Clinical Immunology | Spotlight

Contrasting Patterns of Serologic and Functional Antibody Dynamics to Plasmodium falciparum Antigens in a Kenyan Birth Cohort

Arlene E. Dent, Indu Malhotra, Xuelie Wang, Denise Babineau, Kee Thai Yeo, Timothy Anderson, Rhonda J. Kimmel, Evelina Angov, David E. Lanar, David Narum, Sheetij Dutta, Jack Richards, James G. Beeson, Brendan S. Crabb, Alan F. Cowman, Toshihiro Horii, Eric Muchiri, Peter L. Mungai, Christopher L. King, James W. Kazura
P. P. Wilkins, Editor
DOI: 10.1128/CVI.00452-15

Article Figures & Data

Figures

  • FIG 1
    FIG 1

    Serological responses in infants over time. (A) Detection probability (y axis) of each antibody in infants over time (x axis). Responses to specific antigens are indicated in each plot box. (B) Magnitude of antibodies in cord blood for each indicated antigen expressed as fold increase relative to negative-control North Americans (NAm) (mean + standard error of the mean).

  • FIG 2
    FIG 2

    Infant VSA, GIA, and IIA antibodies over time. (A) Detection probability (y axis) of each VSA measured antibody response in infants over time (x axis). VSA responses to each P. falciparum isolate are indicated. Bar graph to the right of the plot shows the geometric mean fluorescence intensity (GeoMFI) for VSA antibodies in cord blood (mean + standard error of the mean [SEM]). (B) Detection probability (y axis) of W2mef and D10 GIA antibody responses in infants over time (x axis). Bar graph to the right of the plot shows the percentage of growth inhibition of GIA responses in cord blood (mean + SEM). (C) Detection probability (y axis) of Sial Dep and MSP1-19 IIA antibody responses in infants over time (x axis). Bar graph to the right of the plot shows the percentage of invasion inhibition responses in cord blood (mean + SEM).

  • FIG 3
    FIG 3

    Antibodies in cord blood (open circles) compared to 36-month-old young children (open triangles). Dot plots of serologic antibody responses (fold increase relative to North Americans [NAm]) to specified antigens measured in cord blood and 36-month-old young children (A) and to another set of antigens measured in cord blood and 36-month-old young children (B). Note the smaller y axis in (B) than in (A). (C) GeoMFI of VSA responses measured in cord blood and 36-month-old young children. (D) Percent growth inhibition of GIA and IIA antibody responses measured in cord blood and 36-month-old young children. *, P = 0.04; **, P = 0.0005; ***, P = 0.0002; ****, P < 0.0001; horizontal bar when visible represents median values.

Tables

  • TABLE 1

    Magnitude and prevalence of IgG antibodies in cord blood

    Assay/antigen tested (P. falciparum isolate)Sample size (no.)Mean (SD)/median (IQRa)No. (%) positive
    Serology (fold increase in MFI over negative controls)
        LSA17824.7 (42.6)/4.7 (1.6–27.8)59 (75.6)
        CSP7829.5 (39.7)/11.4 (3.3–40.0)68 (87.2)
        PfCelTOS780.6 (1.4)/0.0 (0.0–0.0)15 (19.2)
        SE50780.6 (2.1)/0.0 (0.0–0.0)11 (14.1)
        SE36783.1 (6.9)/0.0 (0.0–2.6)34 (43.6)
        MSP142 (3D7)789.3 (11.9)/5.8 (0.0–12.0)58 (74.4)
        MSP142 (FVO)786.5 (9.5)/2.3 (0.0–10.6)46 (59.0)
        MSP142 (FUP)7812.2 (13.8)/6.8 (2.4–16.6)68 (87.2)
        EBA140788.7 (19.6)/1.7 (0.0–7.3)41 (52.6)
        EBA175789.9 (14.7)/3.7 (0.0–14.5)49 (62.8)
        EBA181789.6 (17.9)/2.7 (0.0–8.6)51 (65.4)
        AMA1 (3D7)7881.0 (46.4)/88.1 (48.4–101.6)76 (97.4)
        AMA1 (FVO)7896.7 (61.2)/113.9 (39.5–131.2)76 (97.4)
    Variant surface antigen assay (geometric mean MFI)
        BFD 20067940.2 (56.4)/17.0 (11.0–46.0)42 (53.8)
        Msambweni 20067937.4 (40.9)/21.0 (13.0–44.0)54 (69.2)
        3D77924.2 (28.0)/13.5 (8.0–30.0)37 (47.4)
    Growth and invasion inhibition assay (percent inhibition)
        Sial Dep IIA842.8 (7.5)/0.0 (0.0–0.0)12 (14.6)
        W2mef GIA8411.3 (15.6)/6.0 (0.0–19.6)31 (37.8)
        MSP1-19 IIA840.8 (2.7)/0.0 (0.0–0.0)5 (6.1)
        D10 GIA844.2 (8.5)/0.0 (0.0–4.6)18 (22.0)

    • ↵a IQR, interquartile range.

  • TABLE 2

    IgG antibody rates of change before and after 6 months of age

    Assay/antigen tested (P. falciparum isolate)Time periodOdds ratio (95% CIa) per 1 mo age changePP difference between rates of changeb
    Serology
        LSA1Before 6 moc0.72 (0.65–0.80)<0.001<0.001
    After 6 mod1.04 (1.02–1.07)<0.001
        CSPBefore 6 mo0.64 (0.57–0.72)<0.001<0.001
    After 6 mo1.04 (1.02–1.06)<0.001
        PfCelTOSBefore 6 mo1.16 (1.04–1.28)<0.0010.08
    After 6 mo1.05 (1.03–1.07)<0.001
        SE50Before 6 mo1.20 (1.07–1.34)0.00250.03
    After 6 mo1.04 (1.02–1.06)<0.001
        SE36Before 6 mo0.88 (0.80–0.98)0.010.003
    After 6 mo1.04 (1.03–1.06)<0.001
        MSP142 (3D7)Before 6 mo0.75 (0.68–0.82)<0.001<0.001
    After 6 mo1.04 (1.02–1.06)<0.001
        MSP142 (FVO)Before 6 mo0.79 (0.73–0.87)<0.001<0.001
    After 6 mo1.05 (1.03–1.08)<0.001
        MSP142 (FUP)Before 6 mo0.66 (0.58–0.74)<0.001<0.001
    After 6 mo1.05 (1.03–1.08)<0.001
        EBA140Before 6 mo0.85 (0.77–0.92)<0.001<0.001
    After 6 mo1.06 (1.04–1.09)<0.001
        EBA175Before 6 mo0.76 (0.70–0.84)<0.001<0.001
    After 6 mo1.05 (1.03–1.07)<0.001
        EBA181Before 6 mo0.75 (0.68–0.82)<0.001<0.001
    After 6 mo1.06 (1.03–1.08)<0.001
        AMA1 (3D7)Before 12 mo0.76 (0.71–0.81)<0.001<0.001
    After 12 mo1.03 (1.01–1.06)0.02
        AMA1 (FVO)Before 12 mo0.79 (0.75–0.83)<0.001<0.001
    After 12 mo1.04 (1.01–1.07)0.003
    Variant surface antigen assay
        BFD 2006Before 6 mo0.76 (0.69–0.84)<0.001<0.001
    After 6 mo1.01 (0.99–1.03)0.33
        Msambweni 2006Before 6 mo0.60 (0.53–0.68)<0.001<0.001
    After 6 mo1.02 (0.98–1.05)0.35
        3D7Before 6 mo0.63 (0.55–0.73)<0.001<0.001
    After 6 mo1.01 (0.97–1.05)0.63
    Growth and invasion inhibition assay
        Sial Dep IIABefore 6 mo1.18 (1.04–1.34)0.010.02
    After 6 mo0.98 (0.93–1.04)0.56
        W2mef GIABefore 6 mo0.77 (0.68–0.89)<0.001<0.001
    After 6 mo1.05 (1.00–1.10)0.07
        MSP1-19 IIABefore 12 mo1.03 (0.94–1.13)0.530.31
    After 12 mo0.93 (0.81–1.08)0.35
        D10 GIABefore 12 mo0.86 (0.78–0.95)0.0040.07
    After 12 mo1.05 (0.92–1.19)0.491

    • ↵a CI, confidence interval.

    • ↵b Difference between rates of change between birth to 6 (or 12) months of age and between 6 months of age and 36 months of age (Fisher's exact test).

    • ↵c Compared to cord blood responses.

    • ↵d Compared to 6-month responses.

  • TABLE 3

    Association between presence of IgG antibodies at 12 months of age and first occurrence of a malaria infection after 12 months of age

    Assay/antigen testedNo. testedNo. of malaria eventsHazard ratio (95% confidence interval)P
    Serology
        LSA167171.84 (0.71–4.77)0.21
        CSP67172.64 (1.00–6.97)0.05
        PfCelTOS67172.67 (0.94–7.61)0.07
        SE5067174.51 (1.46–13.9)0.009
        SE3667172.35 (0.89–6.19)0.08
        MSP142 (3D7)67171.90 (0.73–4.99)0.19
        MSP142 (FVO)67174.37 (1.52–12.6)0.006
        MSP142 (FUP)67173.13 (1.14–8.57)0.03
        EBA14067173.27 (1.19–8.95)0.02
        EBA17567173.12 (1.18–8.25)0.02
        EBA18167171.76 (0.68–4.56)0.25
        AMA1 (3D7)67172.98 (1.07–8.33)0.04
        AMA1 (FVO)67176.21 (1.67–23.1)0.006
    Variant surface antigen assay
        BFD 200667172.43 (0.78–7.56)0.13
        Msambweni 200667171.00 (0.13–7.60)1.00
        3D767172.45 (0.56–10.8)0.23
    Growth and invasion inhibition assay
        Sial Dep IIA65171.64 (0.60–4.47)0.34
        W2mef GIA65171.52 (0.49–4.74)0.47
        MSP1-19 IIA65171.56 (0.36–6.84)0.55
        D10 GIA65171.49 (0.20–11.3)0.70

Additional Files

  • Supplemental material

    • Supplemental file 1 -

      Table S1. IgG antibody rates of change before and after 6 months of age in malaria-sensitized versus -not sensitized infants. Fig. S1. Three examples of the raw data for the longitudinal infant cohort. Fig. S2. Detection probability of infant antibodies over time.

      PDF, 214K
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