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  • Journal article
    White MT, Verity R, Churcher TS, Ghani ACet 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
  • Journal article
    Chertow JH, Alkaitis MS, Nardone G, Ikeda AK, Cunnington AJ, Okebe J, Ebonyi AO, Njie M, Correa S, Jayasooriya S, Casals-Pascual C, Billker O, Conway DJ, Walther M, Ackerman Het al., 2015,

    Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.

    , PLOS Pathogens, Vol: 11, ISSN: 1553-7366

    Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.
  • Journal article
    White MT, Verity R, Griffin JT, Asante KP, Owusu-Agyei S, Greenwood B, Drakeley C, Gesase S, Lusingu J, Ansong D, Adjei S, Agbenyega T, Ogutu B, Otieno L, Otieno W, Agnandji ST, Lell B, Kremsner P, Hoffman I, Martinson F, Kamthunzu P, Tinto H, Valea I, Sorgho H, Oneko M, Otieno K, Hamel MJ, Salim N, Mtoro A, Abdulla S, Aide P, Sacarlal J, Aponte JJ, Njuguna P, Marsh K, Bejon P, Riley EM, Ghani ACet al., 2015,

    Immunogenicity of the RTS,S/AS01 malaria vaccine and implications for duration of vaccine efficacy: secondary analysis of data from a phase 3 randomised controlled trial

    , Lancet Infectious Diseases, Vol: 15, Pages: 1450-1458, ISSN: 1473-3099

    BackgroundThe RTS,S/AS01 malaria vaccine targets the circumsporozoite protein, inducing antibodies associated with the prevention of Plasmodium falciparum infection. We assessed the association between anti-circumsporozoite antibody titres and the magnitude and duration of vaccine efficacy using data from a phase 3 trial done between 2009 and 2014.MethodsUsing data from 8922 African children aged 5–17 months and 6537 African infants aged 6–12 weeks at first vaccination, we analysed the determinants of immunogenicity after RTS,S/AS01 vaccination with or without a booster dose. We assessed the association between the incidence of clinical malaria and anti-circumsporozoite antibody titres using a model of anti-circumsporozoite antibody dynamics and the natural acquisition of protective immunity over time.FindingsRTS,S/AS01-induced anti-circumsporozoite antibody titres were greater in children aged 5–17 months than in those aged 6–12 weeks. Pre-vaccination anti-circumsporozoite titres were associated with lower immunogenicity in children aged 6–12 weeks and higher immunogenicity in those aged 5–17 months. The immunogenicity of the booster dose was strongly associated with immunogenicity after primary vaccination. Anti-circumsporozoite titres wane according to a biphasic exponential distribution. In participants aged 5–17 months, the half-life of the short-lived component of the antibody response was 45 days (95% credible interval 42–48) and that of the long-lived component was 591 days (557–632). After primary vaccination 12% (11–13) of the response was estimated to be long-lived, rising to 30% (28–32%) after a booster dose. An anti-circumsporozoite antibody titre of 121 EU/mL (98–153) was estimated to prevent 50% of infections. Waning anti-circumsporozoite antibody titres predict the duration of efficacy against clinical malaria across different age categories and transmission intensities, and effi
  • Journal article
    Haase S, Zimmermann D, Olshina MA, Wilkinson M, Fisher F, Tan YH, Stewart RJ, Tonkin CJ, Wong W, Kovar DR, Baum Jet al., 2015,

    Disassembly activity of actin depolymerization factor (ADF) is associated with distinct cellular processes in apicomplexan parasites.

    , Molecular Biology of the Cell, Vol: 26, Pages: 3001-3012, ISSN: 1939-4586

    Proteins of the actin depolymerizing factor (ADF)/cofilin family have been shown to be crucial for the motility and survival of apicomplexan parasites. However, the mechanisms by which ADF proteins fulfill their function remains poorly understood. In this study we sought to investigate the comparative activities of ADF proteins from Toxoplasma gondii and Plasmodium falciparum, the human malaria parasite, using a conditional T. gondii ADF-knockout line complemented with ADF variants from either species. We show that P. falciparum ADF1 can fully restore native TgADF activity, demonstrating functional conservation between parasites. Strikingly, mutation of a key basic residue (Lys(72)), previously implicated in disassembly in PfADF1, had no detectable phenotypic effect on parasite growth, motility or development. In contrast, organelle segregation was severely impaired when complementing with a TgADF mutant lacking the corresponding residue (Lys(68)). Biochemical analyses of each ADF protein confirmed the reduced ability of lysine mutants to mediate actin depolymerization via filament disassembly though not severing, in contrast to previous reports. These data suggest that actin filament disassembly is essential for apicomplexan parasite development but not for motility as well as pointing to genus-specific coevolution between ADF proteins and their native actin.
  • Journal article
    Cairns ME, Walker PGT, Okell LC, Griffin JT, Garske T, Asante KP, Owusu-Agyei S, Diallo D, Dicko A, Cisse B, Greenwood BM, Chandramohan D, Ghani AC, Milligan PJet al., 2015,

    Seasonality in malaria transmission: implications for case-management with long-acting artemisinin combination therapy in sub-Saharan Africa

    , Malaria Journal, Vol: 14, ISSN: 1475-2875

    Background: Long-acting artemisinin-based combination therapy (LACT) offers the potential to prevent recurrentmalaria attacks in highly exposed children. However, it is not clear where this advantage will be most important, anddeployment of these drugs is not rationalized on this basis.Methods: To understand where post-treatment prophylaxis would be most beneficial, the relationship betweenseasonality, transmission intensity and the interval between malaria episodes was explored using data from six cohortstudies in West Africa and an individual-based malaria transmission model. The total number of recurrent malariacases per 1000 child-years at risk, and the fraction of the total annual burden that this represents were estimated forsub-Saharan Africa.Results: In settings where prevalence is less than 10 %, repeat malaria episodes constitute a small fraction of thetotal burden, and few repeat episodes occur within the window of protection provided by currently available drugs.However, in higher transmission settings, and particularly in high transmission settings with highly seasonal transmis‑sion, repeat malaria becomes increasingly important, with up to 20 % of the total clinical burden in children estimatedto be due to repeat episodes within 4 weeks of a prior attack.Conclusion: At a given level of transmission intensity and annual incidence, the concentration of repeat malariaepisodes in time, and consequently the protection from LACT is highest in the most seasonal areas. As a result, thedegree of seasonality, in addition to the overall intensity of transmission, should be considered by policy makers whendeciding between ACT that differ in their duration of post-treatment prophylaxis.
  • Journal article
    Olshina MA, Angrisano F, Marapana DS, Riglar DT, Bane K, Wong W, Catimel B, Yin MX, Holmes AB, Frischknecht F, Kovar DR, Baum JACOBet al., 2015,

    Plasmodium falciparum coronin organizes arrays of parallel actin filaments potentially guiding directional motility in invasive malaria parasites

    , Malaria Journal, Vol: 14, ISSN: 1475-2875

    BackgroundGliding motility in Plasmodium parasites, the aetiological agents of malaria disease, is mediated by an actomyosin motor anchored in the outer pellicle of the motile cell. Effective motility is dependent on a parasite myosin motor and turnover of dynamic parasite actin filaments. To date, however, the basis for directional motility is not known. Whilst myosin is very likely orientated as a result of its anchorage within the parasite, how actin filaments are orientated to facilitate directional force generation remains unexplained. In addition, recent evidence has questioned the linkage between actin filaments and secreted surface antigens leaving the way by which motor force is transmitted to the extracellular milieu unknown. Malaria parasites possess a markedly reduced repertoire of actin regulators, among which few are predicted to interact with filamentous (F)-actin directly. One of these, PF3D7_1251200, shows strong homology to the coronin family of actin-filament binding proteins, herein referred to as PfCoronin.MethodsHere the N terminal beta propeller domain of PfCoronin (PfCor-N) was expressed to assess its ability to bind and bundle pre-formed actin filaments by sedimentation assay, total internal reflection fluorescence (TIRF) microscopy and confocal imaging as well as to explore its ability to bind phospholipids. In parallel a tagged PfCoronin line in Plasmodium falciparum was generated to determine the cellular localization of the protein during asexual parasite development and blood-stage merozoite invasion.ResultsA combination of biochemical approaches demonstrated that the N-terminal beta-propeller domain of PfCoronin is capable of binding F-actin and facilitating formation of parallel filament bundles. In parasites, PfCoronin is expressed late in the asexual lifecycle and localizes to the pellicle region of invasive merozoites before and during erythrocyte entry. PfCoronin also associates strongly with membranes within the cell, likely medi
  • Journal article
    Wilson DW, Goodman CD, Sleebs BE, Weiss GE, de Jong NWM, Angrisano F, Langer C, Baum J, Crabb BS, Gilson PR, McFadden GI, Beeson JGet al., 2015,

    Macrolides rapidly inhibit red blood cell invasion by the human malaria parasite, Plasmodium falciparum

    , BMC Biology, Vol: 13, ISSN: 1741-7007

    Background: Malaria invasion of red blood cells involves multiple parasite-specific targets that are easily accessibleto inhibitory compounds, making it an attractive target for antimalarial development. However, no current antimalarialagents act against host cell invasion.Results: Here, we demonstrate that the clinically used macrolide antibiotic azithromycin, which is known to kill humanmalaria asexual blood-stage parasites by blocking protein synthesis in their apicoplast, is also a rapid inhibitor of redblood cell invasion in human (Plasmodium falciparum) and rodent (P. berghei) malarias. Multiple lines of evidencedemonstrate that the action of azithromycin in inhibiting parasite invasion of red blood cells is independent ofits inhibition of protein synthesis in the parasite apicoplast, opening up a new strategy to develop a single drugwith multiple parasite targets. We identified derivatives of azithromycin and erythromycin that are better invasioninhibitors than parent compounds, offering promise for development of this novel antimalarial strategy.Conclusions: Safe and effective macrolide antibiotics with dual modalities could be developed to combat malariaand reduce the parasite’s options for resistance.
  • Journal article
    Walker PGT, White MT, Griffin JT, Reynolds A, Ferguson NM, Ghani ACet al., 2015,

    Malaria morbidity and mortality in Ebola-affected countries caused by decreased health-care capacity, and the potential effect of mitigation strategies: a modelling analysis

    , Lancet Infectious Diseases, Vol: 15, Pages: 825-832, ISSN: 1473-3099

    BackgroundThe ongoing Ebola epidemic in parts of west Africa largely overwhelmed health-care systems in 2014, making adequate care for malaria impossible and threatening the gains in malaria control achieved over the past decade. We quantified this additional indirect burden of Ebola virus disease.MethodsWe estimated the number of cases and deaths from malaria in Guinea, Liberia, and Sierra Leone from Demographic and Health Surveys data for malaria prevalence and coverage of malaria interventions before the Ebola outbreak. We then removed the effect of treatment and hospital care to estimate additional cases and deaths from malaria caused by reduced health-care capacity and potential disruption of delivery of insecticide-treated bednets. We modelled the potential effect of emergency mass drug administration in affected areas on malaria cases and health-care demand.FindingsIf malaria care ceased as a result of the Ebola epidemic, untreated cases of malaria would have increased by 45% (95% credible interval 43–49) in Guinea, 88% (83–93) in Sierra Leone, and 140% (135–147) in Liberia in 2014. This increase is equivalent to 3·5 million (95% credible interval 2·6 million to 4·9 million) additional untreated cases, with 10 900 (5700–21 400) additional malaria-attributable deaths. Mass drug administration and distribution of insecticide-treated bednets timed to coincide with the 2015 malaria transmission season could largely mitigate the effect of Ebola virus disease on malaria.InterpretationThese findings suggest that untreated malaria cases as a result of reduced health-care capacity probably contributed substantially to the morbidity caused by the Ebola crisis. Mass drug administration can be an effective means to mitigate this burden and reduce the number of non-Ebola fever cases within health systems.
  • Journal article
    Cunnington A, Orf K, 2015,

    Infection-related hemolysis and susceptibility to Gram-negative bacterial co-infection

    , Frontiers in Microbiology, Vol: 6, ISSN: 1664-302X

    Increased susceptibility to co-infection with enteric Gram-negative bacteria, particularly non-typhoidal Salmonella, is reported in malaria and Oroya fever (Bartonella bacilliformis infection), and can lead to increased mortality. Accumulating epidemiological evidence indicates a causal association with risk of bacterial co-infection, rather than just co-incidence of common risk factors. Both malaria and Oroya fever are characterised by hemolysis, and observations in humans and animal models suggest that hemolysis causes the susceptibility to bacterial co-infection. Evidence from animal models implicates hemolysis in the impairment of a variety of host defence mechanisms, including macrophage dysfunction, neutrophil dysfunction and impairment of adaptive immune responses. One mechanism supported by evidence from animal models and human data, is the induction of heme oxygenase-1 in bone marrow, which impairs the ability of developing neutrophils to mount a competent oxidative burst. As a result, dysfunctional neutrophils become a new niche for replication of intracellular bacteria. Here we critically appraise and summarize the key evidence for mechanisms which may contribute to these very specific combinations of co-infections, and propose interventions to ameliorate this risk.
  • Journal article
    Malmquist NA, Sundriyal S, Caron J, Chen P, Witkowski B, Menard D, Suwanarusk R, Renia L, Nosten F, Belen Jimenez-Diaz M, Angulo-Barturen I, Santos Maritnez M, Ferrer S, Sanz LM, Gamo F-J, Wittlin S, Duffy S, Avery VM, Ruecker A, Delves MJ, Sinden RE, Fuchter MJ, Scherf Aet 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
  • Journal article
    Griffin JT, Hollingsworth TD, Reyburn H, Drakeley CJ, Riley EM, Ghani ACet al., 2015,

    Gradual acquisition of immunity to severe malaria with increasing exposure

    , Proceedings of the Royal Society B: Biological Sciences, Vol: 282, ISSN: 0962-8452
  • Journal article
    Upton LM, Brock PM, Churcher TS, Ghani AC, Gething PW, Delves MJ, Sala KA, Leroy D, Sinden RE, Blagborough AMet 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
  • Journal article
    Cunnington AJ, 2015,

    The Importance of Pathogen Load

    , PLOS PATHOGENS, Vol: 11, ISSN: 1553-7366
  • Journal article
    Castellano L, Rizzi E, Krell J, Di Cristina M, Galizi R, Mori A, Tam J, De Bellis G, Stebbing J, Crisanti A, Nolan Tet al., 2015,

    The germline of the malaria mosquito produces abundant miRNAs, endo-siRNAs, piRNAs and 29-nt small RNAs

    , Bmc Genomics, Vol: 16
  • Journal article
    Neafsey DE, Waterhouse RM, Abai MR, Aganezov SS, Alekseyev MA, Allen JE, Amon J, Arca B, Arensburger P, Artemov G, Assour LA, Basseri H, Berlin A, Birren BW, Blandin SA, Brockman AI, Burkot TR, Burt A, Chan CS, Chauve C, Chiu JC, Christensen M, Costantini C, Davidson VLM, Deligianni E, Dottorini T, Dritsou V, Gabriel SB, Guelbeogo WM, Hall AB, Han MV, Hlaing T, Hughes DST, Jenkins AM, Jiang X, Jungreis I, Kakani EG, Kamali M, Kemppainen P, Kennedy RC, Kirmitzoglou IK, Koekemoer LL, Laban N, Langridge N, Lawniczak MKN, Lirakis M, Lobo NF, Lowy E, MacCallum RM, Mao C, Maslen G, Mbogo C, McCarthy J, Michel K, Mitchell SN, Moore W, Murphy KA, Naumenko AN, Nolan T, Novoa EM, O Loughlin S, Oringanje C, Oshaghi MA, Pakpour N, Papathanos PA, Peery AN, Povelones M, Prakash A, Price DP, Rajaraman A, Reimer LJ, Rinker DC, Rokas A, Russell TL, Sagnon NF, Sharakhova MV, Shea T, Simao FA, Simard F, Slotman MA, Somboon P, Stegniy V, Struchiner CJ, Thomas GWC, Tojo M, Topalis P, Tubio JMC, Unger MF, Vontas J, Walton C, Wilding CS, Willis JH, Wu Y-C, Yan G, Zdobnov EM, Zhou X, Catteruccia F, Christophides GK, Collins FH, Cornman RS, Crisanti A, Donnelly MJ, Emrich SJ, Fontaine MC, Gelbart W, Hahn MW, Hansen IA, Howell PI, Kafatos FC, Kellis M, Lawson D, Louis C, Luckhart S, Muskavitch MAT, Ribeiro JM, Riehle MA, Sharakhov IV, Tu Z, Zwiebel LJ, Besansky NJet al., 2015,

    Highly evolvable malaria vectors: The genomes of 16 Anopheles mosquitoes

    , Science, Vol: 347
  • Journal article
    Volohonsky G, Terenzi O, Soichot J, Naujoks DA, Nolan T, Windbichler N, Kapps D, Smidler AL, Vittu A, Costa G, Steinert S, Levashina EA, Blandin SA, Marois Eet al., 2015,

    Tools for Anopheles gambiae Transgenesis

    , G3-Genes Genomes Genetics, Vol: 5, Pages: 1151-1163
  • Journal article
    Slater HC, Walker PGT, Bousema T, Okell LC, Ghani ACet al., 2014,

    The Potential Impact of Adding Ivermectin to a Mass Treatment Intervention to Reduce Malaria Transmission: A Modelling Study

    , JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 1972-1980, ISSN: 0022-1899
  • Journal article
    Bousema T, Okell L, Felger I, Drakeley Cet al., 2014,

    Asymptomatic malaria infections: detectability, transmissibility and public health relevance

    , NATURE REVIEWS MICROBIOLOGY, Vol: 12, Pages: 833-840, ISSN: 1740-1526
  • Journal article
    White MT, Karl S, Battle K, Hay SI, Mueller I, Ghani ACet al., 2014,

    Modelling the contribution of the hypnozoite reservoir to Plasmodium vivax transmission

    , eLife, Vol: 3, ISSN: 2050-084X

    Plasmodium vivax relapse infections occur following activation of latent liver-stagesparasites (hypnozoites) causing new blood-stage infections weeks to months after the initialinfection. We develop a within-host mathematical model of liver-stage hypnozoites, and validateit against data from tropical strains of P. vivax. The within-host model is embedded in a P. vivaxtransmission model to demonstrate the build-up of the hypnozoite reservoir following newinfections and its depletion through hypnozoite activation and death. The hypnozoite reservoiris predicted to be over-dispersed with many individuals having few or no hypnozoites, and somehaving intensely infected livers. Individuals with more hypnozoites are predicted to experiencemore relapses and contribute more to onwards P. vivax transmission. Incorporating hypnozoitekilling drugs such as primaquine into first-line treatment regimens is predicted to cause substantialreductions in P. vivax transmission as individuals with the most hypnozoites are more likely torelapse and be targeted for treatment.
  • Journal article
    Okell LC, Cairns M, Griffin JT, Ferguson NM, Tarning J, Jagoe G, Hugo P, Baker M, D'Alessandro U, Bousema T, Ubben D, Ghani ACet al., 2014,

    Contrasting benefits of different artemisinin combination therapies as first-line malaria treatments using model-based cost-effectiveness analysis

    , Nature Communications, Vol: 5, ISSN: 2041-1723

    There are currently several recommended drug regimens for uncomplicated falciparummalaria in Africa. Each has different properties that determine its impact on diseaseburden. Two major antimalarial policy options are artemether–lumefantrine (AL) anddihydroartemisinin–piperaquine (DHA–PQP). Clinical trial data show that DHA–PQP provideslonger protection against reinfection, while AL is better at reducing patient infectiousness.Here we incorporate pharmacokinetic-pharmacodynamic factors, transmission-reducingeffects and cost into a mathematical model and simulate malaria transmission and treatmentin Africa, using geographically explicit data on transmission intensity and seasonality,population density, treatment access and outpatient costs. DHA–PQP has a modestly higherestimated impact than AL in 64% of the population at risk. Given current higher costestimates for DHA–PQP, there is a slightly greater cost per case averted, except in areas withhigh, seasonally varying transmission where the impact is particularly large. We find that alocally optimized treatment policy can be highly cost effective for reducing clinical malariaburden.
  • Journal article
    Takem EN, Roca A, Cunnington A, 2014,

    The association between malaria and non-typhoid Salmonella bacteraemia in children in sub-Saharan Africa: a literature review

    , MALARIA JOURNAL, Vol: 13, ISSN: 1475-2875
  • Journal article
    White MT, Griffin JT, Akpogheneta O, Conway DJ, Koram KA, Riley EM, Ghani ACet al., 2014,

    Dynamics of the Antibody Response to <i>Plasmodium falciparum</i> Infection in African Children

    , JOURNAL OF INFECTIOUS DISEASES, Vol: 210, Pages: 1115-1122, ISSN: 0022-1899
  • Journal article
    Sundriyal S, Malmquist NA, Caron J, Blundell S, Liu F, Chen X, Srimongkolpithak N, Jin J, Charman SA, Scherf A, Fuchter MJet al., 2014,

    Development of Diaminoquinazoline Histone Lysine Methyltransferase Inhibitors as Potent Blood-Stage Antimalarial Compounds

    , CHEMMEDCHEM, Vol: 9, Pages: 2360-2373, ISSN: 1860-7179
  • Journal article
    Pinsent A, Read JM, Griffin JT, Smith V, Gething PW, Ghani AC, Pasvol G, Hollingsworth DTet al., 2014,

    Risk factors for UK Plasmodium falciparum cases

    , Malaria Journal, Vol: 13
  • Journal article
    Imai N, White MT, Ghani AC, Drakeley CJet al., 2014,

    Transmission and Control of Plasmodium knowlesi: A Mathematical Modelling Study

    , PLOS Neglected Tropical Diseases, Vol: 8, ISSN: 1935-2735

    Introduction: Plasmodium knowlesi is now recognised as a leading cause of malaria in Malaysia. As humans come intoincreasing contact with the reservoir host (long-tailed macaques) as a consequence of deforestation, assessing the potentialfor a shift from zoonotic to sustained P. knowlesi transmission between humans is critical.Methods: A multi-host, multi-site transmission model was developed, taking into account the three areas (forest, farm, andvillage) where transmission is thought to occur. Latin hypercube sampling of model parameters was used to identifyparameter sets consistent with possible prevalence in macaques and humans inferred from observed data. We then explorethe consequences of increasing human-macaque contact in the farm, the likely impact of rapid treatment, and the use oflong-lasting insecticide-treated nets (LLINs) in preventing wider spread of this emerging infection.Results: Identified model parameters were consistent with transmission being sustained by the macaques with spill over infectionsinto the human population and with high overall basic reproduction numbers (up to 2267). The extent to which macaques foragein the farms had a non-linear relationship with human infection prevalence, the highest prevalence occurring when macaquesforage in the farms but return frequently to the forest where they experience higher contact with vectors and hence sustaintransmission. Only one of 1,046 parameter sets was consistent with sustained human-to-human transmission in the absence ofmacaques, although with a low human reproduction number (R0H = 1.04). Simulations showed LLINs and rapid treatment providepersonal protection to humans with maximal estimated reductions in human prevalence of 42% and 95%, respectively.Conclusion: This model simulates conditions where P. knowlesi transmission may occur and the potential impact of controlmeasures. Predictions suggest that conventional control measures are sufficient at reducing the risk of infection in humans
  • Journal article
    Walker PGT, ter Kuile FO, Garske T, Menendez C, Ghani ACet al., 2014,

    Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study

    , Lancet Global Health, Vol: 2, Pages: E460-E467, ISSN: 2214-109X
  • Journal article
    White MT, Bejon P, Olotu A, Griffin JT, Bojang K, Lusingu J, Salim N, Abdulla S, Otsyula N, Agnandji ST, Lell B, Asante KP, Owusu-Agyei S, Mahama E, Agbenyega T, Ansong D, Sacarlal J, Aponte JJ, Ghani ACet al., 2014,

    A combined analysis of immunogenicity, antibody kinetics and vaccine efficacy from phase 2 trials of the RTS,S malaria vaccine

    , BMC Medicine, Vol: 12, ISSN: 1741-7015

    Background: The RTS,S malaria vaccine is currently undergoing phase 3 trials. High vaccine-induced antibody titresto the circumsporozoite protein (CSP) antigen have been associated with protection from infection and episodes ofclinical malaria.Methods: Using data from 5,144 participants in nine phase 2 trials, we explore predictors of vaccine immunogenicity(anti-CSP antibody titres), decay in antibody titres, and the association between antibody titres and clinical outcomes.We use empirically-observed relationships between these factors to predict vaccine efficacy in a range of scenarios.Results: Vaccine-induced anti-CSP antibody titres were significantly associated with age (P = 0.04), adjuvant (P <0.001),pre-vaccination anti-hepatitis B surface antigen titres (P = 0.005) and pre-vaccination anti-CSP titres (P <0.001).Co-administration with other vaccines reduced anti-CSP antibody titres although not significantly (P = 0.095).Antibody titres showed a bi-phasic decay over time with an initial rapid decay in the first three months and asecond slower decay over the next three to four years. Antibody titres were significantly associated with protection,with a titre of 51 (95% Credible Interval (CrI): 29 to 85) ELISA units/ml (EU/mL) predicted to prevent 50% of infections inchildren. Vaccine efficacy was predicted to decline to zero over four years in a setting with entomological inoculationrate (EIR) = 20 infectious bites per year (ibpy). Over a five-year follow-up period at an EIR = 20 ibpy, we predict RTS,S willavert 1,782 cases per 1,000 vaccinated children, 1,452 cases per 1,000 vaccinated infants, and 887 cases per 1,000 infantswhen co-administered with expanded programme on immunisation (EPI) vaccines. Our main study limitations includean absence of vaccine-induced cellular immune responses and short duration of follow-up in some individuals.Conclusions: Vaccine-induced anti-CSP antibody titres and transmission intensity can explain variations in observedva
  • Journal article
    Dasgupta S, Auth T, Gov NS, Satchwell TJ, Hanssen E, Zuccala ES, Riglar DT, Toye AM, Betz T, Baum J, Gompper Get al., 2014,

    Membrane-Wrapping Contributions to Malaria Parasite Invasion of the Human Erythrocyte

    , BIOPHYSICAL JOURNAL, Vol: 107, Pages: 43-54, ISSN: 0006-3495
  • Journal article
    Wong W, Bai X-C, Brown A, Fernandez IS, Hanssen E, Condron M, Tan YH, Baum J, Scheres SHWet al., 2014,

    Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine

    , eLife, Vol: 3, Pages: 1-20, ISSN: 2050-084X

    Malaria inflicts an enormous burden on global human health. The emergence of parasite resistance to front-line drugs has prompted a renewed focus on the repositioning of clinically approved drugs as potential anti-malarial therapies. Antibiotics that inhibit protein translation are promising candidates for repositioning. We have solved the cryo-EM structure of the cytoplasmic ribosome from the human malaria parasite, Plasmodium falciparum, in complex with emetine at 3.2 Å resolution. Emetine is an anti-protozoan drug used in the treatment of ameobiasis that also displays potent anti-malarial activity. Emetine interacts with the E-site of the ribosomal small subunit and shares a similar binding site with the antibiotic pactamycin, thereby delivering its therapeutic effect by blocking mRNA/tRNA translocation. As the first cryo-EM structure that visualizes an antibiotic bound to any ribosome at atomic resolution, this establishes cryo-EM as a powerful tool for screening and guiding the design of drugs that target parasite translation machinery.
  • Journal article
    Kan A, Tan Y-H, Angrisano F, Hanssen E, Rogers KL, Whitehead L, Mollard VP, Cozijnsen A, Delves MJ, Crawford S, Sinden RE, McFadden GI, Leckie C, Bailey J, Baum Jet 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

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