A controlled human malaria infection model enabling evaluation of transmission-blocking interventions

Collins, Katharine A.; Wang, Claire; Adams, Matthew; Mitchell, Hayley; Rampton, Melanie; Elliott, Suzanne; Reuling, Isaie J.; Bousema, Teun; Sauerwein, Robert W.; Chalon, Stephan; Möhrle, Jörg J.; McCarthy, James S.

doi:10.1172/jci98012

Cited by 102 publications

(169 citation statements)

References 36 publications

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“…Total gametocyte density, quantified in venous blood by quantitative reverse transcriptase PCR (qRT-PCR) targeting female-specific Pfs25 mRNA and male-specific Pfmget mRNA (29), was positively associated with the proportion of mosquitoes that became infected following direct skin feeding (Spearman ρ=0.415, p=0.0204) or membrane feeding (Spearman ρ=0.596, p = 0.0004) (Figure 1A). The proportion of infected mosquitoes was higher by direct skin feeding as compared to membrane feeding assays (odds ratio 2.01; 95% CI 1.21 – 3.33, p = 0.007), in line with previous studies (9, 10, 30). The medium number of oocysts was 4 (IQR 2-7.5; maximum 38) for mosquitoes that became infected after feeding directly on the skin and 2 (IQR 1-5; maximum 24) for mosquitoes that became infected after feeding on venous blood through a membrane feeder.…”

Section: Resultssupporting

confidence: 90%

“…Again, we observed no evidence for higher concentrations of gametocytes in mosquitoes that fed directly on the skin of gametocyte donors compared to venous blood and observed a very strong association between gametocyte fractions from the different blood compartments. There must therefore be an alternative explanation for the higher infection rates that we, in line with other studies (9, 10), observed in direct skin feeding experiments compared to membrane feeding experiments using venous blood. Gametocyte activation may occur following phlebotomy and may reduce infection rates observed following membrane feeding.…”

Section: Discussionsupporting

confidence: 86%

“…Although heparin is the preferred anticoagulant (39), it may still have a disadvantageous impact on sporogonic development. In malaria-naïve individuals in whom P. falciparum gametocytes were induced during controlled human malaria infection studies, replacement of heparin plasma by serum resulted in increased mosquito infection rates (10). Since human immune responses are unlikely to be of relevance in these gametocytaemic volunteers, this observation provides additional indirect evidence for a transmission modulatory effect of heparin.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, mosquito infections have been observed from gametocyte donors whose low gametocyte density appears incompatible with transmission (8). Mosquito infection rates are typically higher when mosquitoes feed directly on the skin of gametocyte carriers, as compared to feeding on venous blood through an artificial membrane (9, 10). In addition to a strategic adjustment of gametocyte sex-ratio to maximize transmission success (7, 11, 12), gametocyte aggregation and sequestration may facilitate mosquito infections from low gametocyte densities.…”

Section: Introductionmentioning

confidence: 99%

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P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

Meibalan

Barry

et al. 2019

Preprint

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Transmission of Plasmodium falciparum depends on the presence of mature gametocytes that can be ingested by mosquitoes taking a bloodmeal when feeding on human skin. It has long been hypothesised that skin sequestration contributes to efficient transmission. Although skin sequestration would have major implications for our understanding of transmission biology and the suitability of mosquito feeding methodologies to measure the human infectious reservoir, it has never been formally tested. In two populations of naturally infected gametocyte carriers from Burkina Faso, we assessed transmission potential to mosquitoes and directly quantified male and female gametocytes and asexual parasites in: i) finger prick blood, ii) venous blood, iii) skin biopsies, and in pools of mosquitoes that fed iv) on venous blood or, v) directly on the skin. Whilst more mosquitoes became infected when feeding directly on the skin compared to venous blood, concentrations of gametocytes in the subdermal skin vasculature were identical to that in other blood compartments. Asexual parasite densities, gametocyte densities and sex ratios were identical in the mosquito blood meals taken directly from the skin of parasite carriers and their venous blood.We also observed sparse gametocytes in skin biopsies from legs and arms of gametocyte carriers by microscopy. Taken together, we provide conclusive evidence for the absence of significant skin sequestration of P. falciparum gametocytes. Gametocyte densities in peripheral blood are thus informative for predicting onward transmission potential to mosquitoes. Quantifying this human malaria transmission potential is of pivotal importance for the deployment and monitoring of malaria elimination initiatives.IMPORTANCEOur observations settle a long-standing question in the malaria field and close a major knowledge gap in the parasite cycle. By deploying mosquito feeding experiments and stage-specific molecular and immunofluorescence parasite detection methodologies in two populations of naturally infected parasite carriers, we conclusively reject the hypothesis of gametocyte skin sequestration. Our findings provide novel insights in parasite stage composition in human blood compartments, mosquito bloodmeals and their implications for transmission potential. We demonstrate that gametocyte levels in venous or finger prick blood can be used to predict onward transmission potential to mosquitoes. Our findings thus pave the way for methodologies to quantify the human infectious reservoir based on conventional blood sampling approaches to support the deployment and monitoring of malaria elimination efforts for maximum public health impact.

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Section: Resultssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

Meibalan

Barry

et al. 2019

Preprint

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“…Our observation that after adjusting for gametocyte density, the risk of mosquito infection was lower in incident infections suggests that gametocytes arising in the incident cohort were less mature at the time of feeding. The requirement for gametocyte maturation following release into the circulation would be in line with earlier in vitro observations that morphologically mature gametocytes may require several days of maturation to reach peak infectivity 45 and with findings in controlled human infections where infectivity is only observed several days after gametocyte densities plateau 46 .…”

Section: Discussionsupporting

confidence: 83%

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

Barry

Bradley

Guelbeogo

et al. 2020

Preprint

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30We longitudinally assessed P. falciparum parasite kinetics, gametocyte production and infectivity 31 in incident infections that were naturally acquired following infection clearance and in chronic 32 asymptomatic infections in Burkina Faso. 92% (44/48) of the incident cohort developed symptoms 33 and were treated within 35 days, compared to 23% (14/60) of the chronic cohort. All but two 34 individuals with chronic infection were gametocytaemic at enrollment, whereas only 35% (17/48) 35in the incident cohort developed gametocytes within 35 days. The relative abundance of ap2-g 36 transcripts was positively associated with conversion to gametocyte production (i.e. the ratio of 37 gametocytes at day 14 to ring stage parasites at baseline) and was higher in chronic infections. 38Parasite multiplication rate, assessed by daily molecular parasite quantification, was positively 39 associated with prospective gametocyte production. Most incident infections were cleared before 40 gametocyte density was sufficiently high to infect mosquitoes. In contrast, chronic, asymptomatic 41 infections represented a significant source of mosquito infections. If present, gametocytes were 42 significantly less infectious if concurrent with malaria symptoms. Our observations support the 43 notion that malaria transmission reduction may be expediated by enhanced case management, 44 involving both symptom-screening and infection detection.45 46 47 48The epidemiology of P. falciparum transmission stages, gametocytes, is poorly understood. 50Molecular diagnostics show that low density gametocyte carriage is highly prevalent in endemic 51 populations 1 and that many low density infections are infectious to mosquitoes 2 , explaining 52 observations from the 1950s that gametocyte free individuals (as determined by microscopy) 53 frequently infected mosquitoes 3 . Few assessments of the population infectious reservoir of 54 malaria parasites have been undertaken 4,5 , particularly with tools capable of detecting low 55 parasite and gametocyte densities 6,7 . Fewer still have been able to assess the association of 56 infectivity with factors other than parasite density, despite clear evidence that gametocyte 57 maturity 8,9 , intrinsic parasite factors 10,11 , human genetic factors 12 , and human clinical and immune 58 responses 13-15 can have significant influence on the effectiveness of parasite transmission. 59The association between malaria symptoms and gametocyte dynamics is particularly poorly 60 understood. Among similarly immune individuals, higher densities of pathogenic, asexual stage 61 malaria parasites are commonly associated with the presentation of symptoms 16 . Because 62 gametocytes develop from asexual parasites, individuals with clinical malaria and higher parasite 63 densities may have more gametocytes and be more likely to infect mosquitoes 17,18 . On the other 64 hand, the slower development of gametocytes may result in higher densities later in infections. 65This would result in higher gametocyte densities in infecti...

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2010 to 2020: Ten Years of Malaria Drug Discovery

Yeung

Calderón

2021

Burger's Medicinal Chemistry and Drug Discovery

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The seventh edition of Burger's Medicinal Chemistry, Drug Discovery and Development included an extensive review of antimalarial drugs and drug targets. Since it was published nearly 10 years ago, the annual number of deaths due to malaria in endemic countries have steadily declined. However, over the past two years, a stabilization in number of malaria deaths hints to a reversal of this trend. This may be in part due to parasite evolution to overcome efficacy of antimalarial therapies, including the now well‐established spread of resistance to artemisinin‐combination therapies in Southeast Asia. Fortunately, the last decade also witnessed a renewed effort by academic researchers, product development partnerships, and pharmaceutical companies to restart malaria drug discovery. Innovations in high‐throughput screening, assay development, access to large chemical libraries, advancements in parasite biology, and whole‐genome sequencing have resulted in the discovery of new antimalarial drugs as well as novel targets. These new drug candidates, which kill the parasite through new mechanisms of action have bolstered the malaria drug development pipeline since the last edition. This article summarizes the new drug discovery approaches and achievements over the past decade.

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A controlled human malaria infection model enabling evaluation of transmission-blocking interventions

Cited by 102 publications

References 36 publications

P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

P. falciparum gametocyte density and infectivity in peripheral blood and skin tissue of naturally infected parasite carriers

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

2010 to 2020: Ten Years of Malaria Drug Discovery

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