A Plasmodium vivax experimental human infection model for evaluating efficacy of interventions
Katharine A. Collins, … , Joerg J. Moehrle, James S. McCarthy
Katharine A. Collins, … , Joerg J. Moehrle, James S. McCarthy
Published February 11, 2020
Citation Information: J Clin Invest. 2020;130(6):2920-2927. https://doi.org/10.1172/JCI134923.
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Clinical Research and Public Health Infectious disease

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

Abstract

BACKGROUND Interventions 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.METHODS Healthy, 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.RESULTS Parasitemia 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.CONCLUSION We 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 REGISTRATION ACTRN12614000930684 and ACTRN12616000174482.FUNDING (Australian) National Health and Medical Research Council Program Grant 1132975 (Study 1). Bill and Melinda Gates Foundation (OPP1111147) (Study 2).

Authors

Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Greg J. Robinson, Melanie Rampton, Suzanne Elliott, Anand Odedra, David Khoury, Emma Ballard, Todd B. Shelper, Leonardo Lucantoni, Vicky M. Avery, Stephan Chalon, Joerg J. Moehrle, James S. McCarthy

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Figure 4

Infectivity to mosquitoes.

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Infectivity to mosquitoes. Successful transmission was defined as at lea...
Successful transmission was defined as at least 1 oocyst-positive mosquito as determined by 18S qPCR. Mosquito infection rate is reported as prevalence of infection (percentage of mosquitoes infected per feeding assay). (A) Prevalence of mosquito infection in all feeding assays in Study 2 at each time point (n = 113). (B) Prevalence of mosquito infection in successful feeding assays, by feeding assay type (n = 37). Groups compared by Kruskal-Wallis test with Dunn’s multiple comparison test. (C) The gametocytemia for participant samples that were infectious compared with samples that were noninfectious (n = 54). Groups compared by Mann-Whitney test. Box plots indicate the median and whiskers show the minimum and maximum. (D) Representative image from of a P. vivax liver-stage schizont stained with UIS4 and Hoechst33342 following incubation of sporozoites with HC-04 culture for 7 days (left, white channel, Hoechst33342; middle, red channel, Alexa Fluor 488–conjugated UIS4 antibody; right, merge). Image taken at ×40 magnification. Scale bar: 20 μm. Sporozoites were obtained by feeding mosquitoes on enriched gametocytes collected on day 10 from participants in cohort 3 (Supplemental Material).