Developing transmission-blocking strategies for malaria control

Sinden, Robert E.

doi:10.1371/journal.ppat.1006336

Cited by 58 publications

(60 citation statements)

References 101 publications

(91 reference statements)

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“…The renewed focus on malaria elimination requires a thorough understanding of malaria transmission dynamics - when mature male and female gametocytes are first produced upon infection and how long they circulate in peripheral blood ( Sinden, 2017 ). These parameters are difficult to measure in naturally acquired infections where frequent super-infections, immunity and other factors dictate parasite and gametocyte dynamics ( Bousema and Drakeley, 2011 ).…”

Section: Introductionmentioning

confidence: 99%

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Reuling

Schans

Coffeng

et al. 2018

eLife

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Background Malaria elimination strategies require a thorough understanding of parasite transmission from human to mosquito. A clinical model to induce gametocytes to understand their dynamics and evaluate transmission-blocking interventions (TBI) is currently unavailable. Here, we explore the use of the well-established Controlled Human Malaria Infection model (CHMI) to induce gametocyte carriage with different antimalarial drug regimens. Methods In a single centre, open-label randomised trial, healthy malaria-naive participants (aged 18–35 years) were infected with Plasmodium falciparum by bites of infected Anopheles mosquitoes (ClinicalTrials.gov, NCT02836002). Participants were randomly allocated to four different treatment arms (n = 4 per arm) comprising low-dose (LD) piperaquine (PIP) or sulfadoxine-pyrimethamine (SP), followed by a curative regimen upon recrudescence. Male and female gametocyte densities were determined by molecular assays. Findings Mature gametocytes were observed in all participants (16/16, 100%). Gametocytes appeared 8.5–12 days after the first detection of asexual parasites. Peak gametocyte densities and gametocyte burden was highest in the LD-PIP/SP arm, and associated with the preceding asexual parasite biomass (p=0.026). Male gametocytes had a mean estimated circulation time of 2.7 days (95% CI 1.5–3.9) compared to 5.1 days (95% CI 4.1–6.1) for female gametocytes. Exploratory mosquito feeding assays showed successful sporadic mosquito infections. There were no serious adverse events or significant differences in the occurrence and severity of adverse events between study arms (p=0.49 and p=0.28). Conclusions The early appearance of gametocytes indicates gametocyte commitment during the first wave of asexual parasites emerging from the liver. Treatment by LD-PIP followed by a curative SP regimen, results in the highest gametocyte densities and the largest number of gametocyte-positive days. This model can be used to evaluate the effect of drugs and vaccines on gametocyte dynamics, and lays the foundation for fulfilling the critical unmet need to evaluate transmission-blocking interventions against falciparum malaria for downstream selection and clinical development. Funding PATH Malaria Vaccine Initiative (MVI)

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Section: Introductionmentioning

confidence: 99%

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Reuling

Schans

Coffeng

et al. 2018

eLife

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“…Firstly, the process of transmission from human to mosquito in the field typically results in the presence of <5 parasites (oocyst-stage) per mosquito [7] (although this figure is widely variable [8,9]). Conversely, in malaria infected humans, there are typically ~10 9 circulating parasites within the bloodstream, [10] resulting in an evident population bottleneck for the targeted killing of parasites within this stage of the lifecycle. Allied to this, sexually mature parasites are extracellular for ~24 hours in the 4 mosquito (compared to ~30 seconds in humans during merozoite invasion [11]), resulting in a larger window of opportunity to target the parasite for immune/pharmacological destruction.…”

Section: ) Targeting Malarial Transmission -Why?mentioning

confidence: 99%

“…The current stall in efforts to control malaria [1], reliance on a relatively narrow toolkit of clinical interventions, increasing risk of resistance to antimalarial drugs and insecticides [22,23], and the potential of transmission blocking interventions to complement (or synergise with) other anti-malarial control methods currently available, or in the later stages of a development pipeline (e.g. the preerythrocytic vaccine RTS,S) [10] renders this approach particularly opportune. A potential manner of interrupting parasitic transmission directly is by targeting Plasmodium using transmission-blocking interventions (TBIs).…”

Section: ) Targeting Malarial Transmission -Why?mentioning

confidence: 99%

Antimalarial Transmission-Blocking Interventions: Past, Present, and Future

Delves

Angrisano

Blagborough

2018

Trends in Parasitology

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Malaria remains a major global health challenge. Appropriate use of current antimalarial tools has reduced the disease burden, but morbidity and mortality remain unacceptably high. It is widely accepted that, to achieve long-term control/eradication, it will be necessary to use interventions that inhibit the transmission of parasites to mosquitoes - these tools are termed transmission-blocking interventions (TBIs). This article aims to outline the rationale for the development of TBIs, with a focus on transmission-blocking drugs and (parasite-derived) transmission-blocking vaccines. We describe and summarise the current status of each of these intervention classes and attempt to identify future requirements in development, with a focus on the challenges of establishing each method within an integrated malarial control programme in the future.

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“…For example, drugs acting as ecdysone or Bma-EcR antagonists may successfully arrest intramosquito filarial larval development. However, a potential but possibly circumventable difficulty in developing such drugs revolves around pharmacokinetics/pharmacodynamics (Pk/Pd) optimisation [ 55 ], regarding the inability to predetermine or influence the time frame between drug administration to patients and drug uptake by the haematophagous vectors in relation to the drug half-life, as well as the quantity of blood imbibed by the mosquitoes in relation to the volume of blood needed for effective drug action. Characterisation of the parasite- or vector-expressed surface molecules may also allow the isolation of potential transmission-blocking vaccine candidates [ 56 ].…”

Section: Emerging Prospects Of Achieving Lf Eradication Through Immentioning

confidence: 99%

Mosquitoes and the Lymphatic Filarial Parasites: Research Trends and Budding Roadmaps to Future Disease Eradication

Famakinde

2018

TropicalMed

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The mosquito-borne lymphatic filariasis (LF) is a parasitic, neglected tropical disease that imposes an unbearable human scourge. Despite the unprecedented efforts in mass drug administration (MDA) and morbidity management, achieving the global LF elimination slated for the year 2020 has been thwarted by limited MDA coverage and ineffectiveness in the chemotherapeutic intervention. Moreover, successful and sustainable elimination of mosquito-vectored diseases is often encumbered by reintroduction and resurgence emanating from human residual or new infections being widely disseminated by the vectors even when chemotherapy proves effective, but especially in the absence of effective vaccines. This created impetus for strengthening the current defective mosquito control approach, and profound research in vector–pathogen systems and vector biology has been pushing the boundaries of ideas towards developing refined vector-harnessed control strategies. Eventual implementation of these emerging concepts will offer a synergistic approach that will not only accelerate LF elimination, but also augurs well for its future eradication. This brief review focuses on advances in mosquito–filaria research and considers the emerging prospects for future eradication of LF.

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Developing transmission-blocking strategies for malaria control

Cited by 58 publications

References 101 publications

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

A randomized feasibility trial comparing four antimalarial drug regimens to induce Plasmodium falciparum gametocytemia in the controlled human malaria infection model

Antimalarial Transmission-Blocking Interventions: Past, Present, and Future

Mosquitoes and the Lymphatic Filarial Parasites: Research Trends and Budding Roadmaps to Future Disease Eradication

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