Publications
135 results found
Churcher TS, Lissenden N, Griffin JT, et al., 2016, The impact of pyrethroid resistance on the efficacy and effectiveness of bednets for malaria control in Africa, eLife, Vol: 5, ISSN: 2050-084X
Long lasting pyrethroid treated bednets are the most important tool for preventing malaria. Pyrethroid resistant Anopheline mosquitoes are now ubiquitous in Africa though the public health impact remains unclear, impeding the deployment of more expensive nets. Meta-analyses of bioassay studies and experimental hut trials are used to characterise how pyrethroid resistance changes the efficacy of standard bednets, and those containing the synergist piperonyl butoxide (PBO), and assess its impact on malaria control. New bednets provide substantial personal protection until high levels of resistance though protection may wane faster against more resistant mosquito populations as nets age. Transmission dynamics models indicate that even low levels of resistance would increase the incidence of malaria due to reduced mosquito mortality and lower overall community protection over the life-time of the net. Switching to PBO bednets could avert up to 0.5 clinical cases per person per year in some resistance scenarios.
French MD, Churcher TS, Webster JP, et al., 2015, Estimation of changes in the force of infection for intestinal and urogenital schistosomiasis in countries with schistosomiasis control initiative-assisted programmes, PARASITES & VECTORS, Vol: 8, ISSN: 1756-3305
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- Citations: 14
White MT, Verity R, Churcher TS, et al., 2015, Vaccine approaches to malaria control and elimination: Insights from mathematical models, Vaccine, Vol: 33, Pages: 7544-7550, ISSN: 1873-2518
A licensed malaria vaccine would provide a valuable new tool for malaria control and elimination efforts.Several candidate vaccines targeting different stages ofthe malaria parasite’s lifecycle are currently underdevelopment, with one candidate, RTS,S/AS01 for the prevention of Plasmodium falciparum infection,having recently completed Phase III trials. Predicting the public health impact of a candidate malariavaccine requires using clinical trial data to estimate the vaccine’s efficacy profile—the initial efficacyfollowing vaccination and the pattern of waning of efficacy over time. With an estimated vaccine efficacyprofile, the effects of vaccination on malaria transmission can be simulated with the aid of mathematicalmodels.Here, we provide an overview of methods for estimating the vaccine efficacy profiles of pre-erythrocyticvaccines and transmission-blocking vaccines from clinicaltrial data. In the case of RTS,S/AS01, model estimatesfrom Phase II clinical trial data indicate a bi-phasic exponential profile of efficacy against infection,with efficacy waning rapidly in the first 6 months after vaccination followed by a slower rate of waningover the next 4 years. Transmission-blocking vaccines have yet to be tested in large-scale Phase II orPhase III clinical trials so we review ongoing work investigating how a clinical trial might be designed toensure that vaccine efficacy can be estimated with sufficient statistical power. Finally, we demonstratehow parameters estimated from clinical trials can be used to predict the impact of vaccination campaignson malaria using a mathematical model of malaria transmission
Baragana B, Hallyburton I, Lee MCS, et al., 2015, A novel multiple-stage antimalarial agent that inhibits protein synthesis, Nature, Vol: 522, Pages: 315-320, ISSN: 0028-0836
There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery.
Kapulu MC, Da DF, Miura K, et al., 2015, Comparative Assessment of Transmission-Blocking Vaccine Candidates against Plasmodium falciparum, Scientific Reports, Vol: 5, ISSN: 2045-2322
Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasiteswithin the mosquito, with the aim of preventing malaria transmission from one infected individual toanother. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leadingcandidate antigens, have been developed independently and have reported varied transmissionblockingactivities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modifiedvaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated.Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/cmice were boosted by the administration of MVA expressing the same antigen. These antibodiesexhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum inAnopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with antiPfs230-Cand anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibitionwas replicated against P. falciparum African field isolates in A. gambiae in direct membrane feedingassays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first headto-headcomparative analysis of leading antigens using two different parasite sources in two differentvector species, and can be used to guide selection of TBVs for future clinical development using theviral-vectored delivery platform.
Wu Y, Sinden RE, Churcher TS, et al., 2015, Development of malaria transmission-blocking vaccines: from concept to product., Advances in Parasitology, Publisher: Elsevier, Pages: 109-152, ISBN: 978-0-12-803301-2
Despite decades of effort battling against malaria, the disease is still a major cause of morbidity and mortality. Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. In the 1950s, Huff et al. first demonstrated the induction of transmission-blocking immunity in chickens by repeated immunizations with Plasmodium gallinaceum-infected red blood cells. Since then, significant progress has been made in identification of parasite antigens responsible for transmission-blocking activity. Recombinant technologies accelerated evaluation of these antigens as vaccine candidates, and it is possible to induce effective transmission-blocking immunity in humans both by natural infection and now by immunization with recombinant vaccines. This chapter reviews the efforts to produce TBVs, summarizes the current status and advances and discusses the remaining challenges and approaches.
Walker M, Specht S, Churcher TS, et al., 2015, Therapeutic Efficacy and Macrofilaricidal Activity of Doxycycline for the Treatment of River Blindness, CLINICAL INFECTIOUS DISEASES, Vol: 60, Pages: 1199-1207, ISSN: 1058-4838
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- Citations: 68
Delrieu I, Leboulleux D, Ivinson K, et al., 2015, Design of a Phase III cluster randomized trial to assess the efficacy and safety of a malaria transmission blocking vaccine, VACCINE, Vol: 33, Pages: 1518-1526, ISSN: 0264-410X
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- Citations: 29
Ouedraogo AL, Bastiaens GJH, Tiono AB, et al., 2015, Efficacy and Safety of the Mosquitocidal Drug Ivermectin to Prevent Malaria Transmission After Treatment: A Double-Blind, Randomized, Clinical Trial, CLINICAL INFECTIOUS DISEASES, Vol: 60, Pages: 357-365, ISSN: 1058-4838
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- Citations: 77
Churcher TS, Trape J-F, Cohuet A, 2015, Human-to-mosquito transmission efficiency increases as malaria is controlled, Nature Communications, Vol: 6, ISSN: 2041-1723
The efficiency of malaria transmission between human and mosquito has been shown to beinfluenced by many factors in the laboratory, although their impact in the field and how thischanges with disease endemicity are unknown. Here we estimate how human–mosquitotransmission changed as malaria was controlled in Dielmo, Senegal. Mathematical modelswere fit to data collected between 1990 and the start of vector control in 2008. Results showthat asexual parasite slide prevalence in humans has reduced from 70 to 20%, but that theproportion of infectious mosquitoes has remained roughly constant. Evidence suggests thatthis is due to an increase in transmission efficiency caused by a rise in gametocyte densities,although the uneven distribution of mosquito bites between hosts could also contribute. Theresilience of mosquito infection to changes in endemicity will have important implications forplanning disease control, and the development and deployment of transmission-reducinginterventions.
Walker M, Basanez M-G, Ouedraogo AL, et al., 2015, Improving statistical inference on pathogen densities estimated by quantitative molecular methods: malaria gametocytaemia as a case study, BMC BIOINFORMATICS, Vol: 16, ISSN: 1471-2105
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- Citations: 10
Upton LM, Brock PM, Churcher TS, et al., 2015, Lead Clinical and Preclinical Antimalarial Drugs Can Significantly Reduce Sporozoite Transmission to Vertebrate Populations, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 59, Pages: 490-497, ISSN: 0066-4804
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- Citations: 19
Kihara JH, Kutima HL, Ouma J, et al., 2015, Urogenital schistosomiasis in women of reproductive age and pregnant mothers in Kwale County, Kenya, JOURNAL OF HELMINTHOLOGY, Vol: 89, Pages: 105-111, ISSN: 0022-149X
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- Citations: 9
Da DF, Churcher TS, Yerbanga RS, et al., 2014, Experimental study of the relationship between Plasmodium gametocyte density and infection success in mosquitoes; implications for the evaluation of malaria transmission-reducing interventions, Experimental Parasitology, Vol: 149, Pages: 74-83, ISSN: 1090-2449
The evaluation of transmission reducing interventions (TRI) to control malaria widely uses membrane feeding assays. In such assays, the intensity of Plasmodium infection in the vector might affect the measured efficacy of the candidates to block transmission. Gametocyte density in the host blood is a determinant of the infection success in the mosquito, however, uncertain estimates of parasite densities and intrinsic characteristics of the infected blood can induce variability. To reduce this variation, a feasible method is to dilute infectious blood samples. We describe the effect of diluting samples of Plasmodium-containing blood samples to allow accurate relative measures of gametocyte densities and their impact on mosquito infectivity and TRI efficacy. Natural Plasmodium falciparum samples were diluted to generate a wide range of parasite densities, and fed to Anopheles coluzzii mosquitoes. This was compared with parallel dilutions conducted on Plasmodium berghei infections. We examined how blood dilution influences the observed blocking activity of anti-Pbs28 monoclonal antibody using the P. berghei/Anopheles stephensi system.In the natural species combination P. falciparum/An. coluzzii, blood dilution using heat-inactivated, infected blood as diluents, revealed positive near linear relationships, between gametocyte densities and oocyst loads in the range tested. A similar relationship was observed in the P. berghei/An. stephensi system when using a similar dilution method. In contrast, diluting infected mice blood with fresh uninfected blood dramatically increases the infectiousness. This suggests that highly infected mice blood contains inhibitory factors or reduced blood moieties, which impede infection and may in turn, lead to misinterpretation when comparing individual TRI evaluation assays. In the lab system, the transmission blocking activity of an antibody specific for Pbs28 was confirmed to be density-dependent. This highlights the need to carefully in
Turner HC, Walker M, French MD, et al., 2014, Neglected tools for neglected diseases: mathematical models in economic evaluations, TRENDS IN PARASITOLOGY, Vol: 30, Pages: 562-570, ISSN: 1471-4922
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- Citations: 24
Ruecker A, Mathias DK, Straschil U, et al., 2014, A Male and Female Gametocyte Functional Viability Assay To Identify Biologically Relevant Malaria Transmission-Blocking Drugs, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 58, Pages: 7292-7302, ISSN: 0066-4804
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- Citations: 93
Stone WJR, Churcher TS, Graumans W, et al., 2014, A Scalable Assessment of <i>Plasmodium falciparum</i> Transmission in the Standard Membrane-Feeding Assay, Using Transgenic Parasites Expressing Green Fluorescent Protein-Luciferase, JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 1456-1463, ISSN: 0022-1899
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- Citations: 37
Walker M, Churcher TS, Basanez M-G, 2014, Models for measuring anthelmintic drug efficacy for parasitologists, TRENDS IN PARASITOLOGY, Vol: 30, Pages: 528-537, ISSN: 1471-4922
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- Citations: 17
Turner HC, Walker M, Churcher TS, et al., 2014, Reaching the London Declaration on Neglected Tropical Diseases Goals for Onchocerciasis: An Economic Evaluation of Increasing the Frequency of Ivermectin Treatment in Africa, CLINICAL INFECTIOUS DISEASES, Vol: 59, Pages: 923-932, ISSN: 1058-4838
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- Citations: 69
Churcher TS, Cohen JM, Novotny J, et al., 2014, PUBLIC HEALTH Measuring the path toward malaria elimination, Science, Vol: 344, Pages: 1230-1232, ISSN: 0036-8075
In many parts of the world, malaria elimination—defined by the World Health Organization (WHO) as the absence of locally acquired malaria cases in the country—is being considered as a target because of recent successes in reducing disease burden (1, 2). Rigorous evaluation of malaria elimination programs is essential for financial and political support to be maintained. Yet such evaluation remains challenging, and appropriate metrics to ascertain “success” are needed.
Turner HC, Walker M, Churcher TS, et al., 2014, Modelling the impact of ivermectin on River Blindness and its burden of morbidity and mortality in African Savannah: EpiOncho projections, PARASITES & VECTORS, Vol: 7, ISSN: 1756-3305
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- Citations: 49
Yerbanga RS, Lucantoni L, Ouedraogo RK, et al., 2014, Transmission blocking activity of Azadirachta indica and Guiera senegalensis extracts on the sporogonic development of Plasmodium falciparum field isolates in Anopheles coluzzii mosquitoes, Parasites and Vectors, Vol: 7, Pages: 1-10, ISSN: 1756-3305
BackgroundTargeting the stages of the malaria parasites responsible for transmission from the human host to the mosquito vector is a key pharmacological strategy for malaria control. Research efforts to identify compounds that are active against these stages have significantly increased in recent years. However, at present, only two drugs are available, namely primaquine and artesunate, which reportedly act on late stage gametocytes.MethodsIn this study, we assessed the antiplasmodial effects of 5 extracts obtained from the neem tree Azadirachta indica and Guiera senegalensis against the early vector stages of Plasmodium falciparum, using field isolates. In an ex vivo assay gametocytaemic blood was supplemented with the plant extracts and offered to Anopheles coluzzii females by membrane feeding. Transmission blocking activity was evaluated by assessing oocyst prevalence and density on the mosquito midguts.ResultsInitial screening of the 5 plant extracts at 250 ppm revealed transmission blocking activity in two neem preparations. Up to a concentration of 70 ppm the commercial extract NeemAzal® completely blocked transmission and at 60 ppm mosquitoes of 4 out of 5 replicate groups remained uninfected. Mosquitoes fed on the ethyl acetate phase of neem leaves at 250 ppm showed a reduction in oocyst prevalence of 59.0% (CI95 12.0 - 79.0; p < 10-4) and in oocyst density of 90.5% (CI95 86.0 - 93.5; p < 10-4 ), while the ethanol extract from the same plant part did not exhibit any activity. No evidence of transmission blocking activity was found using G. senegalensis ethyl acetate extract from stem galls.ConclusionsThe results of this study highlight the potential of antimalarial plants for the discovery of novel transmission blocking molecules, and open up the potential of developing standardized transmission blocking herbal formulations as malaria control tools to complement currently used antimalarial drugs and combination treatment
Armistead JS, Morlais I, Mathias DK, et al., 2014, Antibodies to a single, conserved epitope in Anopheles APN1 inhibit universal transmission of Plasmodium falciparum and Plasmodium vivax malaria., Infect Immun, Vol: 82, Pages: 818-829
Malaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of the Plasmodium parasite, the Anopheles mosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission of Plasmodium falciparum and Plasmodium vivax across distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria.
Tchioffo MT, Boissiere A, Churcher TS, et al., 2013, Modulation of Malaria infection in anopheles gambiae mosquitoes exposed to natural midgut bacteria, PLoS One, Vol: 8, Pages: 1-9, ISSN: 1932-6203
The development of Plasmodium falciparum within the Anopheles gambiae mosquito relies on complex vector-parasite interactions, however the resident midgut microbiota also plays an important role in mediating parasite infection. In natural conditions, the mosquito microbial flora is diverse, composed of commensal and symbiotic bacteria. We report here the isolation of culturable midgut bacteria from mosquitoes collected in the field in Cameroon and their identification based on the 16S rRNA gene sequencing. We next measured the effect of selected natural bacterial isolates on Plasmodium falciparum infection prevalence and intensity over multiple infectious feedings and found that the bacteria significantly reduced the prevalence and intensity of infection. These results contrast with our previous study where the abundance of Enterobacteriaceae positively correlated with P. falciparum infection (Boissière et al. 2012). The oral infection of bacteria probably led to the disruption of the gut homeostasis and activated immune responses, and this pinpoints the importance of studying microbe-parasite interactions in natural conditions. Our results indicate that the effect of bacterial exposure on P. falciparum infection varies with factors from the parasite and the human host and calls for deeper dissection of these parameters for accurate interpretation of bacterial exposure results in laboratory settings.
French MD, Churcher TS, Basanez M-G, et al., 2013, Reductions in genetic diversity of <i>Schistosoma mansoni</i> populations under chemotherapeutic pressure: the effect of sampling approach and parasite population definition, ACTA TROPICA, Vol: 128, Pages: 196-205, ISSN: 0001-706X
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- Citations: 15
Williams AR, Zakutansky SE, Miura K, et al., 2013, Immunisation against a serine protease inhibitor reduces intensity of <i>Plasmodium berghei</i> infection in mosquitoes, INTERNATIONAL JOURNAL FOR PARASITOLOGY, Vol: 43, Pages: 869-874, ISSN: 0020-7519
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- Citations: 13
Turner HC, Osei-Atweneboana MY, Walker M, et al., 2013, The Cost of Annual versus Biannual Community-Directed Treatment of Onchocerciasis with Ivermectin: Ghana as a Case Study, PLOS NEGLECTED TROPICAL DISEASES, Vol: 7, ISSN: 1935-2735
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- Citations: 36
Churcher TS, Bousema T, Walker M, et al., 2013, Predicting mosquito infection from <i>Plasmodium falciparum</i> gametocyte density and estimating the reservoir of infection, ELIFE, Vol: 2, ISSN: 2050-084X
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- Citations: 142
Blagborough AM, Churcher TS, Upton LM, et al., 2013, Transmission-blocking interventions eliminate malaria from laboratory populations, Nature Communications, Vol: 4, ISSN: 2041-1723
Transmission-blocking interventions aim to reduce the prevalence of infection in endemic communities by targeting Plasmodium within the insect host. Although many studies have reported the successful reduction of infection in the mosquito vector, direct evidence that there is an onward reduction in infection in the vertebrate host is lacking. Here we report the first experiments using a population, transmission-based study of Plasmodium berghei in Anopheles stephensi to assess the impact of a transmission-blocking drug upon both insect and host populations over multiple transmission cycles. We demonstrate that the selected transmission-blocking intervention, which inhibits transmission from vertebrate to insect by only 32%, reduces the basic reproduction number of the parasite by 20%, and in our model system can eliminate Plasmodium from mosquito and mouse populations at low transmission intensities. These findings clearly demonstrate that use of transmission-blocking interventions alone can eliminate Plasmodium from a vertebrate population, and have significant implications for the future design and implementation of transmission-blocking interventions within the field.
Diawara A, Halpenny CM, Churcher TS, et al., 2013, Association between Response to Albendazole Treatment and β-Tubulin Genotype Frequencies in Soil-transmitted Helminths, PLOS NEGLECTED TROPICAL DISEASES, Vol: 7, ISSN: 1935-2735
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- Citations: 101
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