Selected publications

Walker, PGT, Floyd, J, ter Kuile, F, et al., (2017) Estimated Impact on Birth Weight of Scaling-up Intermittent Preventive Treatment for Malaria in Pregnancy Given Sulphadoxine-Pyrimethamine Resistance in Africa: a Mathematical Model, Plos Medicine, ISSN:1549-1277 Publisher's link.

Winskill, P, Walker, PGT, Griffin, JT, Ghani, AC, (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, 2(1), e000090. Publisher's link.

Churcher TS, Sinden RE, Edwards NJ, Poulton ID, Rampling TW, Brock PM, et al. (2017) Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naïve and Vaccinated Hosts. PLoS Pathog 13(1): e1006108. Publisher's link.

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  • Journal article
    Magombedze G, Ferguson NM, Ghani AC, 2018,

    A trade-off between dry season survival longevity and wet season high net reproduction can explain the persistence of Anopheles mosquitoes.

    , Parasites & Vectors, Vol: 11, ISSN: 1756-3305

    BACKGROUND: Plasmodium falciparum malaria remains a leading cause of death in tropical regions of the world. Despite efforts to reduce transmission, rebounds associated with the persistence of malaria vectors have remained a major impediment to local elimination. One area that remains poorly understood is how Anopheles populations survive long dry seasons to re-emerge following the onset of the rains. METHODS: We developed a suite of mathematical models to explore the impact of different dry-season mosquito survival strategies on the dynamics of vector populations. We fitted these models to an Anopheles population data set from Mali to estimate the model parameters and evaluate whether incorporating aestivation improved the fit of the model to the observed seasonal dynamics. We used the fitted models to explore the impact of intervention strategies that target aestivating mosquitoes in addition to targeting active mosquitoes and larvae. RESULTS: Including aestivation in the model significantly improved our ability to reproduce the observed seasonal dynamics of vector populations as judged by the deviance information criterion (DIC). Furthermore, such a model resulted in more biologically plausible active mosquito survival times (for A. coluzzii median wet season survival time of 10.9 days, 95% credible interval (CrI): 10.0-14.5 days in a model with aestivation versus 38.1 days, 95% CrI: 35.8-42.5 days in a model without aestivation; similar patterns were observed for A. arabiensis). Aestivation also generated enhanced persistence of the vector population over a wider range of both survival times and fecundity levels. Adding vector control interventions that target the aestivating mosquito population is shown to have the potential to enhance the impact of existing vector control. CONCLUSIONS: Dry season survival attributes appear to drive vector population persistence and therefore have implications for vector control. Further research is therefore needed to better u

  • Journal article
    Aydemir O, Janko M, Hathaway NJ, Verity R, Mwandagalirwa MK, Tshefu AK, Tessema SK, Marsh PW, Tran A, Reimonn T, Ghani AC, Ghansah A, Juliano JJ, Greenhouse BR, Emch M, Meshnick SR, Bailey JAet al., 2018,

    Drug-resistance and population structure of plasmodium falciparum across the Democratic Republic of Congo using high-throughput molecular inversion probes

    , Journal of Infectious Diseases, Vol: 218, Pages: 946-955, ISSN: 0022-1899

    A better understanding of the drivers of the spread of malaria parasites and drug resistance across space and time is needed. These drivers can be elucidated using genetic tools. Here, a novel molecular inversion probe (MIP) panel targeting all major drug-resistance mutations and a set of microsatellites was used to genotype Plasmodium falciparum infections of 552 children from the 2013–2014 Demographic and Health Survey conducted in the Democratic Republic of the Congo (DRC). Microsatellite-based analysis of population structure suggests that parasites within the DRC form a homogeneous population. In contrast, sulfadoxine-resistance markers in dihydropteroate synthase show marked spatial structure with ongoing spread of double and triple mutants compared with 2007. These findings suggest that parasites in the DRC remain panmictic despite rapidly spreading antimalarial-resistance mutations. Moreover, highly multiplexed targeted sequencing using MIPs emerges as a cost-effective method for elucidating pathogen genetics in complex infections in large cohorts.

  • Journal article
    Hellewell J, Walker P, Ghani A, Rao BV, Churcher Tet al., 2018,

    Using ante-natal clinic prevalence data to monitor temporal changes in malaria incidence in a humanitarian setting in the Democratic Republic of Congo

    , Malaria Journal, Vol: 17, ISSN: 1475-2875

    BackgroundThe number of clinical cases of malaria is often recorded in resource constrained or conflict settings as a proxy for disease burden. Interpreting case count data in areas of humanitarian need is challenging due to uncertainties in population size caused by security concerns, resource constraints and population movement. Malaria prevalence in women visiting ante-natal care (ANC) clinics has the potential to be an easier and more accurate metric for malaria surveillance that is unbiased by population size if malaria testing is routinely conducted irrespective of symptoms. MethodsA suite of distributed lag non-linear models was fitted to clinical incidence time-series data in children under 5 years and ANC prevalence data from health centres run by Médecins Sans Frontières in the Democratic Republic of Congo, which implement routine intermittent screening and treatment (IST) alongside intermittent preventative treatment in pregnancy (IPTp). These statistical models enable the temporal relationship between the two metrics to be disentangled. ResultsThere was a strong relationship between the ANC prevalence and clinical incidence suggesting that both can be used to describe current malaria endemicity. There was no evidence that ANC prevalence could predict future clinical incidence, though a change in clinical incidence was shown to influence ANC prevalence up to 3 months into the future. ConclusionsThe results indicate that ANC prevalence may be a suitable metric for retrospective evaluations of the impact of malaria interventions and is a useful method for evaluating long-term malaria trends in resource constrained settings.

  • Journal article
    White MT, Walker PGT, Karl S, Hetzel M, Freeman T, Waltzman A, Laman M, Robinson L, Ghani A, Mueller Iet al., 2018,

    Mathematical modelling of the impact of expanding levels of malaria control interventions on Plasmodium vivax

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    Plasmodium vivax poses unique challenges for malaria control and elimination, notably the potential for relapses to maintain transmission in the face of drug-based treatment and vector control strategies. We developed an individual-based mathematical model of P. vivax transmission calibrated to epidemiological data from Papua New Guinea (PNG). In many settings in PNG, increasing bed net coverage is predicted to reduce transmission to less than 0.1% prevalence by light microscopy, however there is substantial risk of rebounds in transmission if interventions are removed prematurely. In several high transmission settings, model simulations predict that combinations of existing interventions are not sufficient to interrupt P. vivax transmission. This analysis highlights the potential options for the future of P. vivax control: maintaining existing public health gains by keeping transmission suppressed through indefinite distribution of interventions; or continued development of strategies based on existing and new interventions to push for further reduction and towards elimination.

  • Journal article
    Hogan AB, Winskill P, Verity R, Griffin J, Ghani Aet al., 2018,

    Modelling population-level impact to inform target product profiles for childhood malaria vaccines

    , BMC Medicine, Vol: 16, ISSN: 1741-7015

    BackgroundThe RTS,S/AS01 vaccine for Plasmodium falciparum malaria demonstrated moderate efficacy in 5–17-month-old children in phase 3 trials, and from 2018, the vaccine will be evaluated through a large-scale pilot implementation program. Work is ongoing to optimise this vaccine, with higher efficacy for a different schedule demonstrated in a phase 2a challenge study. The objective of our study was to investigate the population-level impact of a modified RTS,S/AS01 schedule and dose amount in order to inform the target product profile for a second-generation malaria vaccine.MethodsWe used a mathematical modelling approach as the basis for our study. We simulated the changing anti-circumsporozoite antibody titre following vaccination and related the titre to vaccine efficacy. We then implemented this efficacy profile within an individual-based model of malaria transmission. We compared initial efficacy, duration and dose timing, and evaluated the potential public health impact of a modified vaccine in children aged 5–17 months, measuring clinical cases averted in children younger than 5 years.ResultsIn the first decade of delivery, initial efficacy was associated with a higher reduction in childhood clinical cases compared to vaccine duration. This effect was more pronounced in high transmission settings and was due to the efficacy benefit occurring in younger ages where disease burden is highest. However, the low initial efficacy and long duration schedule averted more cases across all age cohorts if a longer time horizon was considered. We observed an age-shifting effect due to the changing immunological profile in higher transmission settings, in scenarios where initial efficacy was higher, and the fourth dose administered earlier.ConclusionsOur findings indicate that, for an imperfect childhood malaria vaccine with suboptimal efficacy, it may be advantageous to prioritise initial efficacy over duration. We predict that a modified vaccine could outpe

  • Journal article
    Routledge I, Chevez JER, Cucunubá ZM, Gomez Rogriguez M, Guinovart C, Gustafson K, Schneider K, Walker PGT, Ghani A, Bhatt Set al., 2018,

    Estimating spatiotemporally varying malaria reproduction numbers in a near elimination setting

    , Nature Communications, Vol: 9, ISSN: 2041-1723

    In 2016 the World Health Organization identified 21 countries that could eliminate malaria by 2020. Monitoring progress towards this goal requires tracking ongoing transmission. Here we develop methods that estimate individual reproduction numbers and their variation through time and space. Individual reproduction numbers, Rc, describe the state of transmission at a point in time and differ from mean reproduction numbers, which are averages of the number of people infected by a typical case. We assess elimination progress in El Salvador using data for confirmed cases of malaria from 2010 to 2016. Our results demonstrate that whilst the average number of secondary malaria cases was below one (0.61, 95% CI 0.55–0.65), individual reproduction numbers often exceeded one. We estimate a decline in Rc between 2010 and 2016. However we also show that if importation is maintained at the same rate, the country may not achieve malaria elimination by 2020.

  • Journal article
    Sherrard-Smith E, Sala KA, Betancourt M, Upton LM, Angrisano F, Morin MJ, Ghani AC, Churcher TS, Blagborough AMet al., 2018,

    Synergy in anti-malarial pre-erythrocytic and transmission-blocking antibodies is achieved by reducing parasite density

    , eLife, Vol: 7, ISSN: 2050-084X

    Anti-malarial pre-erythrocytic vaccines (PEV) target transmission by inhibiting human infection but are currently partially protective. It has been posited, but never demonstrated, that co-administering transmission-blocking vaccines (TBV) would enhance malaria control. We hypothesized a mechanism that TBV could reduce parasite density in the mosquito salivary glands, thereby enhancing PEV efficacy. This was tested using a multigenerational population assay, passaging Plasmodium berghei to Anopheles stephensi mosquitoes. A combined efficacy of 90.8% (86.7–94.2%) was observed in the PEV +TBV antibody group, higher than the estimated efficacy of 83.3% (95% CrI 79.1–87.0%) if the two antibodies acted independently. Higher PEV efficacy at lower mosquito parasite loads was observed, comprising the first direct evidence that co-administering anti-sporozoite and anti-transmission interventions act synergistically, enhancing PEV efficacy across a range of TBV doses and transmission intensities. Combining partially effective vaccines of differing anti-parasitic classes is a pragmatic, powerful way to accelerate malaria elimination efforts.

  • Journal article
    Marshall JM, Wu SL, Sanchez HMC, Kiware SS, Ndhlovu M, Ouedraogo AL, Toure MB, Sturrock HJ, Ghani AC, Ferguson NMet al., 2018,

    Mathematical models of human mobility of relevance to malaria transmission in Africa

    , Scientific Reports, Vol: 8, ISSN: 2045-2322

    As 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.

  • Journal article
    Ghani AC, 2018,

    Can improving access to care help to eliminate malaria?

    , Lancet, Vol: 391, Pages: 1870-1871, ISSN: 0140-6736
  • Journal article
    White MT, Karl S, Koepfli C, Longley RJ, Hofmann NE, Wampfler R, Felger I, Smith T, Nguitragool W, Sattabongkot J, Robinson L, Ghani A, Mueller Iet al., 2018,

    Plasmodium vivax and Plasmodium falciparum infection dynamics: re-infections, recrudescences and relapses

    , Malaria Journal, Vol: 17, ISSN: 1475-2875

    Background: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.

  • Journal article
    Verity RJ, Hathaway N, Waltmann A, Doctor S, Watson O, Patel J, Mwandagalirwa K, Tshefu A, Bailey J, Ghani A, Juliano J, Meshnick Set al., 2018,

    Plasmodium falciparum genetic variation of var2csa in the Democratic Republic of the Congo

    , Malaria Journal, Vol: 17, ISSN: 1475-2875

    Background: 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.

  • Journal article
    Kaslow DC, Okumu F, Wells TNC, Rabinovich R, Bassat Q, Birkett A, Bompart F, Burt A, Chaccour C, Chitnis C, Culpepper J, Domingo G, Duffy P, Ghani A, Greenwood B, Hall BF, Hamon N, Jacobs-Lorena M, James S, Koram KA, Kremsner P, Kumar A, Leroy D, Leroy O, Lindsay S, Majambere S, Mbogo C, McCarthy J, Qi G, Rasgon J, Richardson J, Richie T, Sauerwein R, Slutsker L, Vekemans Jet al., 2017,

    malERA: An updated research agenda for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication

    , PLoS Medicine, Vol: 14, ISSN: 1549-1277

    Since 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.

  • Journal article
    Winskill P, Slater H, Griffin J, Ghani A, Walker Pet al., 2017,

    The US President's Malaria Initiative, Plasmodium falciparum transmission and mortality: A modelling study

    , PLoS Medicine, Vol: 14, ISSN: 1549-1277

    BackgroundAlthough 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

  • Journal article
    Challenger J, Bruxvoort K, Ghani AC, Okell LCet al., 2017,

    Assessing the impact of imperfect adherence to artemether-lumefantrine on malaria treatment outcomes using within-host modelling

    , Nature Communications, Vol: 8, ISSN: 2041-1723

    Artemether-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.

  • Journal article
    Watson O, Slater HC, Verity R, Parr JB, Mwandagalirwa MK, Tshefu A, Meshnick SR, Ghani ACet al., 2017,

    Modelling the drivers of the spread of Plasmodium falciparum hrp2 gene deletions in sub-Saharan Africa

    , eLife, Vol: 6, ISSN: 2050-084X

    Rapid 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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