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  • 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
    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
    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
    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
    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
    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
    Griffin JT, Ferguson NM, Ghani AC, 2014,

    Estimates of the changing age-burden of Plasmodium falciparum malaria disease in sub-Saharan Africa

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

    Estimating the changing burden of malaria disease remains difficult owing to limitations inhealth reporting systems. Here, we use a transmission model incorporating acquisition andloss of immunity to capture age-specific patterns of disease at different transmissionintensities. The model is fitted to age-stratified data from 23 sites in Africa, and we thenproduce maps and estimates of disease burden. We estimate that in 2010 there were 252(95% credible interval: 171–353) million cases of malaria in sub-Saharan Africa that activecase finding would detect. However, only 34% (12–86%) of these cases would be observedthrough passive case detection. We estimate that the proportion of all cases of clinicalmalaria that are in under-fives varies from above 60% at high transmission to below 20% atlow transmission. The focus of some interventions towards young children may need to bereconsidered, and should be informed by the current local transmission intensity.

  • Journal article
    Marshall JM, White MT, Ghani AC, Schlein Y, Muller GC, Beier JCet al., 2013,

    Quantifying the mosquito's sweet tooth: modelling the effectiveness of attractive toxic sugar baits (ATSB) for malaria vector control

    , Malaria Journal, Vol: 12, ISSN: 1475-2875

    Background: Current vector control strategies focus largely on indoor measures, such as long-lasting insecticidetreated nets (LLINs) and indoor residual spraying (IRS); however mosquitoes frequently feed on sugar sourcesoutdoors, inviting the possibility of novel control strategies. Attractive toxic sugar baits (ATSB), either sprayed onvegetation or provided in outdoor bait stations, have been shown to significantly reduce mosquito densities inthese settings.Methods: Simple models of mosquito sugar-feeding behaviour were fitted to data from an ATSB field trial in Maliand used to estimate sugar-feeding rates and the potential of ATSB to control mosquito populations. The modeland fitted parameters were then incorporated into a larger integrated vector management (IVM) model to assessthe potential contribution of ATSB to future IVM programmes.Results: In the Mali experimental setting, the model suggests that about half of female mosquitoes fed on ATSBsolution per day, dying within several hours of ingesting the toxin. Using a model incorporating the number ofgonotrophic cycles completed by female mosquitoes, a higher sugar-feeding rate was estimated for youngermosquitoes than for older mosquitoes. Extending this model to incorporate other vector control interventionssuggests that an IVM programme based on both ATSB and LLINs may substantially reduce mosquito density andsurvival rates in this setting, thereby substantially reducing parasite transmission. This is predicted to exceed theimpact of LLINs in combination with IRS provided ATSB feeding rates are 50% or more of Mali experimental levels.In addition, ATSB is predicted to be particularly effective against Anopheles arabiensis, which is relatively exophilicand therefore less affected by IRS and LLINs.Conclusions: These results suggest that high coverage with a combination of LLINs and ATSB could result insubstantial reductions in malaria transmission in this setting. Further field studies of ATSB in other settings

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