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Journal articleTadesse FG, Slater HC, Chali W, et al., 2018,
The relative contribution of symptomatic and asymptomatic Plasmodium vivax and Plasmodium falciparum infections to the infectious reservoir in a low-endemic setting in Ethiopia
, Clinical Infectious Diseases, Vol: 66, Pages: 1883-1891, ISSN: 1058-4838Background: The majority of P. vivax and P. falciparum infections in low-endemic settings are asymptomatic. The relative contribution to the infectious reservoir of these infections, often of low-parasite-density, compared to clinical malaria cases, is currently unknown but important for malaria elimination strategies. Methods: We assessed infectivity of passively-recruited symptomatic malaria patients (n=41) and community-recruited asymptomatic individuals with microscopy- (n=41) and PCR-detected infections (n=82) using membrane feeding assays with Anopheles arabiensis mosquitoes in Adama, Ethiopia. Malaria incidence and prevalence data was used to estimate the contributions of these populations to the infectious reservoir. Results: Overall, 34.9% (29/83) of P. vivax and 15.1% (8/53) P. falciparum infected individuals infected ≥1 mosquitoes. Mosquito infection rates were strongly correlated with asexual parasite density for P. vivax (ρ = 0.63; P < .001) but not for P. falciparum (ρ = 0.06; P = .770). P. vivax symptomatic infections were more infectious to mosquitoes (infecting 46.5% of mosquitoes, 307/660) compared to asymptomatic microscopy-detected (infecting 12.0% of mosquitoes, 80/667; P = .005) and PCR-detected infections (infecting 0.8% of mosquitoes, 6/744; P < .001). Adjusting for population prevalence, symptomatic, asymptomatic microscopy- and PCR-detected infections were responsible for 8.0%, 76.2% and 15.8% of the infectious reservoir for P. vivax, respectively. For P. falciparum, mosquito infections were sparser and also predominantly from asymptomatic infections. Conclusions: In this low-endemic setting aiming for malaria elimination, asymptomatic infections are highly prevalent and responsible for the majority of onward mosquito infections. The early identification and treatment of asymptomatic infections might thus accelerate elimination efforts.
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Journal articleMarshall JM, Wu SL, Sanchez HMC, et al., 2018,
Mathematical models of human mobility of relevance to malaria transmission in Africa
, Scientific Reports, Vol: 8, ISSN: 2045-2322As Africa-wide malaria prevalence declines, an understanding of human movement patterns is essential to inform how best to target interventions. We fitted movement models to trip data from surveys conducted at 3–5 sites throughout each of Mali, Burkina Faso, Zambia and Tanzania. Two models were compared in terms of their ability to predict the observed movement patterns – a gravity model, in which movement rates between pairs of locations increase with population size and decrease with distance, and a radiation model, in which travelers are cumulatively “absorbed” as they move outwards from their origin of travel. The gravity model provided a better fit to the data overall and for travel to large populations, while the radiation model provided a better fit for nearby populations. One strength of the data set was that trips could be categorized according to traveler group – namely, women traveling with children in all survey countries and youth workers in Mali. For gravity models fitted to data specific to these groups, youth workers were found to have a higher travel frequency to large population centers, and women traveling with children a lower frequency. These models may help predict the spatial transmission of malaria parasites and inform strategies to control their spread.
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Journal articleGhani AC, 2018,
Can improving access to care help to eliminate malaria?
, Lancet, Vol: 391, Pages: 1870-1871, ISSN: 0140-6736 -
Journal articleWhite MT, Karl S, Koepfli C, et al., 2018,
Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses
, Malaria Journal, Vol: 17, ISSN: 1475-2875Background:In malaria endemic populations, complex patterns of Plasmodium vivax and Plasmodium falciparum blood-stage infection dynamics may be observed. Genotyping samples from longitudinal cohort studies for merozoite surface protein (msp) variants increases the information available in the data, allowing multiple infecting parasite clones in a single individual to be identified. msp genotyped samples from two longitudinal cohorts in Papua New Guinea (PNG) and Thailand were analysed using a statistical model where the times of acquisition and clearance of each clone in every individual were estimated using a process of data augmentation.Results:For the populations analysed, the duration of blood-stage P. falciparum infection was estimated as 36 (95% Credible Interval (CrI): 29, 44) days in PNG, and 135 (95% CrI 94, 191) days in Thailand. Experiments on simulated data indicated that it was not possible to accurately estimate the duration of blood-stage P. vivax infections due to the lack of identifiability between a single blood-stage infection and multiple, sequential blood-stage infections caused by relapses. Despite this limitation, the method and data point towards short duration of blood-stage P. vivax infection with a lower bound of 24 days in PNG, and 29 days in Thailand. On an individual level, P. vivax recurrences cannot be definitively classified into re-infections, recrudescences or relapses, but a probabilistic relapse phenotype can be assigned to each P. vivax sample, allowing investigation of the association between epidemiological covariates and the incidence of relapses.Conclusion:The statistical model developed here provides a useful new tool for in-depth analysis of malaria data from longitudinal cohort studies, and future application to data sets with multi-locus genotyping will allow more detailed investigation of infection dynamics.
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Journal articleO'Brien A, Sherrard-Smith E, Sile B, et al., 2018,
Spatial clusters of gonorrhoea in England with particular reference to the outcome of partner notification: 2012 and 2013
, PLoS ONE, Vol: 13, ISSN: 1932-6203Background:This study explored spatial-temporal variation in diagnoses of gonorrhoea to identify and quantify endemic areas and clusters in relation to patient characteristics and outcomes of partner notification (PN) across England, UK.Methods:Endemic areas and clusters were identified using a two-stage analysis with Kulldorff’s scan statistics (SaTScan).ResultsOf 2,571,838 tests, 53,547 diagnoses were gonorrhoea positive (positivity = 2.08%). The proportion of diagnoses in heterosexual males was 1.5 times that in heterosexual females. Among index cases, men who have sex with men (MSM) were 8 times more likely to be diagnosed with gonorrhoea than heterosexual males (p<0.0001). After controlling for age, gender, ethnicity and deprivation rank, 4 endemic areas were identified including 11,047 diagnoses, 86% of which occurred in London. 33 clusters included 17,629 diagnoses (34% of total diagnoses in 2012 and 2013) and spanned 21 locations, some of which were dominated by heterosexually acquired infection, whilst others were MSM focused. Of the 53,547 diagnoses, 14.5% (7,775) were the result of PN. The proportion of patients who attended services as a result of PN varied from 0% to 61% within different age, gender and sexual orientation cohorts. A third of tests resulting from PN were positive for gonorrhoea. 25% of Local Authorities (n = 81, 95% CI: 20.2, 29.5) had a higher than expected proportion for female PN diagnoses as compared to 16% for males (n = 52, 95% CI: 12.0, 19.9).Conclusions:The English gonorrhoea epidemic is characterised by spatial-temporal variation. PN success varied between endemic areas and clusters. Greater emphasis should be placed on the role of PN in the control of gonorrhoea to reduce the risk of onward transmission, re-infection, and complications of infection.
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Journal articleVerity RJ, Hathaway N, Waltmann A, et al., 2018,
Plasmodium falciparum genetic variation of var2csa in the Democratic Republic of the Congo
, Malaria Journal, Vol: 17, ISSN: 1475-2875Background: The Democratic Republic of the Congo (DRC) bears a high burden of malaria, which is exacerbated inpregnant women. The VAR2CSA protein plays a crucial role in pregnancy-associated malaria (PAM), and hence quantifyingdiversity at the var2csa locus in the DRC is important in understanding the basic epidemiology of PAM, and indeveloping a robust vaccine against PAM.Methods: Samples were taken from the 2013–14 Demographic and Health Survey conducted in the DRC, focusingon children under 5 years of age. A short subregion of the var2csa gene was sequenced in 115 spatial clusters, givingcountry-wide estimates of sequence polymorphism and spatial population structure.Results: Results indicate that var2csa is highly polymorphic, and that diversity is being maintained through balancingselection, however, there is no clear signal of phylogenetic or geographic structure to this diversity. Linear modellingdemonstrates that the number of var2csa variants in a cluster correlates directly with cluster prevalence, but not withother epidemiological factors such as urbanicity.Conclusions: Results suggest that the DRC fts within the global pattern of high var2csa diversity and little geneticdiferentiation between regions. A broad multivalent VAR2CSA vaccine candidate could beneft from targeting stableregions and common variants to address the substantial genetic diversity.
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Journal articleKaslow DC, Okumu F, Wells TNC, et al., 2017,
malERA: An updated research agenda for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication
, PLoS Medicine, Vol: 14, ISSN: 1549-1277Since the turn of the century, a remarkable expansion has been achieved in the range andeffectiveness of products and strategies available to prevent, treat, and control malaria,including advances in diagnostics, drugs, vaccines, and vector control. These advanceshave once again put malaria elimination on the agenda. However, it is clear that even withthe means available today, malaria control and elimination pose a formidable challenge inmany settings. Thus, currently available resources must be used more effectively, and newproducts and approaches likely to achieve these goals must be developed. This paper considerstools (both those available and others that may be required) to achieve and maintainmalaria elimination. New diagnostics are needed to direct treatment and detect transmissionpotential; new drugs and vaccines to overcome existing resistance and protect against clinicaland severe disease, as well as block transmission and prevent relapses; and new vectorcontrol measures to overcome insecticide resistance and more powerfully interrupt transmission.It is also essential that strategies for combining new and existing approaches aredeveloped for different settings to maximise their longevity and effectiveness in areas withcontinuing transmission and receptivity. For areas where local elimination has been recentlyachieved, understanding which measures are needed to maintain elimination is necessaryto prevent rebound and the reestablishment of transmission. This becomes increasinglyimportant as more countries move towards elimination.
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Journal articleWinskill P, Slater H, Griffin J, et al., 2017,
The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study
, PLoS Medicine, Vol: 14, ISSN: 1549-1277BackgroundAlthough significant progress has been made in reducing malaria transmission globally inrecent years, a large number of people remain at risk and hence the gains made are fragile.Funding lags well behind amounts needed to protect all those at risk and ongoing contributionsfrom major donors, such as the President’s Malaria Initiative (PMI), are vital to maintainprogress and pursue further reductions in burden. We use a mathematical modellingapproach to estimate the impact of PMI investments to date in reducing malaria burden andto explore the potential negative impact on malaria burden should a proposed 44% reductionin PMI funding occur.Methods and findingsWe combined an established mathematical model of Plasmodium falciparum transmissiondynamics with epidemiological, intervention, and PMI-financing data to estimate the contributionPMI has made to malaria control via funding for long-lasting insecticide treated nets(LLINs), indoor residual spraying (IRS), and artemisinin combination therapies (ACTs). Weestimate that PMI has prevented 185 million (95% CrI: 138 million, 230 million) malariacases and saved 940,049 (95% CrI: 545,228, 1.4 million) lives since 2005. If funding is maintained,PMI-funded interventions are estimated to avert a further 162 million cases (95%CrI: 116 million, 194 million) cases, saving a further 692,589 (95% CrI: 392,694, 955,653)lives between 2017 and 2020. With an estimate of US$94 (95% CrI: US$51, US$166) perDisability Adjusted Life Year (DALY) averted, PMI-funded interventions are highly costeffective.We also demonstrate the further impact of this investment by reducing caseloadson health systems. If a 44% reduction in PMI funding were to occur, we predict that this lossof direct aid could result in an additional 67 million (95% CrI: 49 million, 82 million) cases and290,649 deaths (95% CrI: 167,208, 395,263) deaths between 2017 and 2020. We have notmodelled indirect impacts of PMI funding (such as health systems strengthening
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Journal articleChallenger J, Bruxvoort K, Ghani AC, et al., 2017,
Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling
, Nature Communications, Vol: 8, ISSN: 2041-1723Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated Plasmodium falciparum malaria worldwide. Its safety and efficacy have been extensively demonstrated in clinical trials; however, its performance in routine health care settings, where adherence to drug treatment is unsupervised and therefore may be suboptimal, is less well characterised. Here we develop a within-host modelling framework for estimating the effects of sub-optimal adherence to AL treatment on clinical outcomes in malaria patients. Our model incorporates data on the human immune response to the parasite, and AL’s pharmacokinetic and pharmacodynamic properties. Utilising individual-level data of adherence to AL in 482 Tanzanian patients as input for our model predicted higher rates of treatment failure than were obtained when adherence was optimal (9% compared to 4%). Our model estimates that the impact of imperfect adherence was worst in children, highlighting the importance of advice to caregivers.
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Journal articleWatson O, Slater HC, Verity R, et al., 2017,
Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa
, eLife, Vol: 6, ISSN: 2050-084XRapid diagnostic tests (RDTs) have transformed malaria diagnosis. The most prevalent P. falciparum RDTs detect histidine-rich protein 2 (PfHRP2). However, pfhrp2 gene deletions yielding false-negative RDTs, first reported in South America in 2010, have been confirmed in Africa and Asia. We developed a mathematical model to explore the potential for RDT-led diagnosis to drive selection of pfhrp2-deleted parasites. Low malaria prevalence and high frequencies of people seeking treatment resulted in the greatest selection pressure. Calibrating our model against confirmed pfhrp2-deletions in the Democratic Republic of Congo, we estimate a starting frequency of 6% pfhrp2-deletion prior to RDT introduction. Furthermore, the patterns observed necessitate a degree of selection driven by the introduction of PfHRP2-based RDT-guided treatment. Combining this with parasite prevalence and treatment coverage estimates, we map the model-predicted spread of pfhrp2-deletion, and identify the geographic regions in which surveillance for pfhrp2-deletion should be prioritised.
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Journal articleBretscher MT, Griffin JT, Ghani AC, et al., 2017,
Modelling the benefits of long-acting or transmission-blocking drugs for reducing Plasmodium falciparum transmission by case management or by mass treatment
, MALARIA JOURNAL, Vol: 16, ISSN: 1475-2875BackgroundAnti-malarial drugs are an important tool for malaria control and elimination. Alongside their direct benefit in the treatment of disease, drug use has a community-level effect, clearing the reservoir of infection and reducing onward transmission of the parasite. Different compounds potentially have different impacts on transmission—with some providing periods of prolonged chemoprophylaxis whilst others have greater transmission-blocking potential. The aim was to quantify the relative benefit of such properties for transmission reduction to inform target product profiles in the drug development process and choice of first-line anti-malarial treatment in different endemic settings.MethodsA mathematical model of Plasmodium falciparum epidemiology was used to estimate the transmission reduction that can be achieved by using drugs of varying chemoprophylactic (protection for 3, 30 or 60 days) or transmission-blocking activity (blocking 79, 92 or 100% of total onward transmission). Simulations were conducted at low, medium or high transmission intensity (slide-prevalence in 2–10 year olds being 1, 10 or 40%, respectively), with drugs administered either via case management or mass drug administration (MDA).ResultsTransmission reductions depend strongly on deployment strategy, treatment coverage and endemicity level. Transmission-blocking was most effective at low endemicity, whereas chemoprophylaxis was most useful at high endemicity levels. Increasing the duration of protection as much as possible was beneficial. Increasing transmission-blocking activity from the level of ACT to a 100% transmission-blocking drug (close to the effect estimated for ACT combined with primaquine) produced moderate impact but was not as effective as increasing the duration of protection in medium-to-high transmission settings (slide prevalence 10–40%). Combining both good transmission-blocking activity (e.g. as achieved by ACT or ACT + primaquine) and a long durat
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Journal articleOkell L, Griffin JT, Roper C, 2017,
Mapping sulphadoxine-pyrimethamine-resistant Plasmodium falciparum malaria in infected humans and in parasite populations in Africa
, Scientific Reports, Vol: 7, ISSN: 2045-2322Intermittent preventive treatment (IPT) with sulphadoxine-pyrimethamine in vulnerable populations reduces malaria morbidity in Africa, but resistance mutations in the parasite dhps gene (combined with dhfr mutations) threaten its efficacy. We update a systematic review to map the prevalence of K540E and A581G mutations in 294 surveys of infected humans across Africa from 2004-present. Interpreting these data is complicated by multiclonal infections in humans, especially in high transmission areas. We extend statistical methods to estimate the frequency, i.e. the proportion of resistant clones in the parasite population at each location, and so standardise for varying transmission levels. Both K540E and A581G mutations increased in prevalence and frequency in 60% of areas after 2008, highlighting the need for ongoing surveillance. Resistance measures within countries were similar within 300 km, suggesting an appropriate spatial scale for surveillance. Spread of the mutations tended to accelerate once their prevalence exceeded 10% (prior to fixation). Frequencies of resistance in parasite populations are the same or lower than prevalence in humans, so more areas would be classified as likely to benefit from IPT if similar frequency thresholds were applied. We propose that the use of resistance frequencies as well as prevalence measures for policy decisions should be evaluated.
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Journal articlePatouillard E, Ghani ACH, Bhatt S, et al., 2017,
Global investment targets for malaria control and elimination between 2016 and 2030
, BMJ Global Health, Vol: 2, ISSN: 2059-7908Background Access to malaria control interventions falls short of universal health coverage. The Global Technical Strategy for malaria targets at least 90% reduction in case incidence and mortality rates, and elimination in 35 countries by 2030. The potential to reach these targets will be determined in part by investments in malaria. This study estimates the financing required for malaria control and elimination over the 2016–2030 period.Methods A mathematical transmission model was used to explore the impact of increasing intervention coverage on burden and costs. The cost analysis took a public provider perspective covering all 97 malaria endemic countries and territories in 2015. All control interventions currently recommended by the WHO were considered. Cost data were sourced from procurement databases, the peer-reviewed literature, national malaria strategic plans, the WHO-CHOICE project and key informant interviews.Results Annual investments of $6.4 billion (95% uncertainty interval (UI $4.5–$9.0 billion)) by 2020, $7.7 billion (95% UI $5.4–$10.9 billion) by 2025 and $8.7 billion (95% UI $6.0–$12.3 billion) by 2030 will be required to reach the targets set in the Global Technical Strategy. These are equivalent to annual investment per person at risk of malaria of US$3.90 by 2020, US$4.30 by 2025 and US$4.40 by 2030, compared with US$2.30 if interventions were sustained at current coverage levels. The 20 countries with the highest burden in 2015 will require 88% of the total investment.Conclusions Given the challenges in increasing domestic and international funding, the efficient use of currently available resources should be a priority
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Journal articleBrady OJ, Slater HC, Pemberton-Ross P, et al., 2017,
Role of mass drug administration in elimination of Plasmodium falciparum malaria: a consensus modelling study
, The Lancet Global Health, Vol: 5, Pages: E680-E687, ISSN: 2214-109XBackgroundMass drug administration for elimination of Plasmodium falciparum malaria is recommended by WHO in some settings. We used consensus modelling to understand how to optimise the effects of mass drug administration in areas with low malaria transmission.MethodsWe collaborated with researchers doing field trials to establish a standard intervention scenario and standard transmission setting, and we input these parameters into four previously published models. We then varied the number of rounds of mass drug administration, coverage, duration, timing, importation of infection, and pre-administration transmission levels. The outcome of interest was the percentage reduction in annual mean prevalence of P falciparum parasite rate as measured by PCR in the third year after the final round of mass drug administration.FindingsThe models predicted differing magnitude of the effects of mass drug administration, but consensus answers were reached for several factors. Mass drug administration was predicted to reduce transmission over a longer timescale than accounted for by the prophylactic effect alone. Percentage reduction in transmission was predicted to be higher and last longer at lower baseline transmission levels. Reduction in transmission resulting from mass drug administration was predicted to be temporary, and in the absence of scale-up of other interventions, such as vector control, transmission would return to pre-administration levels. The proportion of the population treated in a year was a key determinant of simulated effectiveness, irrespective of whether people are treated through high coverage in a single round or new individuals are reached by implementation of several rounds. Mass drug administration was predicted to be more effective if continued over 2 years rather than 1 year, and if done at the time of year when transmission is lowest.InterpretationMass drug administration has the potential to reduce transmission for a limited time, but is not an
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Journal articleWinskill P, Walker P, Griffin J, et al., 2017,
Modelling the cost-effectiveness of introducing the RTS,S malaria vaccine relative to scaling up other malaria interventions in sub-Saharan Africa
, BMJ Global Health, Vol: 2, ISSN: 2059-7908Objectives: To evaluate the relative cost-effectiveness of introducing the RTS,S malaria vaccine in sub-Saharan Africa compared with further scale-up of existing interventions.Design: A mathematical modelling and cost-effectiveness study.Setting: Sub-Saharan Africa.Participants: People of all ages.Interventions: The analysis considers the introduction and scale-up of the RTS,S malaria vaccine and the scale-up of long lasting insecticide treated bed nets (LLINs), indoor residual spraying (IRS) and seasonal malaria chemoprevention (SMC).Main outcome measure: The number of Plasmodium falciparum cases averted in all age groups over a ten year period.Results: Assuming access to treatment remains constant, increasing coverage of LLINs was consistently the most cost-effective intervention across a range of transmission settings and was found to occur early in the cost-effectiveness scale-up pathway. IRS, RTS,S and SMC entered the cost-effective pathway once LLIN coverage had been maximised. If non-linear production functions are included to capture the cost of reaching very high coverage, the resulting pathways become more complex and result in selection of multiple interventions.Conclusions: RTS,S was consistently implemented later in the cost-effectiveness pathway than the LLINs, IRS and SMC but was still of value as a fourth intervention in many settings to reduce burden to the levels set out in the international goals.
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