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.
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 previ...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2016-12-01
|
| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | http://europepmc.org/articles/PMC5145139?pdf=render |
| _version_ | 1818458934782984192 |
|---|---|
| author | Paul Griffin Cielo Pasay Suzanne Elliott Silvana Sekuloski Maggy Sikulu Leon Hugo David Khoury Deborah Cromer Miles Davenport Jetsumon Sattabongkot Karen Ivinson Christian Ockenhouse James McCarthy |
| author_facet | Paul Griffin Cielo Pasay Suzanne Elliott Silvana Sekuloski Maggy Sikulu Leon Hugo David Khoury Deborah Cromer Miles Davenport Jetsumon Sattabongkot Karen Ivinson Christian Ockenhouse James McCarthy |
| author_sort | Paul Griffin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T23:06:21Z |
| format | Article |
| id | doaj.art-c69ef26a80be445cbc33a06ebe6523cd |
| institution | Directory Open Access Journal |
| issn | 1935-2727 1935-2735 |
| language | English |
| last_indexed | 2024-12-14T23:06:21Z |
| publishDate | 2016-12-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Neglected Tropical Diseases |
| spelling | doaj.art-c69ef26a80be445cbc33a06ebe6523cd2022-12-21T22:44:19ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352016-12-011012e000513910.1371/journal.pntd.0005139Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission.Paul GriffinCielo PasaySuzanne ElliottSilvana SekuloskiMaggy SikuluLeon HugoDavid KhouryDeborah CromerMiles DavenportJetsumon SattabongkotKaren IvinsonChristian OckenhouseJames McCarthyBACKGROUND: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.http://europepmc.org/articles/PMC5145139?pdf=render |
| spellingShingle | Paul Griffin Cielo Pasay Suzanne Elliott Silvana Sekuloski Maggy Sikulu Leon Hugo David Khoury Deborah Cromer Miles Davenport Jetsumon Sattabongkot Karen Ivinson Christian Ockenhouse James McCarthy 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 Neglected Tropical Diseases |
| title | 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. |
| title_full | 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. |
| title_fullStr | 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. |
| title_full_unstemmed | 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. |
| title_short | 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. |
| title_sort | 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 |
| url | http://europepmc.org/articles/PMC5145139?pdf=render |
| work_keys_str_mv | AT paulgriffin safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT cielopasay safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT suzanneelliott safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT silvanasekuloski safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT maggysikulu safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT leonhugo safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT davidkhoury safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT deborahcromer safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT milesdavenport safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT jetsumonsattabongkot safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT karenivinson safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT christianockenhouse safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission AT jamesmccarthy safetyandreproducibilityofaclinicaltrialsystemusinginducedbloodstageplasmodiumvivaxinfectionanditspotentialasamodeltoevaluatemalariatransmission |