Specificity of the IgG antibody response to Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, and Plasmodium ovale MSP119 subunit proteins in multiplexed serologic assays

Abstract

BackgroundMultiplex bead assays (MBA) that measure IgG antibodies to the carboxy-terminal 19-kDa sub-unit of the merozoite surface protein 1 (MSP119) are currently used to determine malaria seroprevalence in human populations living in areas with both stable and unstable transmission. However, the species specificities of the IgG antibody responses to the malaria MSP119 antigens have not been extensively characterized using MBA.MethodsRecombinant Plasmodium falciparum (3D7), Plasmodium malariae (China I), Plasmodium ovale (Nigeria I), and Plasmodium vivax (Belem) MSP119 proteins were covalently coupled to beads for MBA. Threshold cut-off values for the assays were estimated using sera from US citizens with no history of foreign travel and by receiver operator characteristic curve analysis using diagnostic samples. Banked sera from experimentally infected chimpanzees, sera from humans from low transmission regions of Haiti and Cambodia (N = 12), and elutions from blood spots from humans selected from a high transmission region of Mozambique (N = 20) were used to develop an antigen competition MBA for antibody cross-reactivity studies. A sub-set of samples was further characterized using antibody capture/elution MBA, IgG subclass determination, and antibody avidity measurement.ResultsTotal IgG antibody responses in experimentally infected chimpanzees were species specific and could be completely suppressed by homologous competitor protein at a concentration of 10 μg/ml. Eleven of 12 samples from the low transmission regions and 12 of 20 samples from the high transmission area had antibody responses that were completely species specific. For 7 additional samples, the P. falciparum MSP119 responses were species specific, but various levels of incomplete heterologous competition were observed for the non-P. falciparum assays. A pan-malaria MSP119 cross-reactive antibody response was observed in elutions of blood spots from two 20–30 years old Mozambique donors. The antibody response from one of these two donors had low avidity and skewed almost entirely to the IgG3 subclass.ConclusionsEven when P. falciparum, P. malariae, P. ovale, and P. vivax are co-endemic in a high transmission setting, most antibody responses to MSP119 antigens are species-specific and are likely indicative of previous infection history. True pan-malaria cross-reactive responses were found to occur rarely.Electronic supplementary materialThe online version of this article (10.1186/s12936-018-2566-0) contains supplementary material, which is available to authorized users.

Assessing Performance of HRP2 Antigen Detection for Malaria Diagnosis in Mozambique

“…Rates of non-falciparum malaria are thought to be low in Mozambique, but there are limited data. However, serological studies have shown rates of antibody seropositivity ranging from 35% to 56% to Plasmodium malariae and P. ovale in the north of the country (5,6). A previous study reported a single Pfhrp2-deleted parasite from Mozambique, found among 1,162 samples collected from a single site in the south of the country (7).…”

The Case for Exploiting Cross-Species Epitopes in Malaria Vaccine Design

“…Far lower frequencies of cross-reactivity were observed in other studies. Using a multiplex bead assay, the species specificity of IgG responses to the MSP1 19 region from P. falciparum, P. ovale, P. vivax, and P. malariae was evaluated in sera from experimentally infected chimpanzees, infected individuals living in low transmission settings in Haiti and Cambodia (n = 12), and sera eluted from blood spots collected from individuals living in a high transmission setting in Mozambique (n = 20) (70). All of the antibody responses from the chimpanzees were speciesspecific and recognition was completely blocked by competition with the homologous protein.…”

Screening for malaria antigen and anti-malarial IgG antibody in forcibly-displaced Myanmar nationals: Cox’s Bazar district, Bangladesh, 2018

“…Six Plasmodium antigens were used for IgG antibody detection: the species-specific merozoite surface protein 19kD (MSP1) fragments for P. falciparum, P. vivax, and P. malariae (as described previously [8]), and three other P. falciparum antigens: liver stage antigen 1 (LSA1, [20]), circumsporozoite protein (CSP, NANPx5 repeat, [20]), and glutamate-rich protein R0 fragment (GLURP-R0, [21]). The three Plasmodium MSP1 19 kD antigens were produced recombinantly and purified as described previously [8], and the three other P. falciparum antigens were produced as peptides. The Schistosoma japonicum glutathione-S-transferase antigen was produced recombinantly and served as a generic protein to assess IgG non-specific binding.…”

“…Individuals with high levels of parasite-specific antibodies lower susceptibility to Plasmodium falciparum infection and morbidity [6]. The Plasmodium merozoite surface protein 1 (MSP1) antigen has been well characterized in immunological studies, and is known to induce "long-lived" IgG responses [7], with species-specific isoforms eliciting specific responses with limited cross-reactivity [8]. Plasmodium exposure even at a young age has the potential to induce a decades-long, or even life-long, antibody response.…”