scholarly journals Higher gametocyte production and mosquito infectivity in chronic compared to incident Plasmodium falciparum infections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Aissata Barry ◽  
John Bradley ◽  
Will Stone ◽  
Moussa W. Guelbeogo ◽  
Kjerstin Lanke ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Multiplication Rate ◽  
Chronic Infections ◽  
Symptom Screening ◽  
Transmission Reduction ◽  
Parasite Multiplication ◽  
Asymptomatic Infections ◽  
Incident Cohort

AbstractPlasmodium falciparum gametocyte kinetics and infectivity may differ between chronic and incident infections. In the current study, we assess parasite kinetics and infectivity to mosquitoes among children (aged 5–10 years) from Burkina Faso with (a) incident infections following parasite clearance (n = 48) and (b) chronic asymptomatic infections (n = 60). In the incident infection cohort, 92% (44/48) of children develop symptoms within 35 days, compared to 23% (14/60) in the chronic cohort. All individuals with chronic infection carried gametocytes or developed them during follow-up, whereas only 35% (17/48) in the incident cohort produce gametocytes before becoming symptomatic and receiving treatment. Parasite multiplication rate (PMR) and the relative abundance of ap2-g and gexp-5 transcripts are positively associated with gametocyte production. Antibody responses are higher and PMR lower in chronic infections. The presence of symptoms and sexual stage immune responses are associated with reductions in gametocyte infectivity to mosquitoes. We observe that most incident infections require treatment before the density of mature gametocytes is sufficient to infect mosquitoes. In contrast, chronic, asymptomatic infections represent a significant source of mosquito infections. Our observations support the notion that malaria transmission reduction may be expedited by enhanced case management, involving both symptom-screening and infection detection.

scholarly journals Increased gametocyte production and mosquito infectivity in chronic versus incident Plasmodium falciparum infections

2020 ◽  
Author(s):  
Aissata Barry ◽  
John Bradley ◽  
Will Stone ◽  
Moussa W. Guelbeogo ◽  
Kjerstin Lanke ◽  
...  
Keyword(s):  
Chronic Infection ◽  
Multiplication Rate ◽  
Ring Stage ◽  
Chronic Infections ◽  
Gametocyte Density ◽  
Symptom Screening ◽  
Transmission Reduction ◽  
Parasite Multiplication ◽  
Asymptomatic Infections ◽  
Incident Cohort

AbstractWe longitudinally assessed P. falciparum parasite kinetics, gametocyte production and infectivity in incident infections that were naturally acquired following infection clearance and in chronic asymptomatic infections in Burkina Faso. 92% (44/48) of the incident cohort developed symptoms and were treated within 35 days, compared to 23% (14/60) of the chronic cohort. All but two individuals with chronic infection were gametocytaemic at enrollment, whereas only 35% (17/48) in the incident cohort developed gametocytes within 35 days. The relative abundance of ap2-g transcripts was positively associated with conversion to gametocyte production (i.e. the ratio of gametocytes at day 14 to ring stage parasites at baseline) and was higher in chronic infections. Parasite multiplication rate, assessed by daily molecular parasite quantification, was positively associated with prospective gametocyte production. Most incident infections were cleared before gametocyte density was sufficiently high to infect mosquitoes. In contrast, chronic, asymptomatic infections represented a significant source of mosquito infections. If present, gametocytes were significantly less infectious if concurrent with malaria symptoms. Our observations support the notion that malaria transmission reduction may be expediated by enhanced case management, involving both symptom-screening and infection detection.

scholarly journals Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

2021 ◽  
Author(s):  
Stephen Derek Woolley ◽  
Melissa Fernandez ◽  
Maria Rebelo ◽  
Stacey Llewellyn ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Multiplication Rate ◽  
Weighted Mean ◽  
Cell Bank ◽  
Parasite Multiplication ◽  
Clinical Trials Registry ◽  
Blood Stage Malaria

Abstract Background New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.Methods The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and <0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 hours (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI: 18.5 – 64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI: 8.5 – 15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI: 3.61 – 4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI: 4.16 – 4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration Australian New Zealand Clinical Trials registry numbers:P3487 (3D7-V1): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134

scholarly journals Development and evaluation of a new P. falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

2021 ◽  
Author(s):  
Stephen Derek Woolley ◽  
Melissa Fernandez ◽  
Maria Rebelo ◽  
Stacey Llewellyn ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Multiplication Rate ◽  
Weighted Mean ◽  
Cell Bank ◽  
Parasite Multiplication ◽  
Clinical Trials Registry ◽  
Blood Stage Malaria

Abstract Background New antimalarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating antimalarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. We aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated.Methods We expanded the 3D7-V2 MCB in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and <0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable Plasmodium falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 hours (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI: 18.5 – 64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI: 8.5 – 15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI: 3.61 – 4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI: 4.16 – 4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies.Trial Registration Australian New Zealand Clinical Trials registry numbers:P3487 (3D7-V1): ACTRN12619001085167P3491 (3D7-MBE-008): ACTRN12619001079134

scholarly journals Genotyping cognate Plasmodium falciparum in humans and mosquitoes to estimate onward transmission of asymptomatic infections

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kelsey M. Sumner ◽  
Elizabeth Freedman ◽  
Lucy Abel ◽  
Andrew Obala ◽  
Brian W. Pence ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Odds Ratio ◽  
Asymptomatic Malaria ◽  
Major Contributor ◽  
Western Kenya ◽  
High Transmission ◽  
Transmission Reduction ◽  
Asymptomatic Infections ◽  
Infection Types ◽  
Natural Settings

AbstractMalaria control may be enhanced by targeting reservoirs of Plasmodium falciparum transmission. One putative reservoir is asymptomatic malaria infections and the scale of their contribution to transmission in natural settings is not known. We assess the contribution of asymptomatic malaria to onward transmission using a 14-month longitudinal cohort of 239 participants in a high transmission site in Western Kenya. We identify P. falciparum in asymptomatically- and symptomatically-infected participants and naturally-fed mosquitoes from their households, genotype all parasites using deep sequencing of the parasite genes pfama1 and pfcsp, and use haplotypes to infer participant-to-mosquito transmission through a probabilistic model. In 1,242 infections (1,039 in people and 203 in mosquitoes), we observe 229 (pfcsp) and 348 (pfama1) unique parasite haplotypes. Using these to link human and mosquito infections, compared with symptomatic infections, asymptomatic infections more than double the odds of transmission to a mosquito among people with both infection types (Odds Ratio: 2.56; 95% Confidence Interval (CI): 1.36–4.81) and among all participants (OR 2.66; 95% CI: 2.05–3.47). Overall, 94.6% (95% CI: 93.1–95.8%) of mosquito infections likely resulted from asymptomatic infections. In high transmission areas, asymptomatic infections are the major contributor to mosquito infections and may be targeted as a component of transmission reduction.

Aberrant development of Plasmodium falciparum in hemoglobin CC red cells: implications for the malaria protective effect of the homozygous state

Blood ◽  
2003 ◽  
Vol 101 (8) ◽  
pp. 3309-3315 ◽  
Author(s):  
Rick M. Fairhurst ◽  
Hisashi Fujioka ◽  
Karen Hayton ◽  
Kathleen F. Collins ◽  
Thomas E. Wellems
Keyword(s):  
Plasmodium Falciparum ◽  
Epidemiologic Studies ◽  
Red Cells ◽  
Replication Capacity ◽  
Multiplication Rate ◽  
Hemoglobin C ◽  
Erythrocyte Surface ◽  
Parasite Multiplication ◽  
Parasite Replication

Abstract Although selection of hemoglobin C (HbC) by malaria has been speculated for decades, only recently have epidemiologic studies provided support for HbC protection against malaria in West Africa. A reduced risk of malaria associated with the homozygous CC state has been attributed to the inability of CC cells to support parasite multiplication in vitro. However, there have been conflicting data and conclusions regarding the ability of CC red cells to support parasite replication. Reports that parasites cannot multiply in CC cells in vitro contrast with detection of substantial parasite densities in CC patients with malaria. We have therefore investigated Plasmodium falciparum growth in CC cells in vitro. Our data show that the multiplication rate of several P falciparum lines is measurable in CC cells, but lower than that in AA (HbA-normal) cells. A high proportion of ring forms and trophozoites disintegrates within a subset of CC cells, an observation that accounts for the overall lower replication rate. In addition, knobs present on the surface of infected CC cells are fewer in number and morphologically aberrant when compared with those on AA cells. Events in malaria pathogenesis that involve remodeling of the erythrocyte surface and the display of parasite antigens may be affected by these knob abnormalities. Our data suggest that only a subset of CC cells supports normal parasite replication and that components of malaria protection associated with the CC state may affect the parasite's replication capacity and involve aberrant knob formation on CC cells.

Population dynamics of untreated Plasmodium falciparum malaria within the adult human host during the expansion phase of the infection

Parasitology ◽  
2002 ◽  
Vol 124 (3) ◽  
pp. 247-263 ◽  
Author(s):  
J. A. SIMPSON ◽  
L. AARONS ◽  
W. E. COLLINS ◽  
G. M. JEFFERY ◽  
N. J. WHITE
Keyword(s):  
Plasmodium Falciparum ◽  
Falciparum Malaria ◽  
Prediction Interval ◽  
Growth Dynamics ◽  
Plasmodium Falciparum Malaria ◽  
Host Susceptibility ◽  
Initial Growth ◽  
Multiplication Rate ◽  
Parasite Life Cycle ◽  
Parasite Multiplication

A retrospective analysis was performed of parasite count data recorded from the first 7 days of blood or mosquito transmitted Plasmodium falciparum infections given for the treatment of neurosyphilis in the USA before 1963. The objective of this study was to characterize initial growth dynamics before host defences have significant effects on the infecting parasite population. Of the 328 patients' data available for analysis, 83 were excluded because they had received anti-malarial treatment during the first 7 days of the patent infection. Nonlinear mixed effects modelling was performed to estimate the parameters of interest; ‘parasite multiplication rate per 48 h’ (PMR), and length of the parasite life-cycle (periodicity). The parasitaemia versus time profiles showed great variability between patients. The mean population estimate of ‘PMR’ was approximately 8, and was highly dependent on the P. falciparum ‘strain’. PMR also varied significantly between patients with a 90% prediction interval varying from 5·5 to 12·3-fold. Both intrinsic parasite multiplication rate (an intrinsic virulence determinant), and host susceptibility and defence contribute to expansion of the parasite biomass and thus disease severity in falciparum malaria.

scholarly journals Development and evaluation of a new Plasmodium falciparum 3D7 blood stage malaria cell bank for use in malaria volunteer infection studies

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Stephen D. Woolley ◽  
Melissa Fernandez ◽  
Maria Rebelo ◽  
Stacey A. Llewellyn ◽  
Louise Marquart ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Parasite Clearance ◽  
Blood Stage ◽  
Multiplication Rate ◽  
Weighted Mean ◽  
Cell Bank ◽  
In Vitro Expansion ◽  
Clinical Trials Registry ◽  
Blood Stage Malaria

Abstract Background New anti-malarial therapeutics are required to counter the threat of increasing drug resistance. Malaria volunteer infection studies (VIS), particularly the induced blood stage malaria (IBSM) model, play a key role in accelerating anti-malarial drug development. Supply of the reference 3D7-V2 Plasmodium falciparum malaria cell bank (MCB) is limited. This study aimed to develop a new MCB, and compare the safety and infectivity of this MCB with the existing 3D7-V2 MCB, in a VIS. A second bank (3D7-V1) developed in 1995 was also evaluated. Methods The 3D7-V2 MCB was expanded in vitro using a bioreactor to produce a new MCB designated 3D7-MBE-008. This bank and 3D7-V1 were then evaluated using the IBSM model, where healthy participants were intravenously inoculated with blood-stage parasites. Participants were treated with artemether-lumefantrine when parasitaemia or clinical thresholds were reached. Safety, infectivity and parasite growth and clearance were evaluated. Results The in vitro expansion of 3D7-V2 produced 200 vials of the 3D7-MBE-008 MCB, with a parasitaemia of 4.3%. This compares to 0.1% in the existing 3D7-V2 MCB, and < 0.01% in the 3D7-V1 MCB. All four participants (two per MCB) developed detectable P. falciparum infection after inoculation with approximately 2800 parasites. For the 3D7-MBE-008 MCB, the parasite multiplication rate of 48 h (PMR48) using non-linear mixed effects modelling was 34.6 (95% CI 18.5–64.6), similar to the parental 3D7-V2 line; parasitaemia in both participants exceeded 10,000/mL by day 8. Growth of the 3D7-V1 was slower (PMR48 of 11.5 [95% CI 8.5–15.6]), with parasitaemia exceeding 10,000 parasites/mL on days 10 and 8.5. Rapid parasite clearance followed artemether-lumefantrine treatment in all four participants, with clearance half-lives of 4.01 and 4.06 (weighted mean 4.04 [95% CI 3.61–4.57]) hours for 3D7-MBE-008 and 4.11 and 4.52 (weighted mean 4.31 [95% CI 4.16–4.47]) hours for 3D7-V1. A total of 59 adverse events occurred; most were of mild severity with three being severe in the 3D7-MBE-008 study. Conclusion The safety, growth and clearance profiles of the expanded 3D7-MBE-008 MCB closely resemble that of its parent, indicating its suitability for future studies. Trial Registration: Australian New Zealand Clinical Trials registry numbers: P3487 (3D7-V1): ACTRN12619001085167. P3491 (3D7-MBE-008): ACTRN12619001079134

scholarly journals Efficacy of Artemisinin-lumefantrine for the treatment of uncomplicated malaria after more than a decade of its use in Kenya

2020 ◽  
Author(s):  
Gabriel M. Kishoyian ◽  
Eliud N. M. Njagi ◽  
George O. Orinda ◽  
Francis T. Kimani ◽  
Kevin Thiongo ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Uncomplicated Malaria ◽  
Standard Dose ◽  
Parasite Clearance ◽  
First Line ◽  
Study Population ◽  
Treatment Responses ◽  
Lost To Follow Up ◽  
Line Drug

Abstract Background: Plasmodium falciparum resistance to antimalarial drugs remains to be a major threat to the control of malaria globally. After the deployment of artemisinin-based combination therapy (ACT), there have been reports of reduced sensitivity of the drug to parasite clearance. In Kenya, artemisinin-lumefantrine (AL) is the recommended first-line drug in the treatment of uncomplicated malaria. This study sought to assess the efficacy of AL after its reintroduction in Kenya, a decade later. In this study, we assessed clinical and parasitological responses of children under five years in May and November 2015 in Chulaimbo sub-County, Kisumu, Kenya.Method: Patients of ≥6 and ≤60 months of age with confirmed Plasmodium falciparum mono-infection were enrolled in the study. The patients were treated with a standard dose of AL and followed up for 28 days. During which period we monitored treatment responses and follow-up adherence.Results: Of the 90 patients enrolled, fourteen (14) were lost to follow-up, with 76 completing the study period. Seventy-five patients 75 (98.7%) cleared, parasitemia within 48 hours while one (1.3%) cleared on day 3. There was 100% clinical and parasitological parasite clearance. Conclusion: Artemisinin lumefantrine was found to be highly efficacious to plasmodium falciparum parasites in children aged ≥6 and ≤60 months. Based on this, the drug can be used to treat uncomplicated malaria in the study population. However, there is need for continued monitoring of its effectiveness in children and adults to counter the threat of resistance.

scholarly journals Serious antimalaria resistance, genetic markers of Kelch 13, plasmepsine 2 CNV associated with dihydroartemisinine-piperaquine phosphate resistance in Plasmodium falciparum population in malaria hyperendemic zone of Dak Lak Province (2019-2020)

2020 ◽  
Vol 8 (1) ◽  
pp. 246-253
Author(s):  
Huynh Hong Quang ◽  
Chau Van Khanh ◽  
Phạm Thanh Hien ◽  
Nguyen Thanh Thuy Nhien ◽  
Do Van Nguyen ◽  
...  
Keyword(s):  
Plasmodium Falciparum ◽  
Molecular Markers ◽  
Study Design ◽  
Plasmodium Falciparum Malaria ◽  
Parasite Clearance ◽  
Controlled Study ◽  
In Vivo Test ◽  
Number Variation

Dihydroartemisinin-piperaquine (DHA-PPQ) is a current frontline drug recommended in global by WHO for the treatment of Plasmodium falciparum malaria (WHO, 2015), but is now failing in Vietnam’s provinces where border Cambodia, and has emerged and spread. The purpose of this study was to evaluate the efficacy and molecular markers of DHA-PPQ failures in Dak Lak province. Methods: A study design of non-randomized controlled study design for the 42 day-course follow-up in vivo test, and the molecular markers analysis. Findings: The data showed that adequate clinical and parasitological response was sharply declined to 12,1%, the proportion of late clinical failure was 51.5%, and 36.4% of patients had late parasitological. The proportion of positive parasitemia at D3 was 37%, the slope half-life was 5.36 hrs, and the progressive parasite clearance (PC) PC50, PC75, PC 90, PC95, and PC99 were 13.24; 19.29; 25.69; 29.97 and 39.15 hours, respectively. Molecular markers of C580Y Kelch mutation were observed in 100% (50/50) of the patients, the increased of Plasmepsine 2 copy number variation (CNV) was 72% (36/50), and the proportion of patients who had both K13 and increased Plasmepsine 2 CNV was 72% (36/50). Conclusions: The DHA-PPQ efficacy severely decreased to 12.1%, overall treatment failure was 87.9% with the prominent C580Y mutant plus increased Plasmepsine 2 CNV in delayed asexual P. falciparum parasite clearance. These obvious data suggest the urgency to change antimalarial policy in DHA-PPQ resistance zones, especially in Dak Lak province.

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