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Host Response and Inflammation

Breadth and Magnitude of Antibody Responses to Multiple Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Clinical Malaria

Faith H. A. Osier, Gregory Fegan, Spencer D. Polley, Linda Murungi, Federica Verra, Kevin K. A. Tetteh, Brett Lowe, Tabitha Mwangi, Peter C. Bull, Alan W. Thomas, David R. Cavanagh, Jana S. McBride, David E. Lanar, Margaret J. Mackinnon, David J. Conway, Kevin Marsh
Faith H. A. Osier
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
2London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
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  • For correspondence: fosier@kilifi.kemri-wellcome.org
Gregory Fegan
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
2London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
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Spencer D. Polley
2London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
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Linda Murungi
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
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Federica Verra
2London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
4Dipartimento di Scienze di Sanita' Pubblica, Sezione di Parassitologia, University of Rome “La Sapienza,” 00185 Rome, Italy
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Kevin K. A. Tetteh
2London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
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Brett Lowe
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
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Tabitha Mwangi
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
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Peter C. Bull
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
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Alan W. Thomas
5BPRC, Department of Parasitology, P.O. Box 3306, 2280, GH Rijswijk, The Netherlands
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David R. Cavanagh
6Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, EH9 3JT Edinburgh, United Kingdom
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Jana S. McBride
6Institute of Immunology and Infection Research, School of Biological Sciences, University of Edinburgh, EH9 3JT Edinburgh, United Kingdom
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David E. Lanar
7Department of Immunology, Walter Reed Army Institute of Research, Forest Glen Annex, Silver Spring, Maryland 20910
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Margaret J. Mackinnon
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
3Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, United Kingdom
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David J. Conway
2London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom
8Medical Research Council Laboratories, Fajara, P.O. Box 273, Banjul, The Gambia
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Kevin Marsh
1KEMRI Centre for Geographic Medicine Research, Coast, P.O. Box 230-80108, Kilifi, Kenya
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DOI: 10.1128/IAI.01585-07
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  • FIG. 1.
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    FIG. 1.

    The predicted probability of an episode of malaria in children decreases with increasing antibody titer for most antigens (n = 119). Each panel represents the allelic antigens tested at each locus, as well as parasite schizont extract. The red horizontal line represents the risk of an episode without taking antibody responses to any antigen into account. The final panel combines antibodies to one allelic form of each antigen (and one antigen from each of the three main allelic families of MSP-1 block 2). The lines, from top to bottom, represent MSP-1_B2_Wellcome, MSP-3_K1, MSP-2_Dd2, schizont extract, AMA1_3D7, EBA-175_F2_3D7, MSP-1_B2_3D7, MSP-1_B2_RO33, and MSP-119.

  • FIG. 2.
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    FIG. 2.

    Protective efficacy increased with increasing breadth of response in children from the Chonyi (parasitemic children, n = 119) (a) and hospital cohorts (all children, n = 387) (b). Each bar represents the comparison between individuals making high-titer responses to n number of antigens with those who make no responses to any antigen. Proportions above each bar are the percentage of individuals making high-titer responses to n antigens. The effect of high-titer responses to P. falciparum schizont extract is also shown.

  • FIG. 3.
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    FIG. 3.

    The breadth of antibody specificity increased with age in both the Chonyi cohort (n = 119) (a) and the case-control study (n = 387) (b).

Tables

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  • TABLE 1.

    Protective effectsa of high levels of antibodies to individual antigens

    Antigen% of children with high-titer responseUnivariate analysisbAge-adjusted analysisbAge and schizont adjustedb
    Risk ratio (95% CI)P valueRisk ratio (95% CI)P valueRisk ratio (95% CI)P value
    AMA1_FVO490.45 (0.25-0.80)0.007*0.60 (0.33-1.08)0.0930.65 (0.36-1.21)0.178
    AMA1_3D7510.40 (0.22-0.72)0.002*0.50 (0.28-0.90)0.021*0.54 (0.29-1.00)0.052
    MSP-2_CH150/9540.32 (0.17-0.59)0.000*0.39 (0.21-0.70)0.002*0.41 (0.22-0.74)0.004*
    MSP-2_Dd2540.28 (0.15-0.53)0.000*0.35 (0.18-0.65)0.001*0.36 (0.19-0.70)0.003*
    MSP-3_K1390.39 (0.20-0.78)0.008*0.50 (0.26-0.95)0.037*0.52 (0.27-1.01)0.055
    MSP-3_3D7400.58 (0.32-1.04)0.0720.67 (0.38-1.17)0.1660.70 (0.40-1.22)0.216
    EBA-175_F2_CAMP340.72 (0.40-1.29)0.2741.05 (0.60-1.82)0.8581.25 (0.71-2.19)0.437
    EBA-175_F2_3D7410.41 (0.21-0.79)0.008*0.53 (0.27-1.04)0.0670.57 (0.29-1.14)0.114
    MSP-1_B2_3D7200.43 (0.12-1.12)0.0850.56 (0.20-1.50)0.2520.60 (0.22-1.64)0.328
    MSP-1_B2_PaloAlto180.93 (0.47-1.83)0.8460.91 (0.48-1.71)0.7740.95 (0.50-1.81)0.895
    MSP-1_B2_Wellcome190.33 (0.11-1.00)0.0510.50 (0.16-1.51)0.2220.54 (0.18-1.65)0.286
    MSP-1_B2_MAD20230.48 (0.21-1.12)0.0920.73 (0.32-1.70)0.4780.76 (0.33-1.78)0.543
    MSP-1_B2_RO33151.40 (0.77-2.53)0.2631.20 (0.74-1.93)0.4431.43 (0.86-2.38)0.162
    MSP-119361.44 (0.87-2.38)0.1481.14 (0.74-1.76)0.5441.59 (0.93-2.74)0.089
    • ↵ a Risk of developing clinical malaria associated with high titers compared to low/undetectable titers of antibodies to individual antigens in a subset of the Chonyi cohort (n = 119). Antigens are designated by their locus name and P. falciparum strain ([locus]_[strain]).

    • ↵ b Risk ratios (with 95% confidence intervals [CI]) are presented for univariate and multivariate analyses (adjusted initially for age and subsequently for both age and reactivity to P. falciparum parasite schizont extract as a proxy for exposure). *, P < 0.05.

  • TABLE 2.

    Protective effectsa of combinations of high-titer antibody responses

    AntigenMain effects and interactionbCombination effectc
    Risk ratio (95% CI)dP valueRisk ratio (95% CI)dP value
    AMA1_3D70.59 (0.32-1.08)0.0910.21 (0.05-0.88)0.033*
    MSP-3_K10.56 (0.29-1.08)0.085
    AMA1_3D7 + MSP-3_K10.28 (0.06-1.29)0.104
    AMA1_3D70.66 (0.35-1.25)0.2110.24 (0.09-0.64)0.004*
    MSP-2_Dd20.40 (0.20-0.78)0.008*
    AMA1_3D7 + MSP-2_Dd20.33 (0.09-1.17)0.087
    AMA1_3D70.62 (0.32-1.18)0.1470.61 (0.29-1.29)0.199
    EBA-175_F2_3D70.69 (0.33-1.42)0.320
    AMA1_3D7 + EBA-175_F2_3D71.90 (0.34-10.46)0.459
    AMA1_3D70.58 (0.31-1.08)0.0880.48 (0.17-1.38)0.178
    MSP-1191.44 (0.82-2.54)0.199
    AMA1_3D7 + MSP-1190.39 (0.12-1.30)0.129
    MSP-2_Dd20.40 (0.20-0.78)0.008*Total protection (n = 33)
    MSP-3_K10.62 (0.34-1.13)0.121
    MSP-2_Dd2 + MSP-3_K1Total protection (n = 33)
    MSP-2_Dd20.38 (0.20-0.73)0.004*0.17 (0.04-0.73)0.017*
    EBA-175_F2_3D70.64 (0.33-1.22)0.178
    MSP-2_Dd2 + EBA-175_F2_3D70.26 (0.05-1.27)0.098
    MSP-2_Dd20.36 (0.18-0.71)0.003*0.52 (0.21-1.30)0.166
    MSP-1191.55 (0.92-2.61)0.097
    MSP-2_Dd2 + MSP-1190.62 (0.20-1.88)0.402
    MSP-3_K10.57 (0.29-1.11)0.1010.39 (0.12-1.20)0.103
    EBA-175_F2_3D70.66 (0.33-1.31)0.240
    MSP-3_K1 + EBA-175_F2_3D70.71 (0.17-2.97)0.643
    MSP-3_K10.48 (0.25-0.93)0.030*0.57 (0.25-1.31)0.191
    MSP-1191.74 (1.07-2.84)0.024
    MSP-3_K1 + MSP-1190.65 (0.19-2.27)0.509
    EBA-175_F2_3D70.56 (0.28-1.11)0.1010.69 (0.26-1.78)0.445
    MSP-1191.61 (0.97-2.68)0.062
    EBA-175_F2_3D7 + MSP-1190.70 (0.19-2.52)0.586
    AMA1_3D70.55 (0.30-1.01)0.0550.66 (0.29-1.52)0.336
    MSP-1_B20.87 (0.51-1.50)0.636
    AMA1_3D7 + MSP-1_B21.13 (0.36-3.56)0.829
    MSP-2_Dd20.36 (0.18-0.70)0.008*0.40 (0.15-1.05)0.064
    MSP-1_B21.04 (0.62-1.72)0.875
    MSP-2_Dd2 + MSP-1_B20.57 (0.17-1.90)0.365
    MSP-3_K10.52 (0.27-1.02)0.0590.16 (0.02-1.13)0.067
    MSP-1_B20.87 (0.51-1.49)0.634
    MSP-3_K1 + MSP-1_B20.15 (0.02-1.14)0.068
    MSP-1191.61 (0.95-2.74)0.0730.98 (0.48-2.01)0.972
    MSP-1_B20.80 (0.45-1.41)0.456
    MSP-119 + MSP-1_B20.83 (0.27-2.46)0.737
    EBA-175_F2_3D70.58 (0.30-1.14)0.1190.85 (0.36-2.00)0.720
    MSP-1_B20.88 (0.51-1.51)0.656
    EBA-175_F2_3D7 + MSP-1_B22.11 (0.56-7.94)0.265
    • ↵ a Risk of developing clinical malaria associated with combinations of high titers compared to low/undetectable titers of antibodies to individual antigens in a subset of the Chonyi cohort (n = 119). In the majority of cases, significantly more protection was obtained with high-level antibody responses to pairs of antigens, compared to single antigens (Table 1). No strong evidence of statistical interaction between pairs of antibodies was observed.

    • ↵ b The main effects of antibodies to each antigen were adjusted for each other. Interaction effects (combinations of two antigens) are those over and above the main effects.

    • ↵ c Effects of combinations of high-titer responses (combines the main effects and interaction effects).

    • ↵ d Risk ratios (with 95% confidence intervals [CI]) are from multivariate analyses (adjusted for both age and reactivity to P. falciparum schizont extract). *, P < 0.05.

Additional Files

  • Figures
  • Tables
  • Supplemental material

    Files in this Data Supplement:

    • Supplemental file 1 - Fig. S1. Antibodies to MSP-1 block 2, the F2 subdomain of EBA-175, and MSP-119 in the Chonyi cohort.
      Table S1. Details of recombinant merozoite antigens.
      Table S2. ELISA OD cutoff levels used to define high versus low responders to merozoite antigens in the Chonyi cohort and the case-control study.
      Table S3. Correlations between antibodies to the panel of merozoite antigens.
      Supplemental text. Selection of a single allelic form of each antigen for analysis of combined antibody responses.
      Table S4. Effects of high-titer antibodies to allelic combinations of antigens on the probability of a clinical episode in the Chonyi cohort.
      Table S5. Effects of combinations of high-titer antibodies on admission to hospital with malaria.
      Zipped MS Word document, 132K.
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Breadth and Magnitude of Antibody Responses to Multiple Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Clinical Malaria
Faith H. A. Osier, Gregory Fegan, Spencer D. Polley, Linda Murungi, Federica Verra, Kevin K. A. Tetteh, Brett Lowe, Tabitha Mwangi, Peter C. Bull, Alan W. Thomas, David R. Cavanagh, Jana S. McBride, David E. Lanar, Margaret J. Mackinnon, David J. Conway, Kevin Marsh
Infection and Immunity Apr 2008, 76 (5) 2240-2248; DOI: 10.1128/IAI.01585-07

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Breadth and Magnitude of Antibody Responses to Multiple Plasmodium falciparum Merozoite Antigens Are Associated with Protection from Clinical Malaria
Faith H. A. Osier, Gregory Fegan, Spencer D. Polley, Linda Murungi, Federica Verra, Kevin K. A. Tetteh, Brett Lowe, Tabitha Mwangi, Peter C. Bull, Alan W. Thomas, David R. Cavanagh, Jana S. McBride, David E. Lanar, Margaret J. Mackinnon, David J. Conway, Kevin Marsh
Infection and Immunity Apr 2008, 76 (5) 2240-2248; DOI: 10.1128/IAI.01585-07
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KEYWORDS

Antibodies, Protozoan
Antigens, Protozoan
malaria
Merozoites
Plasmodium falciparum

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