Publications
381 results found
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.
Hodgson SH, Ewer KJ, Bliss CM, et al., 2015, Evaluation of the Efficacy of ChAd63-MVA Vectored Vaccines Expressing Circumsporozoite Protein and ME-TRAP Against Controlled Human Malaria Infection in Malaria-Naive Individuals, JOURNAL OF INFECTIOUS DISEASES, Vol: 211, Pages: 1076-1086, ISSN: 0022-1899
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- Citations: 98
Sinden RE, 2015, The cell biology of malaria infection of mosquito: advances and opportunities, CELLULAR MICROBIOLOGY, Vol: 17, Pages: 451-466, ISSN: 1462-5814
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- Citations: 44
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
Miguel-Blanco C, Lelievre J, Delves MJ, et al., 2015, Imaging-Based High-Throughput Screening Assay To Identify New Molecules with Transmission-Blocking Potential against Plasmodium falciparum Female Gamete Formation, Antimicrobial Agents and Chemotherapy, Vol: 59, Pages: 3298-3305, ISSN: 1098-6596
In response to a call for the global eradication of malaria, drug discovery has recently been extended to identify compounds that prevent the onward transmission of the parasite, which is mediated by Plasmodium falciparum stage V gametocytes. Lately, metabolic activity has been used in vitro as a surrogate for gametocyte viability; however, as gametocytes remain relatively quiescent at this stage, their ability to undergo onward development (gamete formation) may be a better measure of their functional viability. During gamete formation, female gametocytes undergo profound morphological changes and express translationally repressed mRNA. By assessing female gamete cell surface expression of one such repressed protein, Pfs25, as the readout for female gametocyte functional viability, we developed an imaging-based high-throughput screening (HTS) assay to identify transmission-blocking compounds. This assay, designated the P. falciparum female gametocyte activation assay (FGAA), was scaled up to a high-throughput format (Z′ factor, 0.7 ± 0.1) and subsequently validated using a selection of 50 known antimalarials from diverse chemical families. Only a few of these agents showed submicromolar 50% inhibitory concentrations in the assay: thiostrepton, methylene blue, and some endoperoxides. To determine the best conditions for HTS, a robustness test was performed with a selection of the GlaxoSmithKline Tres Cantos Antimalarial Set (TCAMS) and the final screening conditions for this library were determined to be a 2 μM concentration and 48 h of incubation with gametocytes. The P. falciparum FGAA has been proven to be a robust HTS assay faithful to Plasmodium transmission-stage cell biology, and it is an innovative useful tool for antimalarial drug discovery which aims to identify new molecules with transmission-blocking potential.
Marques SR, Ramakrishnan C, Carzaniga R, et al., 2015, An essential role of the basal body protein SAS-6 in <i>Plasmodium</i> male gamete development and malaria transmission, CELLULAR MICROBIOLOGY, Vol: 17, Pages: 191-206, ISSN: 1462-5814
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- Citations: 25
Malmquist NA, Sundriyal S, Caron J, et al., 2015, Histone Methyltransferase Inhibitors Are Orally Bioavailable, Fast-Acting Molecules with Activity against Different Species Causing Malaria in Humans, ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Vol: 59, Pages: 950-959, ISSN: 0066-4804
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- Citations: 37
Sala KA, Nishiura H, Upton LM, et al., 2015, The Plasmodium berghei sexual stage antigen PSOP12 induces anti-malarial transmission blocking immunity both in vivo and in vitro, Vaccine, Vol: 33, Pages: 437-445, ISSN: 1873-2518
Anti-malarial transmission-blocking vaccines (TBVs) aim to inhibit the transmission of Plasmodium from humans to mosquitoes by targeting the sexual/ookinete stages of the parasite. Successful use of such interventions will subsequently result in reduced cases of malarial infection within a human population, leading to local elimination. There are currently only five lead TBV candidates under examination. There is a consequent need to identify novel antigens to allow the formulation of new potent TBVs. Here we describe the design and evaluation of a potential TBV (BDES-PbPSOP12) targeting Plasmodium berghei PSOP12 based on the baculovirus dual expression system (BDES), enabling expression of antigens on the surface of viral particles and within infected mammalian cells. In silico studies have previously suggested that PSOP12 (Putative Secreted Ookinete Protein 12) is expressed within the sexual stages of the parasite (gametocytes, gametes and ookinetes), and is a member of the previously characterized 6-Cys family of plasmodial proteins. We demonstrate that PSOP12 is expressed within the sexual/ookinete forms of the parasite, and that sera obtained from mice immunized with BDES-PbPSOP12 can recognize the surface of the male and female gametes, and the ookinete stages of the parasite. Immunization of mice with BDES-PbPSOP12 confers modest but significant transmission-blocking activity in vivo by active immunization (53.1% reduction in oocyst intensity, 10.9% reduction in oocyst prevalence). Further assessment of transmission-blocking potency ex vivo shows a dose-dependent response, with up to a 76.4% reduction in intensity and a 47.2% reduction in prevalence observed. Our data indicates that PSOP12 in Plasmodium spp. could be a potential new TBV target candidate, and that further experimentation to examine the protein within human malaria parasites would be logical.
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
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
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
Mizutani M, Iyori M, Blagborough AM, et al., 2014, Baculovirus-Vectored Multistage <i>Plasmodium vivax</i> Vaccine Induces Both Protective and Transmission-Blocking Immunities against Transgenic Rodent Malaria Parasites, INFECTION AND IMMUNITY, Vol: 82, Pages: 4348-4357, ISSN: 0019-9567
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- Citations: 30
Talman AM, Prieto JH, Marques S, et al., 2014, Proteomic analysis of the <i>Plasmodium</i> male gamete reveals the key role for glycolysis in flagellar motility, MALARIA JOURNAL, Vol: 13
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- Citations: 37
Kan A, Tan Y-H, Angrisano F, et al., 2014, Quantitative analysis of Plasmodium ookinete motion in three dimensions suggests a critical role for cell shape in the biomechanics of malaria parasite gliding motility, Cellular Microbiology, Vol: 16, Pages: 734-750, ISSN: 1462-5822
Blagborough AM, Churcher T, Upton LM, et al., 2013, TRANSMISSION-BLOCKING INTERVENTIONS ELIMINATE MALARIA FROM LABORATORY POPULATIONS, PATHOGENS AND GLOBAL HEALTH, Vol: 107, Pages: 456-456, ISSN: 2047-7724
Churcher T, Basanez M-G, Blagborough A, et al., 2013, IS PARASITE DENSITY IMPORTANT IN MALARIA TRANSMISSION?, PATHOGENS AND GLOBAL HEALTH, Vol: 107, Pages: 450-451, ISSN: 2047-7724
Ewer KJ, O'Hara GA, Duncan CJA, et al., 2013, Protective CD8(+) T-cell immunity to human malaria induced by chimpanzee adenovirus-MVA immunisation, Nature Communications, Vol: 4, ISSN: 2041-1723
Induction of antigen-specific CD8 þ T cells offers the prospect of immunization against manyinfectious diseases, but no subunit vaccine has induced CD8 þ T cells that correlate withefficacy in humans. Here we demonstrate that a replication-deficient chimpanzee adenovirusvector followed by a modified vaccinia virus Ankara booster induces exceptionally high frequencyT-cell responses (median 42400 SFC/106 peripheral blood mononuclear cells) tothe liver-stage Plasmodium falciparum malaria antigen ME-TRAP. It induces sterile protectiveefficacy against heterologous strain sporozoites in three vaccinees (3/14, 21%), and delaystime to patency through substantial reduction of liver-stage parasite burden in five more(5/14, 36%), P ¼ 0.008 compared with controls. The frequency of monofunctional interferon-g-producingCD8 þ T cells, but not antibodies, correlates with sterile protectionand delay in time to patency (Pcorrected ¼ 0.005). Vaccine-induced CD8 þ T cells provideprotection against human malaria, suggesting that a major limitation of previous vaccinationapproaches has been the insufficient magnitude of induced T cells.
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
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.
Delves MJ, Ruecker A, Straschil U, et al., 2013, Male and female P. falciparum mature gametocytes show different responses to antimalarial drugs., Antimicrob Agents Chemother
It is the mature gametocytes of Plasmodium that are solely responsible for parasite transmission from the mammalian host to the mosquito. They are therefore a logical target for transmission blocking antimalarial interventions which aim to break the cycle of re-infection and reduce the prevalence of malaria cases. Gametocytes however are not a homogeneous cell population. They are sexually dimorphic, both males and females are required for parasite transmission. Using two bioassays, we have explored the effect of twenty antimalarials on the functional viability of both male and female mature gametocytes of Plasmodium falciparum. We show that mature male gametocytes (as reported by their ability to produce male gametes i.e. exflagellate) are sensitive to antifolates, some endoperoxides, methylene blue and thiostrepton with submicromolar IC50s, whereas female gametocytes (as reported by their ability to activate and form gametes expressing the marker Pfs25) are much less sensitive to antimalarial intervention with only methylene blue and thiostrepton showing any significant activity. These findings show firstly that the antimalarial response of both male and female gametocytes differ, and secondly the mature male gametocyte should be considered a more vulnerable target than the female gametocyte for transmission-blocking drugs. Given the female-biased sex ratio of Plasmodium falciparum (∼3-5 females : 1 male), current gametocyte assays without a sex-specific readout are unlikely to identify male-targeted compounds and prioritise them for further development. Both assays reported here are being scaled-up to at least medium throughput, and will permit identification of key transmission-blocking molecules overlooked by other screening campaigns.
Nilsen A, LaCrue AN, White KL, et al., 2013, Quinolone-3-Diarylethers: A New Class of Antimalarial Drug, SCIENCE TRANSLATIONAL MEDICINE, Vol: 5, ISSN: 1946-6234
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- Citations: 171
Oakes RD, Kurian D, Bromley E, et al., 2013, The rhoptry proteome of <i>Eimeria tenella</i> sporozoites, INTERNATIONAL JOURNAL FOR PARASITOLOGY, Vol: 43, Pages: 181-188, ISSN: 0020-7519
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- Citations: 41
Ramakrishnan C, Delves MJ, Lal K, et al., 2013, Laboratory maintenance of rodent malaria parasites., Malaria: Methods and Protocols, Editors: Ménard, Pages: 51-72
Blagborough AM, Delves MJ, Ramakrishnan C, et al., 2013, Assessing Transmission Blockade in Plasmodium spp., Malaria: Methods and Protocols, Editors: Ménard, Pages: 577-600
Sheehy SH, Duncan CJA, Elias SC, et al., 2012, ChAd63-MVA-vectored Blood-stage Malaria Vaccines Targeting MSP1 and AMA1: Assessment of Efficacy Against Mosquito Bite Challenge in Humans, MOLECULAR THERAPY, Vol: 20, Pages: 2355-2368, ISSN: 1525-0016
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- Citations: 160
Wass MN, Stanway R, Blagborough AM, et al., 2012, Proteomic analysis of Plasmodium in the mosquito: progress and pitfalls, Parasitology, Vol: 139, Pages: 1131-1145, ISSN: 1469-8161
Here we discuss proteomic analyses of whole cell preparations of the mosquito stages of malaria parasite development (i.e.gametocytes, microgamete, ookinete, oocyst and sporozoite) of Plasmodium berghei. We also include critiques of theproteomes of two cell fractions from the purified ookinete, namely the micronemes and cell surface. Whereas we summarisekey biological interpretations of the data, we also try to identify key methodological constraints we have met, only some ofwhich we were able to resolve. Recognising the need to translate the potential of current genome sequencing into functionalunderstanding, we report our efforts to develop more powerful combinations of methods for the in silico prediction ofprotein function and location. We have applied this analysis to the proteome of the male gamete, a cell whose very simplestructural organisation facilitated interpretation of data. Some of the in silico predictions made have now been supported byongoing protein tagging and genetic knockout studies. We hope this discussion may assist future studies.
Biagini GA, Fisher N, Shone AE, et al., 2012, Generation of quinolone antimalarials targeting the <i>Plasmodium falciparum</i> mitochondrial respiratory chain for the treatment and prophylaxis of malaria, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 109, Pages: 8298-8303, ISSN: 0027-8424
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- Citations: 119
Sinden RE, Carter R, Drakeley C, et al., 2012, The biology of sexual development of <i>Plasmodium</i>: the design and implementation of transmission-blocking strategies, MALARIA JOURNAL, Vol: 11
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- Citations: 50
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