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. 2016 Mar 21;11(3):e0151900.
doi: 10.1371/journal.pone.0151900. eCollection 2016.

Naturally Acquired Antibody Responses to Plasmodium vivax and Plasmodium falciparum Merozoite Surface Protein 1 (MSP1) C-Terminal 19 kDa Domains in an Area of Unstable Malaria Transmission in Southeast Asia

Qinghui Wang  1 , Zhenjun Zhao  2 , Xuexing Zhang  1 , Xuelian Li  3 , Min Zhu  4 , Peipei Li  2 , Zhaoqing Yang  5 , Ying Wang  6 , Guiyun Yan  7 , Hong Shang  8 , Yaming Cao  1 , Qi Fan  2 , Liwang Cui  9
Affiliations

Naturally Acquired Antibody Responses to Plasmodium vivax and Plasmodium falciparum Merozoite Surface Protein 1 (MSP1) C-Terminal 19 kDa Domains in an Area of Unstable Malaria Transmission in Southeast Asia

Qinghui Wang et al. PLoS One. .

Abstract

Understanding naturally acquired immunity to infections caused by Plasmodia in different malaria endemicity settings is needed for better vaccine designs and for exploring antibody responses as a proxy marker of malaria transmission intensity. This study investigated the sero-epidemiology of malaria along the international border between China and Myanmar, where malaria elimination action plans are in place. This study recruited 233 P. vivax and 156 P. falciparum infected subjects with acute malaria at the malaria clinics and hospitals. In addition, 93 and 67 healthy individuals from the same endemic region or from non-endemic region, respectively, were used as controls. Acute malaria infections were identified by microscopy. Anti-recombinant PfMSP119 and PvMSP119 antibody levels were measured by ELISA. Antibody responses to respective MSP119 were detected in 50.9% and 78.2% patients with acute P. vivax and P. falciparum infections, respectively. There were cross-reacting antibodies in Plasmodium patients against these two recombinant proteins, though we could not exclude the possibility of submicroscopic mixed-species infections. IgG1, IgG3 and IgG4 were the major subclasses. Interestingly, 43.2% of the healthy endemic population also had antibodies against PfMSP119, whereas only 3.9% of this population had antibodies against PvMSP119. Higher antibody levels were correlated with age and parasite density, but not with season, gender or malaria history. Both total IgG and individual IgG subclasses underwent substantial declines during the convalescent period in three months. This study demonstrated that individuals in a hypoendemic area with coexistence of P. vivax and P. falciparum can mount rapid antibody responses against both PfMSP119 and PvMSP119. The significantly higher proportion of responders to PfMSP119 in the healthy endemic population indicates higher prevalence of P. falciparum in the recent past. Specific antibodies against PvMSP119 could serve as a marker of recent exposure to P. vivax in epidemiological studies.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Natural antibody responses to recombinant PvMSP119 (A and C) and PfMSP119 (B and D) antigens.
Plasma samples from healthy endemic control (EC), P. falciparum patients (PF) and P. vivax patients (PV) were used in PvMSP119 or PfMSP119 ELISA, respectively. A and B: IgG levels in these samples for PvMSP119 (A) and PfMSP119 (B). Data shown as median ± interquartile range were analyzed by one-way nonparametric Kruskal-Wallis test and Dunn's test for multiple comparisons. C and D: Prevalence of IgG positive samples for PvMSP119 (C) and PfMSP119 (D). Data were analyzed by χ2 test. OD cutoff value was defined as the average of non-endemic control samples plus two standard deviations. OD ratio was referred to the observed OD value of a test sample divided by the cutoff value. OD ratio ≥ 1.0 was considered positive (above the threshold shown as dashed line at 1). ** and *** indicate significance at p<0.01 and p<0.001, respectively.
Fig 2
Fig 2. IgG subclass responses to acute P. vivax (A and C) or P. falciparum (B and D) infections.
A and B: Levels of IgG subclasses in samples from acute P. vivax or P. falciparum patients against respective PvMSP119 (A) and PfMSP119 (B). Data shown as median ± interquartile range were analyzed by one-way nonparametric Kruskal-Wallis test and Dunn's test for multiple comparisons. C and D: Prevalence of IgG subclasses against PvMSP119 in IgG-positive P. vivax patients (C) and against PfMSP119 in IgG-positive P. falciparum patients (D). OD cutoff value and OD ratio were defined as in Fig 1. OD ratio ≥ 1.0 was considered positive (above the threshold shown as dashed line at 1). *, ** and *** indicate significance at p<0.05, p<0.01 and p<0.001, respectively.
Fig 3
Fig 3. Cumulative positivity of patients’ plasma samples for IgG subclasses against PvMSP119 (A) and PfMSP119 (B).
IgG-positive samples were stratified by their positivity for any of the IgG subclasses. Data are plotted as the percentages of P. vivax or P. falciparum patients postivie for 0–4 IgG subclasses to PvMSP119 (A) and PfMSP119 (B). The five portions (0, 1, 2, 3, and 4) denote the seropositvitiy for 0, 1, 2, 3, and 4 IgG subclasses to the respective MSP119.
Fig 4
Fig 4. Antibody responses in acute P. vivax (A) and P. falciparum (B) patients of different ages.
Patients were stratified into under 5 years old (<5 y), 5–14 years old (5–14 y) and more than 14 years old (>14 y) groups. Data are shown in box plots with median as a line within the box and interquartile value at the edge of box. The range of the column was 1.5 times of interquartile range. Any outlier values exceeding 1.5 and 3 times of the interquartile range were shown as circles and triangles, respectively. Data were analyzed by one-way nonparametric Kruskal-Wallis test and Dunn's test for multiple comparisons. *, ** and *** indicate significance at p<0.05, p<0.01 and p<0.001, respectively.
Fig 5
Fig 5. Antibody responses in acute P. vivax (A) and P. falciparum (B) patients presented with or without fever and with different fever histories.
A and B: Patients were stratified into non-febrile (axillary temperature <37.5°C) and febrile (≥37.5°C) groups and antibody levels against PvMSP119 (A) and PfMSP119 (B) were compared. Data are presented in box plots with the median shown as a line within the box and interquartile value at the edge of box. The whole range of the column was 1.5 times of interquartile range. Any outlier values exceeding 1.5 and 3 times of the interquartile range are shown as circles and triangles, respectively. Data were analyzed by Mann-Whitney’s U test. * and ** indicate significance at p<0.05 and p<0.01, respectively. C and D: Seroprevalence against PvMSP119 (C) and PfMSP119 (D) in patients with different fever histories. Patients were stratified by the recorded numer of days patients experienced fever before seeking treatment (Days with fever) (1–4 and more than 4 days).
Fig 6
Fig 6. Antibody responses in acute P. vivax (A) and P. falciparum (B) patients with different level of asexual parasitemias.
Patients were stratified into low (<500 parasites/μl for P. vivax or <5000 parasites/μl for P. falciparum) and high (≥ 500 parasites/μl for P. vivax or ≥ 5000 parasites/μl for P. falciparum) parasitemia groups. Data are presented in box plots with the median shown as a line within the box and interquartile value at the edge of box. The range of the column was 1.5 times of interquartile range. Any outlier values exceeding 1.5 and 3 times of the interquartile range are shown as circles and triangles, respectively. Data were analyzed by Mann-Whitney’s U test.
Fig 7
Fig 7. Dynamic decays of MSP119 antibodies within 3 months of follow up.
P. vivax (PV) or P. falciparum (PF) infected patients were followed to determine the dynamics of antibody levels for three months since enrolment. The dynamic changes of antibody levels were estimated via linear regression.
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