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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

Controlled Human Infection Models Development Funds UNS58184 17 Nov 2017

The Wellcome CHIM team have invited a Development Award application in the preparation of the full Malawi Accelerated Research in Vaccines by Experimental and Laboratory Systems (MARVELS) grant. The Blantyre international workshop "CHIM in LMIC" (May 2017) identified key areas for MARVELS to address before set-up. These were: Acceptability, ethics and governance Laboratory systems for inoculum preparation and detection Clinical systems for recruitment, safe inoculation and close follow-up. This workshop published proceedings which further detailed the tests to be applied in each of these domains, and form the basis of this application for a Development Award (Wellcome Open Research 2017;2:70). This Development Award will address the three main areas identified by the Blantyre workshop in order to mitigate the set-up risks of MARVELS Phase 1 on which the whole programme depends.

Amount: £11,140
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Identifying the drivers of insecticide resistance in Brazilian Aedes aegypti 21 Nov 2017

At present, four major arboviruses are transmitted by Aedes aegypti mosquitoes, with Brazil a focus of the disease burden. Due to the absence of antiviral therapies and effective candidate vaccines, vector control via insecticide-based approaches remain the chiefly form of disease intervention. The increase in insecticide resistance due to overuse/misuse of insect-killing chemicals has threatened these vector control strategies. This proposal aims to address the knowledge gap in Brazilian Ae. aegypti with respect to the critical issue of the evolution of insecticide resistance and how unregulated use of domestic insecticides is exerting a selection pressure, which may be driving resistance. We will: I) investigate how household insecticides select for mechanisms of resistance/cross-resistance to pyrethroids in Ae. aegypti; II) Perform the first Brazilian Ae. aegypti pyrethroid-resistant RNA-seq transcriptomic profiling to identify gene sets underlying resistance to complex mixtures typical of household products, and III) Develop molecular diagnostic assays to predict the efficacy of vector control interventions based on a validated suite of metabolic-resistance markers. The results from this work will contribute to a better understanding of the genetic basis of resistance in Brazilian Ae. aegypti, while also providing new insights on how indiscriminate use of household insecticides contribute to increased insecticide-resistance.

Amount: £312,914
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Open Access Awards 2017/18 30 Sep 2018

Not available

Amount: £40,930
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Malawi Accelerated Research in Vaccines, Experimental and Laboratory Systems 12 Mar 2018

MARVELS 1 Respiratory infections are common, potentially vaccine-preventable causes of death. Despite dramatic progress in pneumococcal and influenza vaccination, much remains to be done, both to prevent mucosal disease from these pathogens and the complex effects of co-infections. As nasopharyngeal carriage provides the mode of transmission and the source of infection for pneumococcal disease, it is also an excellent point of intervention to prevent respiratory infections. MARVELS 1 will establish respiratory infection models in the human nasopharynx in order to answer 3 main questions: Which vaccines can prevent acquisition of pneumococcal carriage in Malawi? Which vaccines are most effective in vulnerable populations in Malawi, particularly those with substantial exposure to household air pollution, HIV, malnutrition? What are the critical mechanisms of respiratory tract defence that can be harnessed to develop an effective mucosal vaccine suitable for low and middle income country (LMIC) use? This programme of work will transfer our established controlled human infection models (MRC UK Programme grant) to Malawi in order to test vaccines in populations at risk of disease, determine mucosal immune responses, including those in co-infection and in risk populations, in order to accelerate vaccine discovery.

Amount: £744,874
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

When is enough, enough? Physiological responses to fluid resuscitation in sub-Saharan African adults with sepsis 23 May 2018

How are cardiovascular responses to intravenous fluid determined by causative pathogen, duration of illness and pre-existing cardiac disease in patients with sepsis in Malawi? Over 30 million people develop sepsis every year. The first six hours of treatment is critical, as in severe cases mortality is 25-50%, predominantly due to early cardiovascular compromise. In low income countries, intravenous fluids are used as primary supportive treatment. However, the three existing African trials describe higher mortality in those receiving higher fluid volumes, without any pathophysiological explanation. I will identify important mediators of treatment success in Africa examining biologically plausible candidates: 1) pathogen-specific effects; 2) sub-acute physiological compensation from late presentation; 3) existing cardiovascular pathology (related to rheumatic heart disease, HIV and hypertension). I will investigate cardiovascular dynamics in Malawian adults during sepsis resuscitation and unpick the causes of aberrant physiology by careful aetiological description, detailed cardiac and pulmonary ultrasound monitoring, and measures of tissue perfusion. I will investigate novel and existing mathematical models as predictors of specific adverse outcomes (pulmonary oedema, kidney injury, circulatory collapse), providing a theoretical underpinning for personalised fluid management, and the capacity to hypothesis-test alternative strategies for future clinical trials.

Amount: £813,093
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Characterization of insecticide resistance mechanisms and the impact of vector control interventions on malaria vectors of Papua New Guinea 21 Nov 2017

Pyrethroid insecticide resistance has become a major hindrance in the fight against vector borne diseases such as malaria. A debilitating effect of the wide use of pyrethroid is cross- resistance from pyrethroid formulated for agricultural use and or prior exposure to dichlorodiphenyltrichloroethane (DDT). Emergence of insecticide resistance (IR) compromises vector control programs in controlling disease transmission. Papua New Guinea (PNG) utilizes long lasting insecticide treated bed nets (LLINs) in the country’s national malaria control program. Changes in vector behavior post-LLINs are sustaining malaria transmission. In northern PNG, very high transmissions are observed in areas with supposedly near universal LLIN coverage. Although IR monitoring found PNG vector populations to be fully susceptible to insecticides; recent studies observed several individuals surviving beyond 24 hours after exposure to DDT and deltamethrin. Further investigation is essential for resistance mechanism identification. This study aims to investigate further into the impacts of LLIN on vector populations in different transmission foci and the evolution of IR mutations within these vector populations in order to understand the underlying factors driving the observed transmission patterns. In addition, generate insights on strategies to mitigate the onset of phenotypic IR and avoid pyrethroid control failure in PNG.

Amount: £80,847
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Enzyme inhibitors as a novel treatment for snake venom induced necrosis 31 May 2018

Snakebite is a neglected tropical disease that causes both systemic (~125,000 fatalities per annum) and local (up to 500,000 cases of long-term morbidity) toxicities. Snakebite therapy, known as antivenom, is highly ineffective at treating the local tissue destructive effects of snake venom, as antivenom antibodies are poor at crossing the blood-tissue barrier. In this project I will assess the validity of neutralising necrotic snake venoms with an alternative approach - enzyme inhibitors, which will target the toxin families (snake venom metalloproteinases and phospholipases A2) known to cause local tissue destruction. To do so, I will screen a range of small molecules that have been licensed as human medicines or demonstrated to be safe in clinical trials, to facilitate rapid translation. I will first use in-house, small-scale, biochemical assays to characterise the metalloproteinase and phospholipase activity of ten known necrotic venoms, before assessing the neutralising capability of the inhibitors in the same assays. Next, I will use matrigel as a substrate representing the basement membrane extracellular matrix for degradation based assessments. The results of these assays will identify the optimal combination of anti-necrosis enzyme inhibitors that can be taken forward into preclinical assessments of in vivo venom neutralisation in the future.

Malawi Liverpool Wellcome Trust Programme - Core Award 01 Jun 2017

We will achieve internationally excellent translational science to benefit human health with a focus on sub-Saharan Africa. MLW is built around excellent laboratories, strategically located in the largest hospital in Malawi, closely linked with the community and an integral part of the medical school. These relationships provide a valuable opportunity replicated in few centres in Africa to study major health issues spanning both community and hospital. We will manage two major Programmes: (1) Preventing death from severe infection, and (2) Transmission reduction in infectious diseases and continue to publish over 100 papers/year. Over the next 5 years, we will target clinical syndromes of sepsis, meningitis, diarrhoea and pneumonia with vaccine, behavioural and clinical management strategies. We will focus on transmission of HIV, TB and malaria with improved access to care, diagnosis and treatment. In addition, a Strategic Initiative will target selected high burden chronic diseases (lung impairment, stroke, blindness), particularly related to HIV. In partnership with the College of Medicine we will deliver Training that will attract, train and retain local and international senior scientists. Through our partnership with the Ministry of Health, our Policy Aims will ensure that our research is both relevant and applied to improve human health.

Amount: £25,084,066
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

A pragmatic randomised study to optimise screening, prevention and care for tuberculosis in Malawi (PROSPeCT Study) 25 May 2017

Ambitious global targets have been set to eliminate tuberculosis as a public health problem by 2035. However, in Africa, where HIV has driven extremely high incidence rates, progress in reducing new infections and TB deaths remains too slow. My previous research has shown that adults seeking diagnosis and treatment for TB and HIV face considerable barriers, and have high pre-treatment mortality. Efforts to reduce TB mortality have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can be best implemented. The key goals of this Fellowship are: To develop expertise in pragmatic trial design, statistical analysis and policy-translation In a pragmatic randomised trial among adults with TB symptoms in Blantyre, investigate the effects of optimised TB/HIV diagnosis and treatment linkage on case detection and treatment initiation In a nested sub-study, evaluate the accuracy of computer-aided digital chest x-ray triage classification (normal vs. any abnormality) compared to expert radiologist classification and bacteriological diagnosis. This research will provide urgently-needed evidence to inform policy decisions on how best to improve TB/HIV diagnosis and treatment in Africa. The training opportunities will help me develop internationally-recognised expertise in pragmatic randomised trials.

Amount: £1,077,349
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

CHIMs in LMICs, a workshop to explore regulation and ethics 30 Sep 2017

Vaccines provide an efficient strategy to control infectious diseases in LMIC but the discovery pathway rarely involves the LMIC population at risk until Phase 3 clinical trial. Controlled human infection models offer a fast, effective, economic means to down-select vaccine candidates at Phase 2 and hence reduce the risk of Phase 3 failure. Vaccine target populations with endemic exposure to infectious pathogens (e.g. malaria), or a particular immunomodulatory challenge (nutrition, crowding, intense exposure, HIV infection) are likely to show different, and more relevant, results in CHIM studies. There are, however, key methodological, ethical and regulatory issues in the safe conduct of human infection models that must be addressed in any population before CHIM studies can be planned. The rationale for this workshop is to explore the particular methodological, ethical and regulatory issues associated with CHIM in Malawi.

Amount: £48,400
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Ethical concerns for health professionals, media and the public in promoting adequate and safe blood transfusion services in Africa: a case study of Ghana and Zimbabwe. 21 May 2012

Ethical concerns abound in the area of providing effective blood transfusion services. In many parts of Africa, there are strong cultural and spiritual beliefs about blood. Blood transfusion services rely on donations from the general public and therefore the public view of blood and blood donation is absolutely critical. The media have a significant role to play in encouraging a healthy perception of the importance and safety of blood transfusion services, and this raises a series of ethical implications for journalists, health professionals and the public. Strong relationships and partnerships between blood transfusion centers and the media in Africa are vital. This research project in Ghana and Zimbabwe aims to explore the ethical concerns ofdifferent actors in relation to blood transfusion services and work to build stronger partnerships to improve donation rates of safe blood.

Assessing the effects of piperonyl butoxide (PBO) exposure on malaria vector fitness 19 Jun 2017

Malaria occurrence has decreased remarkably across sub-Saharan Africa over the past 15 years. This is largely due to the mass distribution of LLINs. However, the main type of malaria vectors, including Anopheles gambiae and Anopheles funestus, have gained resistance to pyrethroids.This threatens the future effectiveness of LLINs, and alternative solutions and compounds are urgently needed. One solution is a long-lasting insecticidal treated net (LLIN) containing both a pyrethroid and a compound known as piperonyl butoxide (PBO). PBO is a synergist that inhibits a group of enzymes (P450s) inside the insect which metabolise pyrethroids causing resistance.P450 enzymes play a large role in other physiological processes in insects such as maintaining hormonal balance and synthesis of the external cuticle. By inhibiting P450s, exposure to PBO may negatively affect these processes causing further reductions in the Anopheles population. This project will look at the impact of exposing local vector populations in southern Malawi to PBO-LLINs and quantifying the impact of exposure on mosquito longevity and reproduction. Exposure to PBO-LLINs will also determine whether PBO modifies these mechanisms and make mosquitoes more susceptible to pyrethroids. This project will help inform policy makers of the effectiveness of PBO-LLINs as part of vector control strategies.

Amount: £129,219
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

Prenatal malaria exposure and infant health and development: A prospective birth cohort study (PRiME) 22 Nov 2016

Recent evidence suggests that infants born to pregnancies exposed to malaria have more clinical malaria and anaemia following pre-natal exposure to malaria antigens leading, in some children to a blood-stage antigen tolerant phenotype that persists into childhood, yet in others to effective foetal immune priming. This may have important implications for malaria control and vaccination of children in endemic areas. We hypothesise that the timing and frequency of malaria infections during pregnancy affects the efficiency of foetal immune priming and the trans-placental transfer of antimalarial immunoglobulin and therewith the childhood susceptibility to malaria infections. Additionally, that adequate control of malaria during pregnancy may improve trans-placental transfer of protective antibodies to other infections, and potentially the vaccine immune responses to Extended Programme of Immunisation (EPI) related vaccines. Using mostly data from two upcoming funded studies linked to the Wellcome Trust, combined with assessment of vaccine immune responses, we will explore this in 1,123 infants born to HIV-negative pregnant women enrolled in a three-arm trial to determine the efficacy of novel Intermittent Preventive Treatment in pregnancy (IPT) These same infants will subsequently enroll into an observational cohort study to determine incidence of clinical malaria and other severe illnesses during early childhood.

Amount: £143,200
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Evaluation of the Evidence Informed Decision making Network in Malawi (EvIDeNt) using policy analysis and prospective case study 22 Nov 2016

This study will evaluate the effectiveness of the Evidence Informed Decision-making Network for Health Policy and Practice in Malawi (EvIDeNt) in strengthening links between research and policy. There will be a particular focus on uptake of malaria research. The study aims to support evidence-informed health policy by strengthening EvIDeNt and advancing understanding of factors influencing research uptake. The study will have two components: an overall mid-term evaluation of EvIDeNt, and a prospective case study of a malaria trial to trace specific effects of EvIDeNt and identify factors affecting research uptake. The overall EvIDeNt evaluation will assess aspects such as perceived added value, connections between members and initial results. Methods will include a workshop with EvIDeNt members, interviews with members and researchers and policy-makers targeted by EvIDeNt activities, and document analysis. This evaluation will draw on findings from a baseline study conducted in 2017. The case study will examine uptake of findings from a multicentre trial of the safety and efficacy of dihydroartemisinin-piperaquine compared to sulphadoxine-pyrimethamine as intermittent Preventive Treatment in pregnancy in Kenya, Malawi and Tanzania (Feb 2017-Feb 2019). Methods will include interviews with the research team and policy-makers, observation of study and policy activities, document analysis and focus groups.

Amount: £114,514
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine

Costs and cost-effectiveness analysis of larval source management and house improvement when added to standard vector control strategies in a rural setting with high malaria transmission and seasonal variation in Malawi 22 Nov 2016

Malaria transmission reduction relies on prompt case management, preventive treatment in pregnant women and vector control, mainly through long lasting insecticide-treated bed nets (LLINs) and indoor residual spraying (IRS). Insecticide resistance threatens current vector control strategies. Larval source management (LSM) and structural house improvement (HI) are potential additional interventions. LSM is being used in an increasing number of countries, but fears about high implementation costs are a barrier to implementation. The costs and effects of LSM and HI in rural settings have not been systematically assessed. From 2016 to 2018, a randomised controlled trial is evaluating the impact of LSM and HI on malaria transmission when added to LLINs in rural Chikwawa, southern Malawi. Changes in incidence of clinical malaria in children aged 6 to 59 months across trial arms is also being measured. We intend to conduct a within-trial cost-effectiveness analysis to determine the cost and cost-effectiveness of adding LSM and HI to LLINs. Using the societal perspective, we will determine financial and economic costs for each intervention. We will also determine the incremental cost per childhood (6 – 59 months) malaria case averted for each intervention. These findings, we hope, will facilitate policy uptake of positive trial outcomes.

Amount: £153,213
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

Raising awareness and interest in biomedical science research in Malawian schools 27 Nov 2016

The host antiviral immune response is relatively effective at recognising and eliminating most HIV-infected cells. However, HIV manipulates resting memory CD4 T cells and persistently resides in them in a latent state, resulting in formation of viral reservoirs. These reservoirs are poorly recognised by antiviral cytotoxic cells and are less susceptible to the effects of the current antiretroviral therapy (ART), leading to incomplete clearance of the infection. In the lung, alveolar macrophages (AM) have a long life span, can harbour HIV and are relatively resistant to the cytopathic effects of HIV, making them an important potential viral reservoir. Recently, we have shown that HIV persists in AM in HIV-infected individuals on long term ART despite undetectable plasma viraemia. This fellowship proposes using bronchoalveolar lavage (BAL) and peripheral blood obtained from HIV-infected and uninfected Malawian adults to address the hypothesis that HIVs ability to hinder immune recognitio n and block the induction of apoptosis leads to its persistence in AM. Specifically, the following questions will be addressed a) How does HIV hinder immune recognition of HIV-infected AM by cytotoxic cells? b) How does HIV block progression to apoptosis in HIV-infected AM? c) Which viral proteins are responsible for modulation of macrophages?

Amount: £30,800
Funder: The Wellcome Trust
Recipient: Liverpool School of Tropical Medicine