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A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions.

ABSTRACT: BACKGROUNDInterventions that interrupt Plasmodium vivax transmission or eliminate dormant P. vivax liver-stage parasites will be essential for malaria elimination. Development of these interventions has been hindered by the lack of P. vivax in vitro culture and could be accelerated by a safe and reproducible clinical model in malaria-naive individuals.METHODSHealthy, malaria-naive adults were enrolled in 2 studies to assess the safety, infectivity, and transmissibility of a new P. vivax isolate. Participants (Study 1, n = 2; Study 2, n = 24) were inoculated with P. vivax-infected red blood cells to initiate infection, and were treated with artemether-lumefantrine (Study 1) or chloroquine (Study 2). Primary endpoints were safety and infectivity of the new isolate. In Study 2, transmission to mosquitoes was also evaluated using mosquito feeding assays, and sporozoite viability was assessed using in vitro cultured hepatocytes.RESULTSParasitemia and gametocytemia developed in all participants and was cleared by antimalarial treatment. Adverse events were mostly mild or moderate and none were serious. Sixty-nine percent of participants (11/16) were infectious to Anopheles mosquitoes at peak gametocytemia. Mosquito infection rates reached 97% following membrane feeding with gametocyte-enriched blood, and sporozoites developed into liver-stage schizonts in culture.CONCLUSIONWe have demonstrated the safe, reproducible, and efficient transmission of P. vivax gametocytes from humans to mosquitoes, and have established an experimental model that will accelerate the development of interventions targeting multiple stages of the P. vivax life cycle.TRIAL REGISTRATIONACTRN12614000930684 and ACTRN12616000174482.FUNDING(Australian) National Health and Medical Research Council Program Grant 1132975 (Study 1). Bill and Melinda Gates Foundation (OPP1111147) (Study 2).

SUBMITTER: Collins KA

PROVIDER: S-EPMC7259989 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundMalaria-associated anaemia, arising from symptomatic, asymptomatic and submicroscopic infections, is a significant cause of morbidity worldwide. Induced blood stage malaria volunteer infection studies (IBSM-VIS) provide a unique opportunity to evaluate the haematological response to early Plasmodium falciparum and Plasmodium vivax infection.MethodsThis study was an analysis of the haemoglobin, red cell counts, and parasitaemia data from 315 participants enrolled in IBSM-VIS between 2012 and 2019, including 269 participants inoculated with the 3D7 strain of P. falciparum (Pf3D7), 15 with an artemisinin-resistant P. falciparum strain (PfK13) and 46 with P. vivax. Factors associated with the fractional fall in haemoglobin (Hb-FF) were evaluated, and the malaria-attributable erythrocyte loss after accounting for phlebotomy-related losses was estimated. The relative contribution of parasitized erythrocytes to the malaria-attributable erythrocyte loss was also estimated.ResultsThe median peak parasitaemia prior to treatment was 10,277 parasites/ml (IQR 3566-27,815), 71,427 parasites/ml [IQR 33,236-180,213], and 34,840 parasites/ml (IQR 13,302-77,064) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. The median Hb-FF was 10.3% (IQR 7.8-13.3), 14.8% (IQR 11.8-15.9) and 11.7% (IQR 8.9-14.5) in those inoculated with Pf3D7, PfK13 and P. vivax, respectively, with the haemoglobin nadir occurring a median 12 (IQR 5-21), 15 (IQR 7-22), and 8 (IQR 7-15) days following inoculation. In participants inoculated with P. falciparum, recrudescence was associated with a greater Hb-FF, while in those with P. vivax, the Hb-FF was associated with a higher pre-treatment parasitaemia and later day of anti-malarial treatment. After accounting for phlebotomy-related blood losses, the estimated Hb-FF was 4.1% (IQR 3.1-5.3), 7.2% (IQR 5.8-7.8), and 4.9% (IQR 3.7-6.1) in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively. Parasitized erythrocytes were estimated to account for 0.015% (IQR 0.006-0.06), 0.128% (IQR 0.068-0.616) and 0.022% (IQR 0.008-0.082) of the malaria-attributable erythrocyte loss in participants inoculated with Pf3D7, PfK13, and P. vivax, respectively.ConclusionEarly experimental P. falciparum and P. vivax infection resulted in a small but significant fall in haemoglobin despite parasitaemia only just at the level of microscopic detection. Loss of parasitized erythrocytes accounted for < 0.2% of the total malaria-attributable haemoglobin loss.

Project description:BackgroundMultiplicity of infection (MOI) refers to the average number of distinct parasite genotypes concurrently infecting a patient. Although several studies have reported on MOI and the frequency of multiclonal infections in Plasmodium falciparum, there is limited data on Plasmodium vivax. Here, MOI and the frequency of multiclonal infections were studied in areas from South America where P. vivax and P. falciparum can be compared.Methodology/principal findingsAs part of a passive surveillance study, 1,328 positive malaria patients were recruited between 2011 and 2013 in low transmission areas from Colombia. Of those, there were only 38 P. vivax and 24 P. falciparum clinically complicated cases scattered throughout the time of the study. Samples from uncomplicated cases were matched in time and location with the complicated cases in order to compare the circulating genotypes for these two categories. A total of 92 P. vivax and 57 P. falciparum uncomplicated cases were randomly subsampled. All samples were genotyped by using neutral microsatellites. Plasmodium vivax showed more multiclonal infections (47.7%) than P. falciparum (14.8%). Population genetics and haplotype network analyses did not detect differences in the circulating genotypes between complicated and uncomplicated cases in each parasite. However, a Fisher exact test yielded a significant association between having multiclonal P. vivax infections and complicated malaria. No association was found for P. falciparum infections.ConclusionThe association between multiclonal infections and disease severity in P. vivax is consistent with previous observations made in rodent malaria. The contrasting pattern between P. vivax and P. falciparum could be explained, at least in part, by the fact that P. vivax infections have lineages that were more distantly related among them than in the case of the P. falciparum multiclonal infections. Future research should address the possible role that acquired immunity and exposure may have on multiclonal infections and their association with disease severity.

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A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions.

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