who experienced severe malaria also had significantly lower antibody levels to DBLβ3PF11_0521 and the other group A domains than other children. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster and were similar to sequences from other endemic areas. PfEMP1 variants associated with these DBLβ were enriched for DC4 and DC13 head-structures implicated in EPCR-binding and severe malaria, suggesting conservation of dual binding specificity. 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 antibody levels 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% CI: 0.45-0.88; p = 0.007]) and a 25% reduction in risk of low-density clinical malaria (aIRR = 0.75 [95% CI: 0.55-1.01; p = 0.06]), whilst there was no such association for other variants. Children who experienced severe malaria also had significantly lower antibody levels to DBLβ3PF11_0521 and the other group A domains than other children. Furthermore, a subset of PNG DBLβ sequences had ICAM1-binding motifs, formed a distinct phylogenetic cluster and were similar to sequences from other endemic areas. PfEMP1 variants associated with these DBLβ were enriched for DC4 and DC13 head-structures implicated in EPCR-binding and severe malaria, suggesting conservation of dual binding specificity. 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.

    KW - DBLβ

    KW - EPCR

    KW - ICAM1

    KW - Papua New Guinea

    KW - PfEMP1

    KW - Antibodies

    KW - Diversity

    KW - Malaria

    KW - var genes

    U2 - 10.1128/IAI.00485-17

    DO - 10.1128/IAI.00485-17

    M3 - Journal article

    VL - 86

    JO - Infection and Immunity

    JF - Infection and Immunity

    SN - 0019-9567

    IS - 8

    M1 - e00485-17

    ER -