Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission

PLoS Negl Trop Dis. 2016 Dec 8;10(12):e0005139. doi: 10.1371/journal.pntd.0005139. eCollection 2016 Dec.

Abstract

Background: Interventions to interrupt transmission of malaria from humans to mosquitoes represent an appealing approach to assist malaria elimination. A limitation has been the lack of systems to test the efficacy of such interventions before proceeding to efficacy trials in the field. We have previously demonstrated the feasibility of induced blood stage malaria (IBSM) infection with Plasmodium vivax. In this study, we report further validation of the IBSM model, and its evaluation for assessment of transmission of P. vivax to Anopheles stephensi mosquitoes.

Methods: Six healthy subjects (three cohorts, n = 2 per cohort) were infected with P. vivax by inoculation with parasitized erythrocytes. Parasite growth was monitored by quantitative PCR, and gametocytemia by quantitative reverse transcriptase PCR (qRT-PCR) for the mRNA pvs25. Parasite multiplication rate (PMR) and size of inoculum were calculated by linear regression. Mosquito transmission studies were undertaken by direct and membrane feeding assays over 3 days prior to commencement of antimalarial treatment, and midguts of blood fed mosquitoes dissected and checked for presence of oocysts after 7-9 days.

Results: The clinical course and parasitemia were consistent across cohorts, with all subjects developing mild to moderate symptoms of malaria. No serious adverse events were reported. Asymptomatic elevated liver function tests were detected in four of six subjects; these resolved without treatment. Direct feeding of mosquitoes was well tolerated. The estimated PMR was 9.9 fold per cycle. Low prevalence of mosquito infection was observed (1.8%; n = 32/1801) from both direct (4.5%; n = 20/411) and membrane (0.9%; n = 12/1360) feeds.

Conclusion: The P. vivax IBSM model proved safe and reliable. The clinical course and PMR were reproducible when compared with the previous study using this model. The IBSM model presented in this report shows promise as a system to test transmission-blocking interventions. Further work is required to validate transmission and increase its prevalence.

Trial registration: Anzctr.org.au ACTRN12613001008718.

Publication types

  • Clinical Trial
  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anopheles / parasitology*
  • Anopheles / physiology
  • Disease Models, Animal
  • Erythrocytes / parasitology
  • Healthy Volunteers
  • Human Experimentation
  • Humans
  • Malaria, Vivax / drug therapy
  • Malaria, Vivax / parasitology*
  • Malaria, Vivax / transmission*
  • Mosquito Vectors / parasitology*
  • Mosquito Vectors / physiology
  • Oocysts
  • Parasitemia
  • Reproducibility of Results

Associated data

  • ANZCTR/ACTRN12613001008718

Grants and funding

The study was funded by the Program for Appropriate Technology in Health Malaria Vaccine Initiative (PATH MVI), the Government of Queensland (clinical research fellowship to JM), and the National Health Medical and Research Council (practitioner fellowship to JM). Authors CO and KI are employed by PATH MVI. CO and KI played roles in the study design, data collection and analysis, decision to publish, and preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.