11/12/2019 Malaria Transmission: • Malaria – current state of play • Malaria infections – more than wethought When a little isE nough • Malaria transmission – the infectiousreservoir • Transmission reduction – targeting infectivity Chris Drakeley • Conclusions London School of Hygiene & Tropical Medicine,UK 1 4 Malaria – the current s tate of play Disclaimer Fever in children Treatment sought Fevernot managed Trends of declining malaria – linkedto Neither intervention is at optimalcoverage increasing net coverage and provision ofACT Bhatt et al , Nature2015 2 5 Malaria – the current s tate of play • Malaria – current state of play • Malaria infections – more than wethought • Malaria transmission – the infectiousreservoir • Transmission reduction – targeting infectivity • Conclusions • Artemisinin resistance –increased parasite clearancetime • Insecticide resistance widespread in S S Africa Ranson et al., Trends Parasitol 2016; TRAC, NEJM2014 3 6 1
11/12/2019 Malaria infections : The more you look the more you Malaria – the current s tate of play see… WHO World Malaria Report2018 Current investment is insufficient • Large number of studies (n=~300) with siginifcantly less per personat reporting infections beneath the limitof risk invested now thanpreviously microscopy and latterly RDT • Nucleic acid amplification tests (NAA T) such as P C R detect at least twice asmany infections asmicroscopy or RDT Bending the curve • Sensitivity of microscopy increaseswith P C Rprevalence Alternative strategiesand targeting transmission 3 Whittaker et al under review 7 10 Malaria infections: S ubmicroscopic infections and age • Malaria – current state of play Microscopy • Malaria infections – more than wethought • Malaria transmission – the infectiousreservoir • Transmission reduction – targeting infectivity • Conclusions RD T under 5yrs 6-15yrs 15yrs+ Both Microscopy and RDT sensitivity is decreased in older agegroups Ok ll N t C 2013 W N t 2015 8 11 Malaria infections: submicroscopic infections and Malariainfections transmission level Microscopy • Do we unders tand enough about natural infections and their infectivity? RD T 5% 5-20% 20-50% • Symptomatic – readily detectablewith concurrent symptoms • Asymptomatic –no symptoms atthe time of sampling • Patent/detectable by RDT or microscopy (~100 parasites/ul) • Subpatent/submicroscopic – infections that are below thelimit Both RDT and microscopy show more discordance at lower transmissionlevels of detection of conventional diagnostics Okell Nature Comms 2013, Wu Nature 2015 9 12 2
11/12/2019 Malaria Transmission: gametocyte density & infection • Many submicroscopic gametocyte carriers • Malaria – current state of play infect mosquitoes • Malaria infections – more than wethought • Infection rates increase above~5 gametocytes/ μ L • Malaria transmission – the infectiousreservoir • Estimating male and femalegametocytes • Transmission reduction – targeting infectivity improves prediction of infectionrates • Conclusions • Deviation from the best fit association is indication of reduced infectivity (immunity & drugs) Goncalves et al, Nature Comm 2017; Bradley et al. eLife 2018 13 16 Malaria transmission: S ex &Drugs Malaria transmission: gametocytes • The vast majority of asymptomatic infectionshave gametocytes • Antimalarial drugs have varying • Specifically detecting gametocytes may havelimited effects on gametocytes utility • ACT have markedeffect • G ametocyte density loosely associated with asexual parasitaemia • Gametocyte densities highest in younger agegroups AFRICA Methylene blue appears to affect male gametocytes andPrimaquine females ASIA Bousema CMR 2011, Roh Lancet ID2018 WWARN, BMC Med 2016; Goncalves et al, Nature Comm2017 Parasites/µl Haemoglobin g/dL 14 17 Malaria Transmission: assessing infectiousnessto mosquitoes The infectious reservoir of malaria • Measurement of infectiousness istypically done using mosquito feeding experiments Do submicroscopic infections • Colony (or rarely F1) mosquitoes fed onblood contribute to the infectious from potentially infectiousindividuals reservoir ? • Mosquitoes dissected 7 days later for presence of infection • Because of the relative logistical complexity these studies are comparatively rare and on small numbers of samples. Stone et al. Trends Parasitol 2017 15 18 3
11/12/2019 Malaria transmission: historical reservoir estimates Malaria transmission: questionsremain… • More data are needed from low endemic sites (ideally combinedwith transmission networks at molecular level) • Longitudinal data on parasite kinetics and infectiousness of natural infections remain limited • Whilst mosquito biting is higher in adults there aresignificant variations within household and between season • Variability in transmissibility of parasiteclones • Laboratory data suggest mosquitoes with more oocysts aremore infectious 19 22 Malaria transmission: recent reservoirestimates • Cross sectional surveys in wet and dry season with mosquitofeeding (Burkina Faso,Kenya) • Malaria – current state of play • Assesments of natural mosquito biting rates • Malaria infections – more than wethought Before After adjustment forbites Mosquito bitingrates • Malaria transmission – the infectiousreservoir Age & infection • Transmission reduction – targeting infectivity • Conclusions P aras ite density & infection Goncalves et al Nature Comm2017 Guelbeogo et al Elife 2018 20 23 Malariatransmission: natural infection dynamics - Transmission reduction: Do we need to target the modelled reservoir? No Yes • Low density infections are still infectious • Submicroscopic infections infect and predominate in somesettings mosquitoes infrequently • High density asymptomatic infections in • Data from S E Asia suggest clinical cases African settings considerably more infectious than low density • Elimination in mainly lowendemic with historically low transmission • Settings eliminating without specifically targeting • Case management alone may not reduce all transmission and/or • Improving/enhancing case management sufficiently rapidly seems to have significant effect on transmission in somesettings • Drug resistance Drakeley et al, Malaria Elimination INTECH2018 21 24 4
11/12/2019 Transmission reduction: Targetingeveryone Trans mis s ion reduction: what can we do? • How can the information on parasite carriage and infectivitybe used at programme level? • What effects do different controlapproaches have on parasite densities, carriage, age distribution and the infectiousreservoir • Is targeting clinical infections at clinics issufficient? • Zambia - 3 rounds of MDA(DHA-P) delivered in 30 health facility catchment areas • Mildsymptoms commonly occur upon infection can these be detected with • Mass drug administration shown to be effective reducing prevalence and incidence Enhanced community case management before gametocytes arise? • Infections that are initially asymptomatic and missed by CCM maybe • Questions around cost/coverage/sustainability detected/removed by screening and treatment ? • New HS-RDT may change this profoundly and make MSA T a more viable option • Infections need to be treated/cleared (MDA) such that new infectionsilicit symptoms ? Eisele, JID2016 25 28 Transmission reduction: demographictargeting • SMC with SP-AQ inSenegal • Effects on incidence and parasiteprevalence when age range extended • School based in intervention inUganda • Significant reduction in prevalence in individuals in environs of treatedschools Cisse et ak 2017, Staedke et al 2018 26 29 Transmission reduction: Targetingsymptomatics Effective case management to catch infections early but will depend onthe • Malaria – current state of play ratio between symptomatic/asymptomatics • Malaria infections – more than wethought • Malaria transmission – the infectiousreservoir 21 villages in Northern Cambodia • Transmission reduction – targeting infectivity compared clinic derived incidence and community prevalence • Conclusions Surveys identified a number of villages significant infections not detected by CM Requires detailed epidemiological surveillance & stratification Falq Malaria Journal 2016 27 30 5
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