MRC CiC successful applicants 2017

Controlling malaria transmission using environmentally ‘friendly’ sugar baits

Principal Investigator: Alvaro Acosta-SerranoLiverpool School of Tropical Medicine

Co-Investigators: Mark Paine (VBD-LSTM); Dr Rosemary Lees; Helen Williams (LITE-LSTM); Prof Pedro Oliveira (UFRJ, Brazil)

Blood feeding insects (BFI) are vectors of the most prevalent diseases, with a worldwide disease incidence of over 1 billion cases and more than 1 million deaths annually. Control of BFI typically involves the use of neurotoxic insecticides like organophosphates and pyrethroids. Furthermore, the spread of insecticide-resistance in vector populations demands development of novel approaches to block transmission of vector-borne diseases (VBD). In this project, we aim to evaluate the suitability of insect tyrosine metabolism inhibitor, Nitisinone, in Attractive Targeted Sugar Baits (ATSB). Nitisinone-based ATSB may represent a highly specific and more ‘environmentally friendly’ solution to block transmission of VBD. 

Novel Probe Technology for Multiplex Molecular Diagnostics

Principal Investigator: Emily Adams, Liverpool School of Tropical Medicine

Co-Investigators: Luis Cuevas  LSTM, Thomas Edwards LSTM, Christopher Parry LSTM, Guoliang Fu GeneFirst

Molecular diagnostics are commonly used for the simultaneous identification of multiple pathogens. Standard molecular machines can identify < 5 markers per reaction. Recently we have developed tests capable of identifying 8 antimicrobial resistance (AMR) markers, but this is the absolute limit of our multiplexing ability. The patented Multiplex Probe Amplification (MPA) technology developed by GeneFirst enables us to multiplex up to 30 targets, which could allow more comprehensive viral panels or AMR profiles. In this project, we will collaborate with GeneFirst to design probes for an 11-plex viral panel and transfer this technology to the QuRapID platform (BioGene) for direct from blood fever panel diagnostics. We will also design a 20-plex AMR assay to be used on stored isolates. 

In vivo Safety Assessment of the 8-aminoquinoline lead analog SL-6--41

Principal Investigator: Giancarlo Biagini, Liverpool School of Tropical Medicine

Co-Investigators: Prof Stephen Ward (LSTM); Prof Paul O’Neill (UoL); Prof Rosemary Rochford (University of Colorado); Dr Fabian Gusovsky (Eisai Ltd)

Identification of a safe and effective primaquine replacement that offers prophylaxis, transmission-blocking activity and radical cure of relapse malaria is a high priority. We have recently developed a second-generation 8-aminoquinoline, known as SL-6-41, which has been designed to have a lowered haemolytic potential. In vitro assays indicate that SL-6-41 retains efficacy against liver stage P. falciparum, as well as early (I-III) and late (IVV) sexual gametocyte stages. In this project we wish to assess the safety of SL-6-41, in particular the potential for haemolytic toxicity, in a specialised G6PD-deficient human RBCengrafted NOD-SCID mouse model. Demonstration of safety in this model would result in the accelerated progression of this compound into a drug development programme.

Selecting modulators of PAR signalling as adjunct therapies for cerebral malaria.

Principal Investigator: Alister Craig, Liverpool School of Tropical Medicine

Co-Investigators: Chris Moxon (University of Liverpool); Dr. Kentaro Yoshimatsu (Eisai Co. Ltd., Tsukuba, Japan)

Artemisinin reduces overall mortality from severe malaria but does not improve outcome in the subgroup of children with cerebral malaria (CM) who die from rapid progression of brain swelling, typically in the first 24 hours after hospital admission. Drugs to stabilise blood brain barrier (BBB) function and prevent progression of brain swelling are needed. Recent findings indicate the PAR-signalling axis as a key mediator of BBB breakdown. We will use a coculture model of brain endothelium and infected erythrocytes to down-select existing PAR modulators for their ability to restore BBB function and to identify leads for clinical testing.

Pharmacokinetics of azithromycin and ciprofloxacin in the management of typhoid fever

Principal Investigator: Nick Feasey, Liverpool School of Tropical Medicine

Co-Investigators: G Biagini, C Parry (LSTM), Malick Gibani, Celina Jin, Andrew Pollard (All Oxford Vaccine Group, Jenner Institute)

Acquisition of antibiotic resistance, either by mutation or horizontal gene transfer, often incurs a fitness cost. Development of multiple resistances usually incurs a cumulative fitness cost. However, in some instances these resistance determinants interact to either increase or decrease this cumulative fitness costs in a process known as epistasis. We aim in this project to determine if there are treatment regimens that can maximise this fitness cost leading to rapid replacement of multi-drug resistance strains of Escherichia coli following cessation of treatment.

Development and testing of MVA VerOx

Principal Investigator:  Sarah Gilbert. Jenner Institute, University Of Oxford 

Co-Investigators:  Dr. Sarah Sebastian (Jenner Institute, University Of Oxford)

The replication-deficient poxvirus vector MVA is being used to produce vaccines against many pathogens such as malaria, tuberculosis, Ebola, and other tropical diseases. However, the ability to manufacture the vaccine is hindered by the lack of suitable accessible cell lines. We will develop a modified version of MVA (MVA VerOx) that can be manufactured to high titre in the widely available Vero cell line which will remove a major barrier to the use of this safe and highly immunogenic vector in multiple vaccines.

In vivo screening of resistance breaking compounds

Principal Investigator: Gareth Lycett, Liverpool School of Tropical Medicine

Co-Investigators:  Rosemary Lee (LITE); Dave Malone (IVCC)

Great strides are being made in the development of novel and repurposed compounds that break insecticide resistance. As a spin off to basic research into mechanisms of resistance in mosquitoes, we have developed a system in which these novel insecticidal compounds can be rapidly tested in genetically defined mosquitoes for their resistance-breaking efficacy. This prototype system is now being used by industry to prioritise their passage down the deployment pipeline. This CiC award is needed to expand the range of GM mosquitoes available for screening that will encompass the main mechanisms of resistance.

International MDRTB contact e-registry to enhance surveillance and contact management, create platform for research and generate real-time observational cohort.

Principal Investigator:  David Moore LSHTM

Co-Investigators:  Kate Gaskell (LSHTM)

3 million household contacts are exposed to MDRTB annually but optimum management of them is unclear. Results of trials of preventive therapy are expected post-2021, potentially offering a therapeutic option. For now, WHO advises 6-monthly surveillance for 24 months but countries struggle to deliver this. In Bhutan and Somaliland, we will implement an electronic registry, populated by TB nurses during contact tracing using a simple Android-based app, through the established DHIS- 2 platform. This will systematize and improve contact follow-up, simultaneously generate a large international observational cohort, and create a ready-to-go line list of subjects eligible for further preventive therapy. 

Development of smart materials for insect vector control

Principal Investigator:  Mark Paine Liverpool School of Tropical Medicine

Co-Investigators: Prof Rasmita Raval (UoL, Interdisciplinary Research Centre); Helen Williams (LITE) Rosemary Lees (LITE/LSTM); Mark Rowland (LSHTM)

Insecticide treated materials such as bed-nets and sprayed walls are principle methods of vector control. However, wide variation in insecticide efficacy is found when measuring killing efficiency (bioassays) on different surfaces. Very little is known about the molecular detail of insecticides on surfaces. The UK Interdisciplinary Research Centre (IRC) in Surface Science is at the forefront of mapping molecular behaviour at surfaces. This will be applied to determine exactly how insecticides are deposited on surfaces and how to maximise their application. This will be used for the development of smart materials capable of enhancing presentation of compounds for maximum bioefficacy.

Development of a novel bivalent vaccine to prevent both Salmonella Typhi and Paratyphi infections 

Principal Investigator:  Christine Rollier. Jenner Institute, University Of Oxford

Co-Investigators:  Prof Andrew POLLARD (Jenner Institute, University Of Oxford); Dr Christina Dold (Oxford Vaccine Group); Dr Malick Gibani (Oxford Vaccine Group)

The aim of this project is to accelerate the development of a novel bivalent vaccine against enteric fever, based upon a recently described virulence factor common to both Salmonella Typhi and Paratyphi. Enteric fever is a major global-health problem, affecting more than 20 million people in tropical low and middle-income countries. A bivalent vaccine would be a particularly cost-effective approach to improving health in the affected areas. We have created viral-vectored vaccines expressing key subunits of the typhoid toxin, and will compare their immunogenicity and protective capacity in order to select and progress the optimal candidate into clinical development.

Drug target deconvolution in the obligate intracellular bacterium, Wolbachia: a chemical proteomic route to discovering novel antibacterial targets

Principal Investigator: Mark Taylor, Liverpool School of Tropical Medicine

Co-Investigators:  Dr Kelly Johnston (LSTM); Prof Paul O’Neill (University of Liverpool); Dr W. David Hong (LSTM/UoL); Dr Dale Kempf, Dr Tom von Geldern (AbbVie)

Lymphatic filariasis and onchocerciasis are parasitic diseases that can inflict severe disability. Targeting an essential bacterial symbiont, Wolbachia, with drugs leads to death of the adult worms: an important advance over currently used treatments. The Anti-Wolbachia (A·WOL) consortium has discovered thousands of potential new drugs that kill Wolbachia, but the specific targets within the bacteria are unknown. This project will utilise chemical biology techniques to identify the proteins targeted by selected anti-Wolbachia drugs with the aim of developing workflows and technologies to identify novel antibacterial targets and tools to monitor resistance.

Development of pyrazolopyrimidines as anti-tuberculosis agents – hit identification, confirmation and hit-to-lead optimisation

Principal Investigator: Steve Ward, Liverpool School of Tropical Medicine

Co-Investigators: Prof G. Biagini (LSTM), Prof P. O’Neill (University of Liverpool), Dr Ann Rawkins (PHE, Porton Down), Dr D. Hong (University of Liverpool), Dr G. Nixon (University of Liverpool) Dr Fabian Gusovsky (Eisai Ltd)

The co-investigators have identified novel pyrazolopyrimidines with in vitro activity against Mycobacterium tuberculosis and favourable DMPK properties. In this MRC CiC we wish to undertake proof-of-concept studies to determine the in vivo efficacy of this class of inhibitors in a validated Mtb rodent model (PHE, proton Down). In addition, a more detailed SAR of the pyrazolopyrimidines will be undertaken using both existing in-house and newly synthesised pyrazolopyrimidines tested against a number of Mtb in vitro assays including MDR Mtb clinical isolates. If successful, these data will form the basis of a full drug discovery programme.

Development of Methylcitrate Metabolism Inhibitors, a Novel Class of Antibiotic for Chronic Intracellular Infections

Principal Investigator:  Sam Willcocks. LSHTM

Co-Investigators: Prof Brendan Wren (LSHTM); Dr Mark (Gardner, Salvensis)

We have invented a new class of antibiotic that selectively targets intracellular infection. Such infections are the cause of chronic diseases caused by pathogens such as Mycobacterium tuberculosis and Burkholderia pseudomallei. Modern antibiotics are poor at treating chronic disease, and they are associated with drug resistance, high cost and duration of treatment, and often relapse and spread of the pathogen. We aim to optimise the best compound design for in vivo activity in the mouse model, so that we can move towards clinical testing of a single novel antibiotic.