Natural infections with different Plasmodium species induce antibodies reactive to a chimeric Plasmodium vivax recombinant protein

Abstract

Background As malaria incidence and transmission in a region decreases, it becomes increasingly difficult to identify areas of active transmission. Improved methods for identifying and monitoring foci of active malaria transmission are needed in areas of low parasite prevalence in order to achieve malaria elimination. Serological assays can provide population-level infection history to inform elimination campaigns. Methods A bead-based multiplex antibody detection assay was used to evaluate a chimeric Plasmodium vivax MSP1 protein (PvRMC-MSP1), designed to be broadly immunogenic for use in vaccine studies, to act as a pan-malaria serological tool based on its ability to capture IgG in plasma samples obtained from naturally exposed individuals. Samples from 236 US travellers with PCR confirmed infection status from all four major Plasmodium species infecting humans, Plasmodium falciparum (n = 181), Plasmodium vivax (n = 38), Plasmodium malariae (n = 4), and Plasmodium ovale (n = 13) were tested for IgG capture using PvRMC-MSP1 as well as the four recombinant MSP1-19 kD isoforms representative of these Plasmodium species. Results Regardless of infecting Plasmodium species, a large proportion of plasma samples from infected US travellers provided a high assay signal to the PvRMC-MSP1 chimeric protein, with 115 high responders out of 236 samples assessed (48.7%). When grouped by active infection, 38.7% P. falciparum-, 92.1% of P. vivax-, 75.0% P. malariae-, and 53.4% of P. ovale-infected individuals displayed high assay signals in response to PvRMC-MSP1. It was also determined that plasma from P. vivax-infected individuals produced increased assay signals in response to the PvRMC-MSP1 chimera as compared to the recombinant PvMSP1 for 89.5% (34 out of 38) of individuals. PvRMC-MSP1 also showed improved ability to capture IgG antibodies from P. falciparum-infected individuals when compared to the capture by recombinant PvMSP1, with high assay signals observed for 38.7% of P. falciparum-infected travellers in response to PvRMC-MSP1 IgG capture compared to just 1.1% who were high responders to capture by the recombinant PvMSP1 protein. Conclusions These results support further study of designed antigens as an approach for increasing sensitivity or broadening binding capacity to improve existing serological tools for determining population-level exposure to Plasmodium species. Including both broad-reacting and Plasmodium species-specific antigen-coated beads in an assay panel could provide a nuanced view of population-level exposure histories, an extensive IgG profile, and detailed seroestimates. A more sensitive serological tool for detection of P. vivax exposure would aid malaria elimination campaigns in co-endemic areas and regions where P. vivax is the dominant parasite.

The use of a chimeric antigen for Plasmodium falciparum and P. vivax seroprevalence estimates from community surveys in Ethiopia and Costa Rica

“…It was evident from this study that this chimeric antigen captured IgG from a majority of returning U.S. travelers with PCR confirmed malaria infection regardless of the Plasmodium species responsible for infection [15]. Furthermore, an increased assay signal was observed for PvRMC-MSP1 compared to recombinant PvMSP1 in 34 out of 38 active P. vivax infections [15].…”

“…The structure and production of the chimeric P. vivax merozoite surface protein 1 has been previously described [15,16]. Briefly, the P. vivax recombinant modular chimera based on MSP1 (PvRMC-MSP1) was based on the P. vivax Belem sequence (GenBank: XP_001614842.1) and contains five promiscuous T cell epitopes, with two also functioning as B cell epitopes, as well as an extended version of the P. vivax MSP1 19 kDa fragment containing two T helper epitopes from the MSP1 33 kDa fragment, and the (NANP) 6 repeat peptide from P. falciparum circumsporozoite protein (CSP) [16].…”

“…Magnetic MagPlex microspheres (Luminex Corp.) were covalently linked to the chimeric PvRMC-MSP1 protein, the recombinant PfMSP1 and PvMSP1 antigens, and the PfCSP peptide as previously described [12,15], with all three recombinant proteins conjugated at a concentration of 20 μg/mL and the peptide at a concentration of 30 μg/mL. To obtain whole blood from the filter paper, a 6 mm diameter hole punch from individual DBS samples were eluted overnight at 4˚C in buffer containing: PBS, 0.05% Tween 20, 0.5% polyvinylpyrrolidone, 0.5% poly(vinyl) alcohol, 0.1% casein, 0.5% BSA, 0.02% NaN 3 , and 3 μg/mL E. coli extract to prevent nonspecific binding.…”

“…A recent study from our laboratory described the pattern of serological response in U.S. travelers [15] using a chimeric protein based on Plasmodium vivax MSP1 and P. falciparum circumsporozoite protein (CSP) repeat epitopes [16], known as PvRMC-MSP1. It was evident from this study that this chimeric antigen captured IgG from a majority of returning U.S. travelers with PCR confirmed malaria infection regardless of the Plasmodium species responsible for infection [15]. Furthermore, an increased assay signal was observed for PvRMC-MSP1 compared to recombinant PvMSP1 in 34 out of 38 active P. vivax infections [15].…”

Antibody Profile Comparison against MSP1 Antigens of Multiple Plasmodium Species in Human Serum Samples from Two Different Brazilian Populations Using a Multiplex Serological Assay

“…Despite the minor number of cases reported in many parts of the world, a significant part of the population shows serologic evidence of recent exposure to P. malariae , suggesting that asymptomatic infections with this species may be frequent [ 6 , 7 , 8 , 9 ]. In fact, P. malariae is known to produce low parasitemia infections that are frequently non-symptomatic and long-lasting [ 10 ], possibly due its reduced growth rate [ 11 ] and preference for older erythrocytes [ 12 ].…”