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Results

Quantifying the influence of wind on mosquito flight and consequences for malaria transmission in southern Malawi 21 May 2018

Spatially targeting malaria control interventions in areas of high disease burden will become a more cost-effective and sustainable approach for national programmes in the era of elimination. To achieve this the geographical scale in which to implement control and identify the most likely sources and routes of infection are critical. Wind-assisted mosquito dispersal is an important, yet currently undervalued, source of information to track the spread of malaria and predict outbreaks. We will develop and apply a model, previously and successfully used to track the wind-borne spread of Bluetongue virus by midges, to predict the spread of malaria in a rural region of southern Malawi. The ‘spatial-temporal wind-outbreak trajectory simulation’ (SWOTS) model will use wind data, household infection status and insect flight parameters to determine the most likely source and route of infection during the rainy season. We will empirically validate the output from SWOTS using a simple mark-recapture field experiment to determine the influence of wind direction and speed on vector movement. This pilot project will determine the applicability of SWOTS as a risk assessment and disease preparedness tool for malaria in rural Africa and lay the foundations to extend to other transmission settings and vector-borne disease systems.

Amount: £94,334
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Fracture union in HIV positive patients 17 Jun 2015

HIV and highly active antiretroviral therapy (HAART) have been shown to decrease bone mineral density and mineralisation. Researchers have suggested that they both contribute to the development of delayed bone union and nonunion following a fracture. However, the true effect of HIV and HAART on bone healing is very poorly understood. Our aim is to establish the effect of HIV and HAART on the fracture repair process, addressing three key goals: 1. To determine whether HIV-infected adults have a higher rate of delayed bone union and nonunion, compared to HIV-uninfected adults following a fracture 2. To establish whether HIV is a potential risk factor for the development of non-union after fracture surgery 3. To investigate the effect of HAART on the fracture repair process These goals will be addressed by two studies: Goal 1 will be achieved through a case-cohort study investigating bone union (controls) and delayed bone union (cases) in adults following fracture surgery, by HIV s tatus (exposure). Goal 2 and 3 will be addressed through an in vivo study. The rate of nonunion, using an established fracture model, in HIV-1 transgenic rats treated with HAART, will be compared to an untreated control and HIV-1 transgenic group.

Amount: £432,264
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Exploring conflict and trust within community engagement activities as part of a community-based HIV/TB intervention trial in urban Blantyre, Malawi. 14 Apr 2014

SPECIFIC OBJECTIVES 1. To map out the roles of community representatives as Key Informants and Cluste2. To explore perceptions of cluster representatives from the perspective of comm3. To critically examine concepts around trust within the context of the interven4. To document specific case studies where trust or distrust has impacted on rela5. To provide recommendations for future community-based intervention trials on oMETHODOLOGY This will be a small qualitative research study in urban Blantyre, Malawi. Recruiting cluster representatives, study team members and communities we willcombine Focus Group Discussions with individual semi-structured interviews. Participants will be purposively selected and data analysed iteratively to build understanding through targeted interviewing in pursuit of the research objectives. DATA COLLECTION We will begin data collection with community level meetings in each of the three study wards to minimize potential concerns about the study amongst communities and cluster representatives. The Senior Community Liaison Officerwho established the system for the HIV/TB intervention will conduct the research. A total of 6 focus group discussions (FGD) will be conducted, two with each of the three groups of interest: cluster representatives, study teams and communities. Three at the start of the fieldwork with a defined setof deductively generated themes and three at the end to respond to and clarifyfindings from the individual semi-structured interviews. We expect a total ofapproximately 15 semi-structured interviews, five with each participant group,selected purposively following the initial FGDs. Themes for these interviews will be generated inductively from preliminary analysis of the initial FGDs and iteratively as understanding is developed.

Treating netting eave baffles with pirimiphos-methyl to control indoor-feeding Anopheles funestus malaria vectors at an affordable cost 25 Nov 2013

The arsenal of insecticides available for vector control is limited to only four classes and resistance to both pyrethroids and organo-chlorines has emerged among malaria vectors in Zambia. The new organophosphate pirimiphos-methyl is an attractive alternative for inclusion in resistance management strategies because its biochemical mode of action is distinct from both these classes and it is activated by the oxidases that mediate cross-resistance to pyrethroids and organo-chlorines [28]. Howeve r this insecticide is prohibitively expensive to treat all roofs and walls by conventional indoor residual spraying (IRS). I therefore propose to develop and evaluate netting eave baffles treated with pirimiphos-methyl placed around the eaves of houses [3,36] as means to target lower quantities of insecticide to entry and exit points for mosquitoes. Treating netting eave baffles should also have practical programmatic advantages over IRS because it can be safely achieved by soaking at the level of centralized pre-treatment facilities all the way down to communities and households. I therefore aim to demonstrate that the application of pirimiphos-methyl eave baffles, at the lowest dosage required to achieve maximum mortality of vectors can be far more efficacious, durable and affordable than spraying the whole house using conventional IRS at recommended dosage.

Amount: £68,840
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Supporting excellence in basic and clinical research: A flow cytometry/sorting and cell imaging platform for the genotypic and phenotypic analysis of Hazard Group 3 pathogens. 25 Jun 2014

Funding is requested for a BD-FACS-Aria-Fusion cell-sorter and a Zeiss-LSM-710-confocal microscope to be housed in LSTM's Hazard-Group-3 (HG3)-containment laboratories. This equipment is principally to support Trust-funded investigators/fellows requiring HG3-biosafety to comply with HSE requirements. The Schools focus on pathogens (many HG3) that cause disease rather than non-pathogenic surrogates has imposed stringent biological safety requirements. The ability to carry out technically ch allenging image-based science for our internal programmes and clinical samples derived from Wellcome Trust Overseas Programmes (e.g.Malawi/Kenya/Vietnam) while ensuring the highest levels of operator safety requires investment. The complementary imaging platform of flow-cytomety (with sorting) and confocal microscopy (real-time live imaging of cells/tissues) will allow PIs the ability of genotyping and phenotyping live HG3-pathogens. This is an essential requirement in order to facilitate s tudies into the temporal responses of important pathogens to experimental perturbations and the isolation of organisms/cells with specific genotypic/phenotypic traits for further investigation. The described HG3-imaging facility, set in one of CTIDs 22 HG3-containment laboratories, will be the first dedicated facility in the North West and possibly the UK, supporting LSTM's and UK's position as an international leader in tropical disease research.

Amount: £598,054
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Identifying the mechanisms of insecticide resistance in Anopheles gambiae s.s. and Anopheles arabiensis in Chikwawa, Malawi 19 Jun 2017

Malaria is a major cause of morbidity and mortality in Malawi. There has been an increase in the use of insecticides for malaria control either through Long Lasting Insecticide Treated Bednets or Insecticide Residual Spraying. Insecticide resistance in the primary malaria vectors has been reported and may impact the efficacy of current anti-vector control strategies. To maximise the efficacy and to ensure continued use of these insecticides it is necessary for the National Malaria Control Programme (NMCP) to develop an Insecticide Resistance Management (IRM) plan. The IRM plan will be most effective if we have detailed understanding of the genes which are associated with the resistance phenotype. My project aims to use transcriptomic approaches to characterise expression patterns linked to insecticide resistance in Anopheles gambiae s.s. and An. arabiensis in Chikwawa, an area of high malaria transmission. The study will establish the resistance patterns in the common malaria vectors and the molecular markers which can be used to predict and manage insecticide resistance.

Amount: £147,484
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Characterising metabolic mechanisms conferring deltamethrin resistance in Anopheles albimanus, major malaria vector in Guatemala 22 Nov 2016

Malaria is still a publich health in Guatemala, reportin a total of 4,931 confirmed malaria cases for 2014. The main malaria vector is An. albimanus because is the most abundant and widely distributed species. Insecticide-based vector control strategies are maily used in Guatemala, which includes pyrethroid LLIN's. Unfortunately, the emergence of resistance to insecticides is threatening the continued success of the insecticide-based vector control interventions. Bioassays, molecular and biochemical assays indicated development of pyrethroids resistance in An. albimanus from Guatemala with early evidences suggesting a predominant role of metabolic resistance mechanisms. Therefore, this project aims at elucidatin the metabolic resistance mechanisms involved in the deltamethrin resistance in Guatemalan An. albimanus. So, insecticide resistance profile will be assessed in field populations of An. albimanus throughout Guatemala using CDC bottle bioassays and synergist assays. Resistant mosquitoes will be used to detect key genes conferring metabolic resistance using RNA-seq transcriptomic approach with Illumina and quantitative PCR. In addition, deltamethrin resistance markers will be detected by sequencing of candidate genes between resistant and susceptible mosquitoes. This will allow us to design DNA-based diagnostic tools which will to enhance the sentinel surveillance to detect insecticide resistance at early stage.

Amount: £140,950
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

INTRAHOST DYNAMICS IN TREATED AND UNTREATED MALARIA PATIENTS. 26 Feb 2013

Plasmodium falciparum malaria infections in sub-Saharan Africa often consist of mixtures of different parasite genotypes. While current methods for genotyping infections can distinguish whether or not multiple parasite genotypes are present, they fail to resolve haplotypes present. This limits our ability to understand multiple-haplotype infections (MIs) which are thought to play key roles in disease severity, drug resistance evolution and malaria transmission. I aim to develop a Fluorescence Ac tivated Cell Sorting (FACS) method to examine the genetic composition of MIs from an area of intense malaria transmission in Malawi. I will isolate component clones of MIs using FACS or limiting dilution cloning and genotype these at 384 genome-wide polymorphic SNPs to determine the number and relatedness of parasite haplotypes within MIs. These data will be used to assess the relationship between within-host parasite genetic diversity and malaria severity, and to understand how malaria superinf ection is regulated in high transmission regions. I also propose to examine the impact of MIs on our ability to detect emerging drug-resistant malaria in the field, and to evaluate the suitability of an in vitro assay for measuring parasite susceptibility to artemisinin, a key antimalarial drug in sub-Saharan Africa.

Amount: £450,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Spatial and temporal distribution of the N1575Y allele and his impact on the malaria vector control activities. 26 Feb 2013

The primary goal of the proposed project is to understand the driving forces selecting for an emerging insecticide resistance mutation in the malaria mosquito, Anopheles gambiae. Pyrethroid resistance threatens to compromise the gains made in reducing malaria from large-scale distribution of long-lasting insecticide treated nets (LLINs) and indoor residual spraying (IRS) [8]. The pyrethroid resistance mutations, commonly referred to as knockdown resistance or kdr (L1014F/L1014S) are extending th eir range, and in the case of L1014F, approach fixation over much of West Africa. A secondary mutation, N1575Y, was recently detected at low but rising frequencies in Burkina Faso suggesting an ongoing selective sweep [5]. The resistant haplotype provided added benefit to mosquitoes exposed to pyrethroids/DDT (odds ratios = 1.93 2.60). The discovery of a new resistance mechanism while at a relatively low frequency is a unique opportunity to address some of the key questions in our understanding of resistance management strategies while providing important information for vector control operations within the local setting. The project will tackle these questions by estimating the selection of N1575Y over the past 20 years; investigating potential sources of selection pressures and exploring the fitness costs associated with kdr haplotypes.

Amount: £111,220
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Surveillance for influenza in the context of pandemic H1N1 in an African population with a high burden of HIV, malaria and malnutrition. 16 Apr 2012

Sub-Saharan countries such as Malawi have a very high infectious disease burden. Although influenza is likely to be prevalent, there is little or no infrastructure to capture the contribution of influenza to morbidity and mortality or define the potential for pandemic influenza to be more severe in these frequently more immunocompromised populations. In this project we will: 1) Assess the burden of Influenza-like Illness (ILI) and Severe Acute Respiratory Infection (SARI) amongst adults and c hildren presenting to a large Central Hospital in Malawi and to determine the contribution of seasonal (including H3N2 and H1N1) and pandemic H1N1 influenza virus to this disease. 2) Describe the severity and outcome of laboratory proven seasonal and pandemic H1N1 influenza in a population with a high prevalence of HIV, malnutrition and malaria. 3) Determine the influence of HIV on the duration of shedding of seasonal and pandemic H1N1 influenza virus. 4) Document the frequency of secon dary invasive bacterial infections in adults and children with influenza-associated SARI. The findings that arise from this study will provide the detailed understanding of the epidemiology, clinical presentation and outcome of influenza urgently required by public health planners and policy makers in Africa.

Amount: £64,917
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Investigation of putative causal factors for low rate of parasitological cure of standard dose praziquantel for intestinal schistosomiasis in Ugandan infants and pre-school children 05 Apr 2012

The project will build upon excellent established collaborations between Natural History Museum and Vector Control Division researchers. We will investigate the occurrence of intestinal schistosomiasis in infants and preschool children to develop best treatment options for this ageclass and assess their role in local disease transmission. These two complementary objectives will combine field-based and laboratory-based epidemiological investigations namely, 1. field-based: monitoring biannually a n enrolled study cohort of mother and child pairs over a 3-year period collecting epidemiologically and clinically relevant information pertaining to treatment with praziquantel and reinfection dynamics, as well as, recording monthly environmentally relevant data describing local S. mansoni infection dynamics in intermediate snail hosts. 2. laboratory-based: molecular DNA typing of genetic diversity within S. mansoni larval forms shed from snails (cercariae) and selected mother and child pairs ( eggs); conducting multivariate statistical modelling comparing parasite burdens and putative risk factors to identify best praziquantel treatment regime. The project will better elucidate parasite transmission biology in young children. The main goal will be to further develop the Ugandan national policy for control of intestinal schistosomiasis in infants and preschool children and, through realignment of ongoing integrated preventive chemotherapy campaigns, more broadly improve maternal and ch ild health in sub-Saharan Africa.

Amount: £92,700
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

The Art in Global Health. 13 Feb 2012

Not available

Amount: £38,000
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Malaria Research Capacity Development in West and Central Africa 05 May 2015

The vision of this programme is to establish a core group of internationally-competitive scientists, in West and Central Africa who can contribute significantly with new information from research to the current fight local governments, are waging against malaria, eventually leading to pre-elimination and then elimination of this disease in these countries. The new programme will be built on the achievements of the PhD and post-doctoral programmes conducted by the Malaria Capacity Development Consortium (MCDC) which followed the Gates Malaria Partnership (GMP). The overall strategy of the new programme is to extend capacity building to the next level by supporting research groups and institutions. More specifically, we will (1) create research teams "in training" comprising a senior post-doctoral fellow (potential research leader with at least 3 years post PhD training), early postdoctoral fellows and PhD students supported by senior researchers at the host institution and (2) integrate early postdoctoral fellows and PhD studentsinto established research teams. Research projects will be fully integrated within the ongoing research programmes that are focusing on malaria control/elimination in West and Central Africa. Malaria control activities in West and Central Africa have resulted in a substantial decrease in the incidence of malaria during the last five years, thanks to the contribution of research that has guided policy. Despite these successes, new challenges such as the emergence of insecticide and drug resistance, a shift in the age groups most at risk, the maintenance of transmission by unidentified malaria hot spots and, lastly, difficulties in deciding the most cost-effective combinations of interventions call for additional research to better target existing interventions and identify new ones. In this changing environment, a new world-class generation of African scientists able to provide relevant answers to the challenges encountered by National Malaria Control Programmes is needed, possibly contributing towards the point where elimination becomes a realistic target in the near future. Scientists involved in the programme will work as complementary groups/teams within the consortium; previous members of the MCDC known as 'MCDC investigators' will be encouraged to support this new programme. The collaboration within this consortium will be a South-North, South-South and research multi-disciplinary including basic, qualitative and quantitative research. It will benefit from the diverse, established range of expertise within the partner institutions. Skills in leadership, project development and management, fund raising, scientific writing, communication and advocacy will be prioritised during training. Development of the next generation of malaria researchers will take place in institutions where research and financial management is sound. The quality of research management in the participating institutions will be ensured by continuous monitoring and evaluation. Translation of relevant research findings into policy and practice will be achieved by early and continuous engagement with national and regional policy makers and other relevant stakeholders. Sustainability beyond the programme will be ensured by exploring additional national and international funding opportunities.

Amount: £222,047
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Open access award 2015/16. 21 Sep 2015

Not available

Amount: £54,754
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Public Engagement Provision 21 Sep 2015

MLW is strategically placed to conduct high quality laboratory, clinical and epidemiological science relevant to health in sub-Saharan Africa. The programme is embedded within a rapidly growing medical school, co-located within the largest teaching hospital in Malawi with direct access to urban and rural populations. In the next 5 years, MLW research will increase fundamental understanding of disease mechanisms and burden, test novel interventions and ensure translation into health care. The cor e programme will ensure MLW delivers the following aims: (1) Pursuit of cutting-edge research focused on health problems with a high disease burden. Research management, mentorship, development of bioinformatics expertise, and clinical and diagnostic laboratory competencies, ensuring the highest quality. (2) Provision of a research training environment for clinicians, epidemiologists and laboratory scientists. Local research infrastructure, operational and financial systems, data manageme nt and research governance support. (3) Development of globally competitive research leaders. Moving towards local leadership, embedded within the University of Malawi College of Medicine, attracting further intermediate and senior Fellows, and encouraging re-entry of trained Malawian scientists. (4) Translation of scientific advances into human health improvements. Defining national and international research agendas through policy relevant evidence; policy committee membership; research synthesis workshops; and public engagement

Amount: £346,737
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Population genetics of resistance to alternative insecticides in southern Ghana 23 Nov 2010

Resistance to DDT and pyrethroids is now ubiquitous in Anopheles gambiae in southern Ghana (Coetzee et al 2006; Adasi & Hemingway 2008; Adeniran et al. 2009; Mawejje et al. in prep), reducing insecticidal efficacy for malaria control. The national malaria control programme (NMCP) urgently needs to switch to application of insecticides with a different mode of action, i.e. carbamates or organophosphates, as alternatives or supplements to pyrethroids. However resistance to carbamates, the more favoured alternative, has been documented in Ghana, necessitating extremely careful application of insecticide to manage the development and spread of resistance. To achieve this objective, data are required on how best to predict the dynamics of carbamate resistance. This is the primary goal addressed by the current project. The goal will be achieved via determination of how geographical variation in resistance to carbamates (and to a more limited extent organophosphates) relates to, and can be predicted, by gene flow, assesed using neutral microsatellite markers, and a strongly resistance-linked mutation ace-1R. Since the predictive value of ace-1R frequencies could be compromised if alleles have independent origins, the project will also conduct long range haplotype analysis both to determine mutational origins and to quantify the strength of selection acting on ace-1R.

Amount: £92,867
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Landscape genetics in the control of Anopheles gambiae 26 Nov 2015

In the last few years carbama te and organophosphate insecticides have become increasing important for indoor residual spraying (IRS) as a response to heightening levels of resistance to pyrethroids. However, the scale-up ofIRS in West Africa,provides the potential for resistance to spread dramatically from the agricultural areas where currently most prevalent. This project aims to understand how the interplay between mosquito migration and changing environmentaI and scapes de termines the movement of insecticide resistance.Such informationis criti cal to help prevent resistance rapidly undermining current initiatives inIRS-based control. The work would exploti recent advances in cost-effective molecular marker screening, analysis techniques and identification of key insecticide resistance mutations to address key aims.lwill investigate how movements of the dominant West African malaria vectors,Anopheles gambiae and An. coluzzii, within and across heterogeneous environments throughout Ghana can spread insecticide resistance. Individual mosquitoes will be screened at thousands of genomewide markers, in a sta tistically powerful design tailored towardindividual-based landscape genetic analyses. Alongside diagnostic screening of mutations causing strong insecticide resistance,and studies of their fitness costs and benefits, the work will provide timely insight into factors promoting and retardina spread of resistance to important insecticide classes

Amount: £179,384
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Accelerating malaria elimination efforts in the Sudano-Sahelian region of Africa: elucidation of factors driving transmission and unravelling the molecular basis of insecticide resistance in the major malaria vectors 22 Jun 2016

Malaria still devastates the tropical world; with a quarter of overall estimated mortality (~438,000 deaths) occurring in Nigeria alone. Achievement of 90% reduction in malaria cases and death by 2030 requires significant progress in control of the disease in Nigeria, and other neighbouring countries, such as Niger, Cameroon and Chad. The disease dynamics, i.e. composition and distribution of the malaria vectors, dynamics of malaria transmission and profiles of insecticides resistance and factors driving is poor characterised in the Sudano-Sahelian regions of these countries. Understanding the bionomics of the malaria vectors from these regions is indispensable to malaria control and elimination. To fill this important gap we intend to characterise the major malaria vectors from the Sudano-Sahelian regions of sub-Saharan Africa, to establish their contribution toward malaria transmission, and elucidate the features of insecticide resistance. Specifically, we aim to: 1- Establish the distribution of the major malaria vectors from Sudano-Sahelian region, their seasonality and vectorial capacity; 2- Characterise insecticide resistance and cross-resistance status of the mosquito populations, identify potential synergists and candidate resistance genes; 3- Identify the major genes responsible for metabolic resistance, and discover molecular markers of the resistance to detect and track it in the field.

Amount: £281,800
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Optimising antimicrobial therapy for sepsis in Malawi 30 Sep 2016

Mortality from severe sepsis in Malawi is extremely high – 50% compared to 20-30% in high-income settings. Guidelines on optimal use of available therapies (antimicrobials, intravenous fluids and oxygen) are extrapolated from high-income settings and/or based on expert opinion. Data to inform acute care guidelines for Malawi and sub-Saharan Africa (SSA), are urgently needed. Data from SSA suggest sepsis is caused by diverse pathogens including M. tuberculosis, not covered by current empiric therapy, and I propose that broadening the spectrum of empiric antimicrobial chemotherapy may play a role in improving outcomes. Great care must be taken with such a strategy to minimise development of antimicrobial resistance (AMR). The epidemiology of this emerging threat is not well understood in Malawi, but longitudinal surveillance reveals an alarming increase in drug resistant infection. I propose to: Conduct a prospective case-cohort study of severe sepsis patients in Malawi to provide a detailed description of sepsis, including microbiological causes and determinants of poor outcome. Use deep sequencing to study survivors and describe acquisition and duration of carriage of resistant bacteria. Ultimately, this will guide antimicrobial strategies to achieve the twin aims of improving clinical outcomes while minimising the development of AMR in Malawi.

Amount: £396,007
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Ex vivo combined co-cultures of host cells, plasma and parasites isolated from patients: a new approach to cerebral malaria pathogenesis. 05 Dec 2006

The overall objective of this project is to analyse interactions between the different elements of the host (endothelium, plasma and platelets) and parasite present within brain post-capillary venules, and leading to the microvascular lesion during CM. For this, I will study the responsiveness of EC isolated from CM patients (post-mortem) to pro-inflammatory stimulation, compared to tissue-derived cells from non-fatal malaria patients (needle aspirate). In addition to endothelium, parasites will be isolated from all patients, and I will compare cytotoxicity levels among diagnostic groups. Thiswill be performed by measurement of endothelial alteration after cytoadherenceof parasite only, or clumped with platelets on human brain EC. Finally, I will set up a 'single patient' ex vivo model of CM pathogenesis by culturing EC, parasites and platelet-rich plasma isolated from the same patients. I willmeasure variations in endothelial permeability, electrical resistance and viability. By restricting in vitro bias, this model will allow more precise analysis of parameters involved in endothelial impairment in CM.

Amount: £275,473
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine