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. 2012 Nov 15;206(10):1612-21.
doi: 10.1093/infdis/jis566. Epub 2012 Sep 10.

New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women

Freya J I Fowkes  1 , Rose McGready, Nadia J Cross, Mirja Hommel, Julie A Simpson, Salenna R Elliott, Jack S Richards, Kurt Lackovic, Jacher Viladpai-Nguen, David Narum, Takafumi Tsuboi, Robin F Anders, François Nosten, James G Beeson
Affiliations

New insights into acquisition, boosting, and longevity of immunity to malaria in pregnant women

Freya J I Fowkes et al. J Infect Dis. .

Abstract

Background: How antimalarial antibodies are acquired and maintained during pregnancy and boosted after reinfection with Plasmodium falciparum and Plasmodium vivax is unknown.

Methods: A nested case-control study of 467 pregnant women (136 Plasmodium-infected cases and 331 uninfected control subjects) in northwestern Thailand was conducted. Antibody levels to P. falciparum and P. vivax merozoite antigens and the pregnancy-specific PfVAR2CSA antigen were determined at enrollment (median 10 weeks gestation) and throughout pregnancy until delivery.

Results: Antibodies to P. falciparum and P. vivax were highly variable over time, and maintenance of high levels of antimalarial antibodies involved highly dynamic responses resulting from intermittent exposure to infection. There was evidence of boosting with each successive infection for P. falciparum responses, suggesting the presence of immunological memory. However, the half-lives of Plasmodium antibody responses were relatively short, compared with measles (457 years), and much shorter for merozoite responses (0.8-7.6 years), compared with PfVAR2CSA responses (36-157 years). The longer half-life of antibodies to PfVAR2CSA suggests that antibodies acquired in one pregnancy may be maintained to protect subsequent pregnancies.

Conclusions: These findings may have important practical implications for predicting the duration of vaccine-induced responses by candidate antigens and supports the development of malaria vaccines to protect pregnant women.

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Figures

Figure 1.
Figure 1.
Antibodies to Plasmodium species blood-stage antigens at enrollment. Antibody levels were determined in all available case (n = 124) and control (n = 320) samples at enrollment (median 10 weeks gestation). (A) Seroprevalence with standard errors and (B) boxplots of antibody levels in case and control subjects. Horizontal lines represent medians, boxes represent interquartile range, and lines represent ranges with outliers represented as dots. Antibody prevalences and levels were significantly higher in case than in control subjects (P < .001). Antibody levels according to gravidity in control subjects (C) and case subjects (D). In case and control groups, there was no association between gravidity and antibody levels (P > .17).
Figure 2.
Figure 2.
Antibody levels over gestation could be classified as relatively stable or dynamic. For each individual woman, the mean antibody response over gestation time and standard deviation (SD; ie, how far the individuals IgG response fluctuated from their mean response) was calculated. Use of a cutoff of a SD of 0.1 broadly classified individual woman as having dynamic (SD ≥ 0.1) or relatively stable responses (SD < 0.1). (A) The categorization of relatively stable and dynamic responses to PfAMA1 is shown as a representative example of antimalarial IgG responses throughout pregnancy (each line represents antibody levels in an individual over time). (B) The proportion (%) of dynamic antibody responses according to longitudinal exposure group. Species-specific cases refers to women who were infected with Plasmodium falciparum or Plasmodium vivax during pregnancy for P. falciparum and P. vivax antigens, respectively. The proportion of women with dynamic responses during pregnancy was associated with species-specific longitudinal exposure groups PfVAR2CSA, P < .001; PfAMA1, P < .001; PfEBA175 P = .24; PfMSP2, P < .001; PfMSP3, P < .001; PvAMA, P = .006.
Figure 3.
Figure 3.
Examples of individuals with relatively stable and dynamic antimalarial responses. Each woman was classified as having dynamic (antibody optical density [OD] standard deviation [SD] ≥ 0.1) or relatively stable responses (antibody OD SD < 0.1). Relatively stable responses to PfAMA1, PfVAR2CSA, and PvAMA1 in the same 10 women (one color is the same woman). Dynamic responses to Plasmodium falciparum antigens PfAMA1, PfVAR2CSA in another 10 women, and dynamic responses to Plasmodium vivax antigens in an additional 10 women (with the exception of the yellow individual who had dynamic responses for all 3 antigens).
Figure 4.
Figure 4.
Anti–Plasmodium falciparum levels increase with each successive P. falciparum infection. Multivariable linear mixed-effects modeling of the association between antibody levels and number of episodes in species-specific cases (n = 94 and n = 83 for P. falciparum and P. vivax analysis, respectively). The coefficients (95% confidence interval [CI]) for the estimated mean increase in antibody levels per increase in P. falciparum episode number were as follows: PfVAR2CSA 0.03 (0.01–0.05), P = .011; PfAMA1 0.05 (0.02–0.08), P < .001; PfEBA175 0.05 (0.02–0.07) P < .001; PfMSP2 0.02 (0.003–0.04), P = .025; PfMSP3 0.018 (−0.001 to 0.04), P = .063; PvAMA1 − 0.0004 (−0.01 to 0.01), P = .96; measles −0.003 (−0.015 to 0.01), P = .63.
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