MRC CIC successful applicants 2019

Dr Anne Wilson

LSTM

Prof Philip McCall (LSTM, UK) Jakob Knudsen (Royal Danish Academy of Fine Arts) Prof Steve Lindsay and Majo Carrasco Tenezaca (Durham University, UK) Prof Umberto d’Alessandro and Musa Jawara (MRC Unit The Gambia at LSHTM)

Simple, affordable house ventilation for cooler, mosquito-free nights

Malaria mosquitoes are attracted to carbon dioxide and human odours which emanate from inhabited houses at night. We will develop a simple air ventilation system that will expel warm human exhalations and body odours through a chimney, while drawing in cooler air through a screened vent in the wall. We propose that this controlled removal of carbon dioxide and host odours will reduce the number of malaria mosquitoes entering the house, and the simultaneous intake of cooler air will provide better thermal comfort at night.

£45,977. 

Professor Roger Hewson

PHE

Ian Jones (University of Reading)

Development of a Rapid, Low-Cost, Near Patient Microcapillary Fluidic Test for the Detection of CCHFV Antibodies

The development of diagnostic assays for Crimean-Congo haemorrhagic fever (CCHF) has been identified as a strategic goal in WHO’s CCHF R&D Roadmap. This project would demonstrate the feasibility of utilising a low-cost fluoropolymer microfluidic platform, that is suitable for near patient testing and the rapid detection of CCHFV antibodies. It would establish the viability of this approach versus current methods that are costly and not suitable for use in the remote regions of CCHFV endemic countries that bare the largest burden of disease. Thereby accelerating translational research with the potential to deliver positive change.

£44,721.2

Professor David Moore

LSHTM

Prof Tim McHugh (UCL)

The Molecular Bacterial Load Assay for the management of drug resistant tuberculosis

The speed with which patients treated for multidrug resistant tuberculosis (MDRTB) respond to therapy determines how long they need to remain in respiratory isolation and whether treatment needs to be changed. Current phenotypic tools are slow, only confirming culture-negativity 6 weeks after a sample is taken, whilst faster molecular (DNA-based) methods cannot distinguish live from dead bacteria. The Mycobacterial Bacterial Load Assay (MBLA) developed at UCL accurately reflects changes over time in viable mycobacterial burden in sputum. We plan to demonstrate the use of MBLA in the clinic to track declining mycobacterial load

£46,000. 

Professor Roger Hewson

PHE

None

X-ray irradiation for inactivation of acutely infected cellular samples for downstream immunological processing

This proposal concerns the development of a high energy X-ray irradiation methodology for the inactivation of bloods collected from patients with acute viral haemorrhagic fevers and other high consequence infectious disease (HCID), for analysis by flow cytometry outside high/maximum containment (i.e. CL3 and 4 laboratories). This novel approach will ease pressure on high-containment facilities, expand capability at lower containment and make available specialised reagents to the wider scientific community. In addition, it will catalyse research through the identification of biomarkers and correlates of protection for high-consequence pathogens, which so far has only been possible in a limited number of high containment laboratories. Additionally, this approach will also support a reduction in the use of animal models for biomarker development.

£39,138.64

Dr Kirsty McHugh

Jenner, Oxford

Prof Simon J Draper (Jenner Institute), Prof Richard J Pleass (LSTM)

Antibody engineering to improve efficacy of prophylactic monoclonal antibody-based drugs against human malaria

A significant challenge in the development of a malaria vaccine is the lack of effective formulations of an antigen that can induce the high concentrations of functional antibodies required to achieve an effective and protective antibody response; consequently a highly effective vaccine remains lacking. Using long-lived potent monoclonal antibodies (mAbs) as prophylactics, combined with anti-malarial drugs, could provide an alternative route to accelerate malaria control and elimination programmes. Maximising mAb potency will be central to success of this approach. Increased mAb potency would greatly reduce the serum concentration of mAb required, make alternative routes of administration feasible and extend the effective mAb half-life, providing a cost-effective malaria control strategy. Here we propose a proof-of-concept study that takes previously characterised mAbs against two leading malaria targets (CSP and RH5) and seeks to substantially improve their efficacy through simple proprietary molecular engineering of their Fc region to increase avidity and effector function.

£41,400. 

Professor Nick Casewell

LSTM

Prof. Robert Harrison (LSTM)

Selection and validation of small molecule toxin inhibitors for combatting morbidity associated with snakebite

Half a million people suffer from snakebite morbidity each year, and current therapy is largely ineffective. We previously demonstrated that small molecules offer great potential as early interventions against systemic pathologies caused by snakebite, but their efficacy against local tissue damage remains unknown. Here, we will screen 2,000 small molecules, provided to us by our commercial partner Johnson & Johnson, to quantify their inhibitory activity against snake venom cytotoxins. We will do so using a rational selection strategy consisting of in vitro and ex vivo assays. We anticipate identifying lead compounds for future translation into community-based treatments for preventing snakebite morbidity.

£44,925.44

Professor Luis Cuevas

LSTM

Emily Adams (LSTM) and John Bimba (Bingham University, Nigeria)

The super-dry cup for the appropriate transport of sputum for TB diagnosis in low-income countries.

Tests for tuberculosis require ‘good-quality’ sputum transported in a cold-chain to maintain its DNA integrity. In low-income-countries the cold-chain is poor, and sputum often reaches the laboratory in poor condition. We propose a low-cost Super-Dry-Cup (SDCup), which filtrates and desiccates the sputum at the time of sample collection, preserving the MTB-DNA during transport at ambient temperature. This project will optimise the SDCup to reach a design-lock and demonstrate the cup’s fitness to preserve MTB-DNA for Xpert /Line-Probe Assay testing for diagnosis, drug-sensitivity testing and culture. The cup can create a paradigm-shift to access TB diagnostics in low-income-countries.

£45,566.68

Dr Emma Kennedy

PHE

Roger Hewson (PHE)

Developing a vaccine for Lassa fever: Efficacy of vaccine candidates in a guinea pig model

This project aims to continue the investigation into vaccine candidates for Lassa fever. Following on from previous successful immunogenicity studies; this study will advance the most promising vaccine candidate/s into a challenge model in guinea pigs. Animals will be split into groups and either vaccinated in a prime/prime-boost regime or remain as controls. They will be challenged with guinea pig adapted Lassa virus. This project will analyse the efficacy of the vaccine candidate/s as well as comparing viral load analysis, histopathological differences and immune responses of the vaccinated versus non-vaccinated animals.

£49,438.96

Professor Hilary Ranson

LSTM

Prof Giancarlo Biagini, LSTM, Professor Paul O’Neill, UofL, Dr Lisa Reimer, LSTM, Dr Vicky Ingham, LSTM

A pipeline to evaluate the impact of current and new insecticides and drugs on malaria development in insecticide resistant mosquitoes

We will establish a robust pipeline of Plasmodium falciparum infections in insecticide resistant populations of Anopheles mosquitoes maintained at LSTM. This will be used to address critical unanswered questions on the impact of insecticide resistance on malaria transmission and to screen new insecticides, emerging from our industry partners and IVCC, to determine whether exposure to these chemistries impacts the development of the malaria parasite in the mosquito. Finally, we will use this platform to develop preliminary data on the potential for the new quinoline antimalarials developed by UoL/LSTM could be incorporated into vector control tools.

£45,515.16

Dr Robin Basu Roy

LSHTM

Dr Jamilah Meghji, (LSTMed). Professor Serge Mostowy, (LSHTM). Dr Rachel Davies, (Imperial College Healthcare NHS Trust)

Pulmonary arterial hypertension agents as adjunctive host-directed therapy for tuberculosis – a dual benefit of enhanced mycobacterial control and prevention of post-TB lung disease?

This project investigates the potential for a prostacyclinbased host directed therapy to improve TB patient outcomes. Preliminary experimental data suggest that the prostacyclin pathway is involved in effective host mycobacterial control. This axis is also involved in the pathophysiology of pulmonary artery hypertension (PAH), which may be common amongst TB-survivors. We hypothesise that manipulating the prostacyclin axis during TB treatment could enhance mycobacterial killing and prevent TB-related PAH. We will collect clinical data to estimate the prevalence of PAH amongst TB-survivors, and experimental data on the role of prostacyclin in vascular pathology and mycobacterial killing in the zebrafish TB model.

£46,000. 

Dr Joseph Turner

LSTM

Mark Taylor (LSTM), Steve Ward (LSTM), Paul O’Neill (University of Liverpool), Fabian Gusovsky (Eisai Inc)

Combination therapy of the anti-Wolbachia candidate, AWZ1066, with albendazole: preclinical assessment of dose, dose-duration and mode-of-action

There is urgent requirement to develop a short-course cure for filariasis. An ideal candidate would deliver macrofilaricidal activity following ≤7-day treatment. We recently discovered a drug synergy when combining registered antibiotics with the standard anthelmintic, albendazole (ABZ) in enhancing anti-Wolbachia and embryostatic activities with shorter drug durations. Pilot data confirms synergy is also apparent when drugging ABZ with the preclinical anti-Wolbachia candidate, AWZ1066. This project will determine the minimum time frames required to mediate relevant anti-Wolbachia depletions and/or embryostatic activity of ABZ+AWZ1066 combination against the human filaria, Brugia malayi, in a mouse model. Simultaneously, we will collect pilot data to test a hypothesised mode-of-action of drug synergy. The project will deliver a minimum drug combination regimen to inform phase II clinical trial design.

£47,255.8

Dr Joseph Turner

LSTM

Professor Mark Taylor (LSTM), Dr Patricia Graves, (James Cook University, Australia)

Non-steroidal anti-inflammatory drugs: affordable and safe treatment for filarial lymphoedema?

Filarial lymphoedema (LE: elephantiasis / hydrocoele) remains a leading cause of global disability. In the face of potential elimination of lymphatic filariasis by 2030, an estimated 40 million LF patients will endure a life-time of progressive and stigmatising disability. New, affordable antimorbidity strategies are required to treat filarial LE. Our preclinical evidence has determined an immune-mediated inflammatory pathway inducing filarial lymphatic pathology following experimental infection. In this project, we will characterise eicosanoid inflammatory mediator profiles (e.g. prostaglandins, leukotrienes) before testing specific registered, small molecule, non-steroidal anti-inflammatory drugs (NSAID) targeting facets of eicosanoid metabolism for efficacy in an in vivo filarial-associated lymphatic pathology model. We will further validate putative eicosanoid drug targets using a clinical LF biobank.

£44,876.68