MRC CiC successful applicants 2016

Facilitating Candidate Selection of E209 - a tetraoxane based rapidly acting antimalarial

Principal Investigator: Prof Stephen Ward  Liverpool School of Tropical Medicine
Prof G. Biagini (CI - LSTM)
Prof P. O’Neill (CI – University of Liverpool)
Dr G. Nixon (CI – University of Liverpool)
Dr Fabian Gusovsky (CI – Eisai Ltd)
E209 is a tetraoxane based rapidly acting antimalarial currently in development which has been invited for candidate selection by MMV. To complete this process a key toxicological study needs to be repeated to include a recovery period omitted in the original study. Funds are sought to carry out a 7 day dose range finding toxicity study in rats with a 14 day recovery period. Completion of this study will facilitate candidate selection by MMV. Funders GHIT have indicated that this endorsement by MMV would enable them to release funds to progress the compound through a pre-clinical package to first-in-man studies.

New tool to predict insecticide resistance: development of Activity Based Probes to identify metabolic resistance genes in tropical disease transmitting insects

Principal Investigator:  Dr Mark Paine. Liverpool School of Tropical Medicine

Hanafy Ismail – LSTM
Mark Rowland – LSHTM
James Austin – BASF
Michael David – BASF
Paul O’Neill – University of Liverpool
Insecticide resistance is the major barrier to disease control. Insects contain >100 P450 genes that metabolise xenobiotic compounds. Detoxification due to elevated expression of one or more P450s is a major cause of resistance. Chlorfenapyr is a new pro-insecticide product being introduced for malaria control that is activated and inactivated by P450s. We can design ABPs that rapidly identify the individual P450s that metabolise target compounds. This will be applied to fast track the identification of CFP metabolising P450 enzymes for the development of a diagnostic ‘pre-resistance’ platform for monitoring augmenting and resistance P450 markers ahead of the resistance curve.  

The development of a multiplex assay, using the Biogene QuRapid direct PCR system, for the detection of antimicrobial resistance markers and bacterial identification in Gram-negative sepsis 

Principal Investigator: Dr Emily Adams, Liverpool School of Tropical Medicine
Dr. Thomas Edwards (LSTM)
Dr. Nick Feasey (LSTM)
Dr. Glyn Hobbs (LJMU)
Dr. Katie Evans (LJMU)
Dr David Edge (Biogene, Cambridge).
We aim to develop a High Resolution Melt (HRM) assay capable of the detection of common sepsis causing bacteria, and identification of antimicrobial resistance markers, including ESBL and AmpC production, and CAT genes, in a single tube.

Development and application of a Recombinase Polymerase Amplification (RPA) point-of-care test for the detection of Giardiasis in resource limited settings. 

Principal Investigator: Dr Amaya Bustinduy, London School of Hygiene & Tropical Medicine
Prof. Michael Miles, LSHTM
Prof. Russell Stothard, LSTM
Prof. Steve Allen, LSTM
Giardiasis is a significant gastro-intestinal disease caused by Giardia lamblia with over 50 million children infected annually. In tropical regions, giardiasis is much under-reported as access to current point-of-care (POC) tests is limited and the available faecal-antigen tests have much lower sensitivity than real-time PCR assays, the diagnostic ‘gold standard’. With advances in isothermal DNA amplification technology, we intend to refine and adapt a novel field-appropriate, POC test based on recombinase polymerase amplification (RPA) useful in resource-poor settings and able to differentiate infection intensities. Validated on laboratory reference material, an external evaluation will be undertaken in a prospective cross-sectional survey in Uganda.

Development of a new virus-like particle (VLP) vaccine for blood-stage Plasmodium falciparum malaria

Principal Investigator:  Dr Jing Jin
Prof Simon J Draper (Co-I), (Jenner) 
Dr Wian de Jongh (ExpreS2ion Biotechnologies, Denmark)
Dr Karin Lövgren Bengtsson (Novavax AB, Sweden)
A significant challenge for vaccine immunologists is the identification of effective formulations of an antigen that can induce the high levels of antibody required to protect against complex parasites. We have recently established a novel ‘plug-anddisplay’ approach to enable the production of viruslike particles that can array antigens that have been refractory to genetic fusion. We now wish to assess this system for proof-of-concept using an improved second-generation immunogen against the PfRH5 antigen. This antigen has been shown to induce broadly-neutralising antibodies against the blood-stage human malaria parasite Plasmodium falciparum.

InFliTE: mosquito behavioural simulation package for rapid evaluation of control tools

Principal Investigator:  Dr Gregory Murray, Liverpool School of Tropical Medicine
JEA Parker (Vector Biology Dept, LSTM)
PJ McCall (Vector Biology Dept, LSTM)
Prof DE Towers, Dr CE Towers, C Kroner (Mechanical and Process Engineering University of Warwick)
Disease vector control methods are under constant pressure to innovate, iterate and improve; whether to combat insecticide resistance, exploit new knowledge of vector biology or to accommodate changes in abiotic conditions. Similarly, control tools are sought that may increase efficacy, reduce costs and improve usability. However, testing the designs of new tools requires time and resources.
Recently, video-tracked behavioural data has allowed this team to tightly define parameters of mosquito host-seeking behaviour. These parameters can now be exploited in order to create a novel virtual testing simulation, allowing a wide range of innovative vector control ideas to be rapidly and easily assessed at marginal cost. In the proposed project, this team will deliver an easy to use computer software package, capable of simulating vector behaviour, allowing an end user to compare alternative designs for vector control tools or systems, initially focussed on LLIN designs, before expanding into traps, screens or larger-scale control methods.

Towards the next generation of Disease Surveillance Systems.

Principal Investigator: Dr Michael Coleman  Liverpool School of Tropical Medicine
Knut Staring (University of Oslo)
Currently, two main solutions for managing disease control programmes in Africa and Asia exist, the Disease Data Management System and the District Health Information System. Both have complementary functionality: the DDMS supports operational decision-making, including disease outbreak detection, entomology, and intervention monitoring. The DHIS2 possesses a strong community of health users. Creating a consolidated analytical platform combining the functionality of both systems will have a transformative impact on the way data is used as an intervention. We expect that such a system would greatly increase the availability of data for use in decision-making in current (malaria) and novel (Zika) programs.

Rational design of a global, pathology-specific antivenom to treat lethal, snake venom-induced haemorrhage.

Principal Investigators: Dr Nicholas Casewell and Dr. Robert A. Harrison, Liverpool School of Tropical Medicine
Antivenoms for treating snakebite have, because of current manufacturing protocols, limited cross-species neutralising efficacy, weak specificity and poor safety profiles. We seek to address these deficiencies by generating a first-of-its-kind “pathology-specific” antivenom. Using the haemorrhagic snake venom metalloproteinases as our target, we will use phage display to identify cross-species conserved epitopes as immunogens, and test the efficacy of IgG from the immunogen-immunised mice to neutralise venom-induced haemorrhage in vitro and in vivo. The outputs from this proof-of-principle study will springboard the development of a novel antivenom with global efficacy against venom-induced haemorrhage – the most frequently lethal pathology of snake envenoming.

Pandemic Preparedness for Endemic Viral Disease in West Africa

Principal Investigator: Dr Teresa Lambe, Jenner Institute
Prof Sarah Gilbert (Co-I), (Jenner)
Prof Adrian Hill (Co-I), (Jenner)
Prof Stephan Becker (External Co-I), Philipps University Marburg
Dr Edward Wright (External Co-I), University of Westminster
Filoviruses (Ebolaviruses & Marburg virus) and Arenaviruses (Lassa virus) are endemic in several West African countries and are causative agents for viral haemorrhagic fever. There is a clear need for vaccines that confer protective efficacy against Ebola, Marburg and Lassa viral infection. This research proposal focuses on the development of a discrete number of vaccines which can be manufactured and deployed in pandemic preparedness for the next haemorrhagic fever outbreak caused by Ebola, Marburg or Lassa fever viruses. We aim to generate proof-of-concept data supporting subsequent clinical trials.

Evaluation of a Zika virus fowlpox-based vaccine construct in a murine model of infection

Principal Investigator: Prof Miles Carroll, Public Health England
Simon Funnell
Roger Hewson
Stuart Dowall 
Julia Vipond
All from Public Health England, Porton Down

This project is intended to evaluate the protective efficacy of a fowlpox-based vaccine based on addition of important conserved antigens present on the Zika virus. The antigen set will be common to those used in other candidate vaccine modalities with the benefit of greater freedom to pursue commercialisation of the candidate vaccine. PHE has developed a murine model of infection which is essential to evaluate this and other candidate vaccines

Development of a novel biocompatible matrix for sugar membrane technology for thermostability of an adjuvanted malaria vaccine.

Principal Investigator: Prof Adrian Hill, Jenner Institute
Co-Investigators: Prof. Zhanfeng Cui, Professor of chemical engineering, Jenner
Dr. Adam Walters, Post-doctoral fellow, Jenner
Dr. Rebecca Ashfield, project manager, Jenner
Pawan Dulal (DPhil, thesis due for submission, Researcher), Jenner
The sugar-membrane technology currently being advanced at the Jenner Institute has been shown to improve thermostability of a wide range of vaccines including polio, measles, liposome and alum adjuvanted subunit vaccines, and viral vectored vaccines. One of the two key components of the technology, the fibrous membranes comes with a disadvantage of potential fibre shedding and difficulty in GMP standard manufacture. We have identified biocompatible polymers to replace existing matrix. The project aims to produce and test thermostability of an adjuvanted vaccine for malaria on a novel biocompatible GMP manufacturable matrix.