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. 2019 Nov 6;220(12):1950-1961.
doi: 10.1093/infdis/jiz407.

Induction and Kinetics of Complement-Fixing Antibodies Against Plasmodium vivax Merozoite Surface Protein 3α and Relationship With Immunoglobulin G Subclasses and Immunoglobulin M

Damian A Oyong  1   2 , Danny W Wilson  3   4 , Bridget E Barber  1   5   6 , Timothy William  5   7 , Jianlin Jiang  8 , Mary R Galinski  8   9 , Freya J I Fowkes  4   10   11   12   13 , Matthew J Grigg  1   5 , James G Beeson  4   14   15 , Nicholas M Anstey  1   5 , Michelle J Boyle  1   4   6
Affiliations

Induction and Kinetics of Complement-Fixing Antibodies Against Plasmodium vivax Merozoite Surface Protein 3α and Relationship With Immunoglobulin G Subclasses and Immunoglobulin M

Damian A Oyong et al. J Infect Dis. .

Abstract

Background: Complement-fixing antibodies are important mediators of protection against Plasmodium falciparum malaria. However, complement-fixing antibodies remain uncharacterized for Plasmodium vivax malaria. P. vivax merozoite surface protein 3α (PvMSP3α) is a target of acquired immunity and a potential vaccine candidate.

Methods: Plasma from children and adults with P. vivax malaria in Sabah, Malaysia, were collected during acute infection, 7 and 28 days after drug treatment. Complement-fixing antibodies and immunoglobulin M and G (IgM and IgG), targeting 3 distinctive regions of PvMSP3α, were measured by means of enzyme-linked immunosorbent assay.

Results: The seroprevalence of complement-fixing antibodies was highest against the PvMSP3α central region (77.6%). IgG1, IgG3, and IgM were significantly correlated with C1q fixation, and both purified IgG and IgM were capable of mediating C1q fixation to PvMSP3α. Complement-fixing antibody levels were similar between age groups, but IgM was predominant in children and IgG3 more prevalent in adults. Levels of functional antibodies increased after acute infection through 7 days after treatment but rapidly waned by day 28.

Conclusion: Our study demonstrates that PvMSP3α antibodies acquired during P. vivax infection can mediate complement fixation and shows the important influence of age in shaping these specific antibody responses. Further studies are warranted to understand the role of these functional antibodies in protective immunity against P. vivax malaria.

Keywords: Plasmodium vivax; Complement-fixing antibodies; PvMSP3α; malaria.

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Figures

Figure 1.
Figure 1.
Seroprevalence and magnitude of C1q-fixing antibodies targeting Plasmodium vivax merozoite surface protein 3α (PvMSP3α) in children and adults with P. vivax malaria and in uninfected adults. A, Seroprevalence of C1q-fixing antibodies against different regions of PvMSP3α. The positive threshold for seroprevalence was calculated as above the mean plus 3 standard deviations of absorbance detected in malaria-naive Australian donors. Numbers atop brackets are P values; the χ 2 test was used for comparisons between groups. B, Cumulative C1q-fixing antibody responses targeting different regions of PvMSP3α. Data represent the percentage of individuals who are positive for the proteins tested. C, Magnitudes of C1q-fixing antibody responses against different regions of PvMSP3α. For boxplots, the lower and upper lines of boxplot represent the first and third quartiles, the whisker lines correspond to the highest and lowest values no further than 1.5 times the interquartile range, and horizontal lines within boxes indicate medians. Data beyond the whisker lines are treated as outliers, represented as circles, squares and triangles. Numbers atop brackets are P values; the Mann-Whitney test was used for comparisons between groups. Abbreviation: OD450, optical density at 450 nm.
Figure 2.
Figure 2.
Seroprevalence and magnitude of immunoglobulin G and M (IgG and IgM) antibodies to Plasmodium vivax merozoite surface protein 3α (PvMSP3α) in children and adults with P. vivax malaria and uninfected adults. A, Seroprevalence of IgG and IgM antibodies against different regions of PvMSP3α. The positive threshold for seroprevalence was calculated as above the mean plus 3 standard deviations of absorbance detected in malaria-naive Australian donors. Numbers atop brackets are P values; the χ 2 test was used for comparisons between groups. B, Cumulative IgG and IgM antibody responses targeting different regions of PvMSP3α. Data represent percentage of individuals who are positive for the protein regions tested. C, Magnitudes of IgG and IgM antibody responses against different regions of PvMSP3α. For boxplots, the lower and upper lines of boxplot represent the first and third quartiles, whisker lines correspond to the highest and lowest values no further than 1.5 interquartile range, and horizontal lines within boxes indicate medians. Data beyond the whisker lines are treated as outliers, represented as circles, squares and triangles. Numbers atop brackets are P values; the Mann-Whitney test was used for comparisons between groups. Abbreviation: OD450, optical density at 450 nm.
Figure 3.
Figure 3.
Seroprevalence and magnitude of immunoglobulin G1 and G3 (IgG1 and IgG3) antibodies to Plasmodium vivax merozoite surface protein 3α (PvMSP3α) in children and adults with P. vivax malaria and uninfected adults. A, Seroprevalence of IgG1 and IgG3 antibodies against different regions of PvMSP3α. The positive threshold for seroprevalence was calculated as above the mean plus 3 standard deviations of absorbance detected in malaria-naive Australian donors. Numbers atop brackets are P values; the χ 2 test was used for comparisons between groups. B, Cumulative IgG1 and IgG3 antibody responses targeting different regions of PvMSP3α. Data represent percentage of individuals who are positive for the proteins tested. C, Magnitudes of IgG1 and IgG3 antibody responses against different regions of PvMSP3α. For boxplots, lower and upper lines of boxplot represent first and third quartiles, whisker lines correspond to the highest and lowest values no further than 1.5 interquartile range, and horizontal lines within boxes indicate medians. Data beyond the whisker lines are treated as outliers, represented as circles, squares and triangles. Numbers atop brackets are P values; the Mann-Whitney test was used for comparisons between groups. Abbreviation: OD450, optical density at 450 nm.
Figure 4.
Figure 4.
Functional C1q-fixing capacity of antibody isotypes. A, Correlations matrixes between immunoglobulin G1, G3, and M (IgG1, IgG3, and IgM) and C1q-fixing antibodies to Plasmodium vivax merozoite surface protein 3α (PvMSP3α) in infected children, infected adults, and uninfected adults. Values represent Spearman correlation coefficients, and blue boxes indicate statistical significance (P < .05). B, Total immunoglobulin G (IgG) and IgM absorbance readings against PvMSP3α central region from purified IgG and IgM fractions in malaria-infected plasma pools. C, C1q fixation absorbance readings against PvMSP3α central region from purified IgG and IgM fractions from malaria-infected (n = 5) and malaria-unexposed (n = 14) plasma pools. Abbreviation: OD450, optical density at 450 nm.
Figure 5.
Figure 5.
Antibody kinetics profile across 28-day follow-up against Plasmodium vivax merozoite surface protein 3α (PvMSP3α). Magnitudes of C1q-fixing antibodies, immunoglobulin G1 G3, and M (IgG1, IgG3, and IgM) against different regions of PvMSP3α were compared between day 0 and days 7 and 28 follow-up. Gray dots and lines represent individual antibody magnitudes over time; horizontal lines, medians. Numbers atop brackets are P values, calculated with the Wilcoxon signed ranked test. Abbreviation: OD450, optical density at 450 nm.
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