RCDD Tropical Infectious Disease Consortium, MRC CiC – mini-portfolio

The MRC CiC Tropical Infectious Disease Consortium, is a partnership between leading UK institutes involved in translational research in tropical infectious diseases and includes the Research Centre for Drugs and Diagnostics (RCDD) at the Liverpool School of Tropical Medicine, the London School of Hygiene and Tropical Medicine, the Jenner Institute at Oxford University and Public Health England Microbiology Services in Porton Down. 

 

 

 

The funded themes have so far included 10 drug/biologics discovery projects, 1 adjunct therapy project, 1 intervention (bed nets), 16 vaccines development projects (including an evaluation of a Zika virus fowlpox-based vaccine), 11 diagnostic discovery/development projects, 2 anti-venom, and 6 new insecticide resistance, surveillance and control tools.  MRC CiC project funding has directly contributed to 6 patent applications and 1 trademark.  Completed projects have gone on to lever over £9.5 million in additional external funding from a variety of sources including UKRC, Wellcome Trust, Bill & Melinda Gates Foundation and Industry.

The Consortium was successful in securing MRC funding for 2016-17 and a new call for projects will be made in Q2 2017.

The funding philosophy of the consortium will remain the same i.e. funding translational research based on potential medical impact and ‘developability’ and an ambition of significant acceleration in time to product delivery. 

Current MRC CiC Awards:

PI Surname & Institution

Co-Is & Institutions

Title

Synopsis

Amount awarded

 

2013/14 

Emily Adams

Liverpool School of Tropical Medicine

Luis Cuevas (LSTM), Matthew Walls (Epistem), Peter Foster (Epistem)

 

Integrated diagnosis of TB and HIV using Genedrive® technology

Our aim is to develop an integrated cartridge based on Epistem’s Genedrive® technology for the simultaneous diagnosis of Tuberculosis and HIV, including TB drug resistance markers, which is suitable for use at the point of care.

 

 

 

 

£46,260.00

 

Giancarlo Biagini

Liverpool School of Tropical Medicine

 

Stephen Ward (LSTM), Neil Berry (UoL), Paul O’Neill (UoL) and Ann Rawkins (PHE, Porton Down)

Identification of Early Antitubercular Leads using Syngenta assets

 

A 100,000-diverse small molecule library is presently being screened against Mycobacterium tuberculosis (MtB) in the Cat3 laboratories at LSTM. The current funding will only allow for hit confirmation (IC50) against replicating (RP) Mtb in liquid culture (assessed by almar blue 5-day assay). In this MRC CiC proposal we wish to take tractable hits to generate early leads with a data package that would allow for follow-on funding (TBA, MRC DPFS, Wellcome Trust). The Co-Is are involved in a number of TB drug discovery projects (e.g. MRC DPFS) and TB drug consortiums (e.g. IMI TB Predict) and through this experience and in discussions with the TBA (TB Alliance) have identified an accelerated route to lead identification. The Lead Identification (LI) pathway includes; (i) chemoinformatics to remove non-tractable hits, (ii) in house Wayne model to select RP and non-replicative (NRP) Mtb active compounds, (iii) Time-kill assays to identify bactericidal inhibitors, (iv) determination of microsomal stability of compounds to measure in vitro intrinsic clearance (or to identify metabolites formed), (v) Synthesis of prioritised leads and (vi) in vivo testing and preliminary in vivo DMPK.

£46,750.00

 

Simon Croft

London School of Hygiene and Tropical Medicine

Elaine Warburton (QuantuMDx), Prof Sanjeev Krishna and Dr Henry Staines (both St George’s, University of London)

 

Development of a Leishmania identification PCR assay for use with next generation PoC diagnostic devices

The project aims to provide proof of principle for an accurate, rapid and cheap PCR-based point-of-care diagnostic assay for kinetoplastids. This will be achieved by developing a simple Leishmania diagnostic assay that will be ported directly onto a novel point-of-care diagnostic device developed to diagnose and provide resistance status for malaria.

£44,880.00

Alexander Douglas

The Jenner Institute, University of Oxford

Professor Adrian Hill, DPhil FRCP, Jenner Institute, University of Oxford, Collaborator: Erik Jans, Maxcyte Inc

Test many, test quickly, test cheaply- accelerating clinical proof-of-principle for novel vaccines using flow-electroporation-mediated transient transfection of mammalian cells for GMP antigen production.

Production of clinical-grade antigen to Good Manufacturing Practice (GMP) standards is expensive and time-consuming and represents a critical bottleneck in the protein subunit vaccine development pipeline. This project proposes to adapt for use in the vaccine field a proven flow electroporation technology which has been in use for over a decade in the pharmaceutical industry for GMP cell-therapy and small-scale monoclonal antibody production. This has the potential to facilitate clinical translation of future candidate vaccine antigens by dramatically reducing the cost and increasing the throughput of GMP manufacture.

£46,285.00

Simon Draper

The Jenner Institute, University of Oxford

Dr Jack Eby (Vedantra Pharmaceuticals) – External / Industrial Collaborator]

Improving the Longevity of Vaccine-Induced Antibody Responses against the Blood-Stage Plasmodium falciparum Malaria Parasite

Significant challenge for vaccine immunologists is to better understand how to achieve the induction and maintenance of high level protective antibody titres. A novel vaccine delivery platform based on interbilayer-crosslinked multilamellar vesicles (ICMVs) has shown a remarkable ability to lead to high and sustained antibody responses without waning over time. We now wish to assess this system for proof-of-concept using a clinical-grade PfRH5 protein vaccine which has been shown to induce broadly-neutralising antibodies against the blood-stage malaria parasite.

£46,750.00

Philip McCall

Liverpool School of Tropical Medicine

Prof David Towers, Dr Cathy Towers (School of Engineering (Uni Warwick), Dr Fabian Mashauri (NIMR, Mwanza, Tanzania)

Novel bednet designs to improve insecticide-treated net efficacy and combat insecticide resistance

Insecticide treated bednets (LLINs) are essential tools for malaria prevention but their future is threatened by resistance to pyrethroids, the only insecticides permitted on bednets. Using state-of-the-art video-tracking systems, our unique research team of vector biologists and optical engineers has gained extraordinary insight into host seeking behaviour of the major African malaria vector Anopheles gambiae at human-occupied LLINs. Exploiting these newly revealed behaviours we have devised novel LLINs designed to target mosquitoes, while minimising risk of human contact, with a range of insecticidal formulations. In the proposed project, this team will deliver evidence to demonstrate: (1) that An. gambiae will come into contact with the new LLINs, as designs intended; (2) that lethal doses of insecticide can be delivered during those contacts; (3) that pyrethroid-resistant An. gambiae can be killed in this way. The project will involve analysis of video-tracked behaviour and bioassay of mosquitoes, in purpose-built insectary at Liverpool and an experimental field hut in Tanzania.

£46,745.00

Anita Milicic

The Jenner Institute, University of Oxford

Helen Fletcher (LSHTM), Helen McShane,The Jenner Institute (Uni of Oxford)

Novel vaccine encapsulation technology for a single dose prime-boost immunisation against TB

We plan to develop a novel vaccine technology that would enable conversion of prime-boost vaccines into a single dose immunisation, where the boost vaccine is encapsulated for delayed release in vivo, admixed with the priming vaccine and delivered as a single injection. As a proof of concept, we propose to address vaccination against tuberculosis (TB), a major tropical disease threat. Following the optimisation of microcapsule synthesis with a model protein, we will encapsulate the major Mycobacterium tuberculosis (Mtb) secreted protein, Ag85A together with an adjuvant. We will test the delayed release technology by immunising mice with a mixture of BCG and encapsulated adjuvanted Ag85A, and assessing immunogenicity and protective efficacy against TB. To explore this approach further, we will modify the system to administer encapsulated chimpanzee adenoviral (ChAd) vector encoding Ag85A (ChAd-85A) as the boost vaccine, based on our recent pre-clinical observations of high efficacy against TB following a BCG prime, ChAd- 85A boost regimen. The use of this type of microencapsulation would benefit any prime-boost vaccine but could also be adapted to vaccines that require multiple doses for efficacy. The design and composition of the capsules would determine the period of capsule dormancy in vivo, prior to the release of the vaccine, and could be tailored to different vaccines’ prime-boost intervals. Reducing the number of administrations would simplify vaccine deployment by reducing costs and increasing uptake rates. Success in the proposed work would make a strong case for future clinical testing.

£46,750.00

Mark Paine

Liverpool School of Tropical Medicine

Mark Rowland – Head, Department of Disease Control (LSHTM), Hanafy Ismail –Vector Biology (LSTM), Paul Millner –  Professor of Bionanotechnology and Head of School of Biomedical Science (Leeds Uni), Paul O’Neill – Chemistry Dept (Uni of Liverpool)

Development of Adhiron based insecticide monitoring tools

 

Our objective is to develop a set of novel Adhirons that can bind DDT with high specificity.  By producing DDT-Haptens and screening them against the Adhiron library we will be able to produce a simple ELISA based assay that can be benchmarked against our current DDT IQK and HPLC in field operations in India.  This will establish the base-line data necessary to move forward and expand the insecticide range and engage with industry for commercialisation.  The latter is facilitated as we (MP) have an existing commercialisation pipeline of insecticide quantification kits via the Indian Wellcome Trust Translation programme and IVCC partners.

£27,955.00

Ann Rawkins

Public Health England, Porton Down

 

Prof. Helen McShane (Co-investigator, Jenner Institute, University of Oxford), Dr. Christopher Woelk (Co-investigator, University of Southampton)

Evaluation of new antigens for subunit vaccines against Mycobacterium tuberculosis.

This project will evaluate the immunogenicity of TB vaccine candidates previously predicted by a sophisticated reverse vaccinology approach in order to facilitate the formulation of new subunit vaccines against Mycobacterium tuberculosis.

£40,000.00

 

Britta Urban

Liverpool School of Tropical Medicine

Alister Craig(LSTM), Richard Pleass(LSTM) and Simon Draper (Jenner Institute)

Isolation of human monoclonal antibodies that reverse adhesion of Plasmodium falciparum infected erythrocytes to ICAM-1

Adhesion of Plasmodium falciparum Infected erythrocytes to ICAM--‐ 1 is central for the pathology of severe cerebral malaria. We propose to produce recombinant human monoclonal antibodies, which can block or reverse adhesion of infected erythrocytes to ICAM--‐1.  

£46,750.00

Steve Ward

Liverpool School of Tropical Medicine

Giancarlo Biagini (LSTM), Neil Berry (UoL), Paul O’Neill (UoL)

Identification of Early Antimalarial Leads using Syngenta assets

A 100,000-diverse small molecule library from Syngenta is presently being screened at LSTM. A quarter of the compounds have thus far been screened with 0.1% of the compounds

displaying an IC50 < 1uM. Current funding will only support the screening activity and in this MRC CiC we wish to request for further investment to support hit-to-lead activities. Using an accelerated pathway to lead identification, we will use (i) Chemoinformatics to remove non-tractable compounds or those

containing metabolic alerts, (ii) in house high content imaging to find ring/fast killers, (iii) a luciferase-based viability assay (in collaboration with Dr Paul Horrocks, Keele University) to confirm inhibitor parasite reduction rates, (iv) microsomal stability testing to predict intrinsic clearance, (v) chemical synthesis for small scale up of early leads and (vi) in vivo testing with concurrent DMPK (P. berghei rodent model). We anticipate that molecules occupying novel chemical space that progress to early leads displaying fast killing kinetics will be competitive for follow-on support in lead optimisation studies.

£41,700.00

 

 

2014/15

David Baker 

London School of Hygiene and Tropical Medicine

Mark Gardner, Andy Bell, Tanya Parkinson (Salvensis); Alan Brown (Pfizer); Giancarlo Biagini (LSTM)

Investigation of Pfizer & public domain cyclic nucleotide phosphodiesterase (PDE) inhibitors as possible antimalarial drugs that treat disease and block transmission

We aim to identify anti-malarial chemotypes which act through inhibition of PfPDEs with potential for good PK. We have demonstrated potent Pfal blood stage growth inhibition with good evidence of on-target activity using a small panel of Pfizer hPDE inhibitors. PK of the compounds tested so far is poor. Here we will examine a broad spectrum of hPDE hemotypes from Pfizer and the literature for potency against the parasite, on target activity, non-cytotoxicity and good PK. Success will lead to a compound good enough to demonstrate activity in the SCID mouse or a chemistry program to deliver such an agent.

£46,750

Giancarlo Biagini

Liverpool School of Tropical Medicine

David Baker (LSHTM), Stephen Ward (LSTM), Paul O’Neill (University of Liverpool/ School of Tropical Medicine), Mark Wenlock (AstraZeneca, Alderley Edge), Raman Sharma (LSTM)

Towards the generation of safe 8-aminoquinolines: Development of Quantitative structure activity/quantitative structure property (QSAR/QSPR) relationships of primaquine analogs to accurately predict redox potentials

Despite its development some 60 years ago, the mode of action of primaquine, the only drug proven to be clinically effective against liver and sexual stage human malaria parasites, is unknown. This knowledge gap is a major barrier to the development of safer alternative therapies based on rational redesign of molecules that share this mechanism of action. We have new data demonstrating that hydroxylated primaquine metabolites are redox cycled in vitro by P. falciparum ferredoxin-NADP+ reductase (PfFNR). Significantly, this data is the first demonstration of specific parasite enzymes involved in the mode of action of the 8-aminoquinolines and represents a starting point for drug discovery. In this project, we aim to develop Quantitative structure activity/quantitative structure property (QSAR/QSPR) relationships allowing the prediction of redox potentials. This information will form the foundation for future rational drug redesign strategies aimed at delivering the next generation of transmission blocking/radical curative antimalarials with utility for the malaria elimination agenda

£40,200

Simon Croft

London School of Hygiene and Tropical Medicine

 

Dr Kelly S. Davidge, Dr J. Malcolm Wilkinson (Kirkstall Ltd, UK); Dr Mo Alavijeh (Pharmidex, UK); Dr Abhishek Ananthanarayan (InVitroCue, Singapore); Dr Emily Adams (LSTM))

Development of 2D and 3D in vitro dynamic/flow infection models for drug evaluation against Leishmania

This project will focus on the development of 2D and 3D dynamic/flow infected culture models, with multi-time points, to measure the activity of novel compounds against Leishmania. Current anti-protozoal in vitro assays for determining the selective activity of novel chemical entities are based on static cultures with a single time point reading and more predictive models of infection are required for translation to in vivo activities in rodent models.

£39,350

Luis Cuevas

Liverpool School of Tropical Medicine

Dr. Emily Adams (LSTM)

Dr. Thomas Edwards (LSTM)

Dr. Jane Theaker (Qiagen, UK)

Design and development of commercial multiplex qPCR and isothermal assays fit for chikungunya and dengue virus diagnosis, surveillance and dengue vaccine evaluation.

We aim to develop an rt-qPCR CE marked diagnostic for the differentiation of chikungunya virus and the four main dengue virus serotypes for surveillance and a prototype near-patient test for differentiation of Chikungunya and dengue. Improved diagnostics are required to facilitate patient management, improved surveillance and to monitor the efficacy of future dengue vaccines. The assays will be co-developed as commercial products by LSTM and Qiagen In Vitro Diagnostics (Manchester. The tests will be evaluated in Ecuador and Brazil.

£41,700

Nicholas Feasey

Liverpool School of Tropical Medicine

David Cook (Blueberry Therapeutics Ltd); Christopher Parry (LSHTM); Giancarlo Biagini (LSTM)

Formulation of ceftriaxone into nanoparticles to improve intracellular penetration and hasten intracellular killing of Salmonellae

 

Typhoid fever is responsible for an estimated 225,000 deaths/year. Resistance to standard antimicrobials is commonly seen, making ceftriaxone the first-line agent in many settings, however ceftriaxone penetrates the intracellular compartment more slowly than ciprofloxacin and is associated with prolonged fever clearance times and high relapse rates.

Formulation of ceftriaxone into nanoparticles offers the potential to enhance intracellular delivery, thus improving its efficacy. Preliminary data has demonstrated we can formulate ceftriaxone into nanoparticles without reducing in-vitro activity. We propose to evaluate nano-formulations of ceftriaxone against standard ceftriaxone using the Operetta High Content Imaging System to determine intracellular clearance of S. Typhi.

£43,950

 

Roger Hewson

Public Health England, Porton Down

Dr Stuart Dowall (PHE); Prof Miles Carroll (PHE); Dr Alison Turner (The Jenner Institute)

Redevelopment of a promising vaccine candidate for Crimean-Congo Haemorrhagic Fever virus (CCHFv) into a markerless MVA vector suitable for commercial development

 

Scientists at Public Health England have constructed an experimental vaccine against Crimean-Congo Haemorrhagic Fever virus (CCHFv) by insertion of the glycoprotein-encoding region into a recombinant modified Vaccinia Ankara (MVA) viral vector. The vaccine has been shown to confer protection against an otherwise lethal challenge dose of virus in a susceptible mouse strain (type-I interferon receptor deficient), the accepted CCHF animal model. Immunogenicity results have shown the vaccine induces both cellular and humoral arms of the immune response. Recent passive and adoptive transfer studies have indicated that both T-cell and antibody-mediated immunity is required to exert any protective effects. The vaccine construct is currently a research-grade construct, containing regions encoding green-fluorescent protein (GFP), tissue plasminogen activator (tPA) and a V5-tag. To make the vaccine more suitable for commercialisation and clinical trials, a markerless MVA vector would be required. Therein, this project will transfer the CCHFv glycoprotein into a markerless MVA platform and compare immunogenicity and efficacy with the novel construct versus the existing vaccine candidate.

£31,800

 

Mark Paine

Liverpool School of Tropical Medicine

Mark Rowland (LSHTM); Manas Sarkar (Godrej); Ben Cobb (Epistem); David Weetman (LSTM); Emily Adams (LSTM); Hilary Ranson (LSTM)

Field Diagnostic Kits for Insecticide Resistance

Our aim is to develop ‘point of care’ systems for the screening of insecticide resistance markers in tropical disease transmitting insects in the field.

£29,900

Lisa Reimer

Liverpool School of Tropical Medicine

Bruce Alexander (Xeroshield); Nana-Kwadwo Britwum (Ghana Health Services); Darren Cook (LSTM), Emily Adams (LSTM)

VESS: Vector excreta surveillance system for lymphatic filariasis

We propose the development of a tool to collect, concentrate and filter wild mosquito excreta for the purpose of filarial DNA detection. The vector excreta surveillance system (VESS) is a xenomonitoring tool that directly responds to the emerging need of lymphatic filariasis (LF) elimination programmes to sensitively detect LF resurgence. Our preliminary work has shown that wild mosquitoes exploit artificial sugar sources and resting sites, and that filarial DNA can be recovered from mosquito excreta at least five days’ post-exposure to an infected bloodmeal. This proposal enables the development of this approach into a field-testable prototype through stakeholder consultation.

£43,600

Arturo Reyes-Sandoval

The Jenner Institute, Oxford University

Prof John Professor John M. Kelly (LSHTM)

Pre-clinical protective efficacy of novel Chagas vaccine candidates: A final step towards clinical application.

Chagas disease, caused by Trypanosoma cruzi remains a neglected tropical disease in the Americas, affecting approximately 7.5 million people. An efficacious vaccine would be a major, cost-effective approach to improving public health in the Americas. Two leading Chagas vaccine antigens (Tc24, TSA-1) have been used to develop MVA and adenoviral vectored vaccines at the Jenner Institute. The vaccine candidates induced outstanding immunogenicity in mice and we are joining efforts with LSHTM scientists to assess protective efficacy using novel transgenic parasites developed in this institution. Efficacy demonstration will be key for translation to a clinical trial supported by the MRC-DPFS scheme.

£46,750

Jamie Rylance

Liverpool School of Tropical Medicine

Ben Morton, Daniela Ferreira, Jesus Reine (all LSTM)

The whole blood phagocytosis assay: a near patient test to promote a personalised approach to immunomodulatory therapy.

We wish to investigate a novel; clinically relevant ex vivo assay that utilises P4 peptide to measure phagocytic activity in patients with severe infection. We have developed the current assay using Liverpool Health Partners funding and will now prospectively validate our promising preliminary data in patients admitted to the hospital with infection. This project will generate data to support an application for NIHR i4i funding to commercialise the assay. We have previous successful experience of translating CiC funding in to DPFS award using the therapeutic rather than diagnostic limb of the P4 programme.

£42,500

Ahmed Salman

The Jenner Institute, Oxford University

 

Florian Brod (Jenner Institute); Prof Chris J. Janse and Dr Shahid Khan (Leiden University Medical Centre); Prof Adrian V. S. Hill (Jenner Institute)

Evaluation of Plasmodium falciparum SPECT-1 as a novel pre-erythrocytic vaccine candidate

The most advanced malaria vaccine is RTS,S/AS01, based on the circumsporozoite protein (PfCSP). Using new transgenic parasite technology, we have recently screened 15 P. falciparum pre-erythrocytic antigens for their ability to protect against antigen-matched transgenic P. berghei parasites and identified a sporozoite antigen, PfSPECT-1 which induces high level efficacy mediated by antibodies. PfSPECT-1 is more protective in mice than PfCSP, which has been the leading sporozoite vaccine antigen for decades. We will compare the immunogenicity and efficacy of PfSPECT-1 as a vaccine candidate in several forms, particularly as virus-like particles in adjuvant, aiming to provide a promising new vaccine candidate.

£46,750

George Warimwe

The Jenner Institute, Oxford University

Prof Sarah Gilbert (Jenner Institute); Prof Musaad Al-dubaib (Qassim University)

 

A One Health approach to MERS-CoV vaccines for camels and humans

 

Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging zoonosis that is highly prevalent in camels and causes life-threatening respiratory disease in humans. No licensed camel or human vaccines are currently available for MERS-CoV. Here, utilising a chimpanzee adenovirus platform with an established safety profile in camels and humans, we will develop a MERS-CoV vaccine for deployment in both these species. We aim to demonstrate induction of high titre neutralizing antibody and protective efficacy against experimental MERS-CoV challenge in camels, thus providing proof-of-concept for further development of a deployable product for use in camels and in subsequent human clinical trials.

£46,750

 

2015/16

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)

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

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.

 

£44,735

Amaya Bustinduy

London School of Hygiene and Tropical Medicine

Prof. Michael Miles, LSHTM.  Prof. Russell Stothard, LSTM. Prof. Steve Allen, LSTM.

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

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.

£47,339

Miles Carroll

Public Health England, Porton Down

Simon Funnell, Roger Hewson, Stuart Dowall and Julia Vipond.
All from Public Health England, Porton Down

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

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.

£47,829

Nicholas Casewell

Liverpool School of Tropical Medicine

Dr. Robert A. Harrison (LSTM)

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

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.

£47,682

Michael Coleman

Liverpool School of Tropical Medicine

Knut Staring (University of Oslo)

Towards the next generation of Disease Surveillance Systems.

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.

£48,239

Adrian Hill

Jenner Institute, University of Oxford

Prof. Zhanfeng Cui, Professor of chemical engineering
Dr. Adam Walters, Post-doctoral fellow
Dr. Rebecca Ashfield, project manager
Pawan Dulal (DPhil, thesis due for submission, Researcher)

 

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

 

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 come 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.

£48,239

 

Jing Jin

Jenner Institute, University of Oxford

Prof Simon J Draper (Jenner Institute, University of Oxford)
Dr Wian de Jongh (ExpreS2ion Biotechnologies, Denmark)
Dr Karin Lövgren Bengtsson (Novavax AB, Sweden)

 

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

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.

£38,192

Teresa Lambe

Jenner Institute, University of Oxford

Prof Sarah Gilbert (Co-I), The Jenner Institute, University of Oxford
Prof Adrian Hill (Co-I), The Jenner Institute, University of Oxford
Prof Stephan Becker (External Co-I), Philipps University Marburg
Dr Edward Wright (External Co-I), University of Westminster

 

Pandemic Preparedness for Endemic Viral Disease in West Africa

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.

£48,239

Gregory Murray

Liverpool School of Tropical Medicine

JEA Parker, PJ McCall (PI) (Vector Biology Dept, LSTM)
Prof DE Towers, Dr CE Towers, C Kroner (Mechanical and Process Engineering Univ Warwick)

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

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.

£33,127

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

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

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.  

£48,140

Steve 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)

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

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.

£48,239

 

2016/17

Alvaro Acosta-Serrano

Liverpool School of Tropical Medicine

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

Controlling malaria transmission using environmentally ‘friendly’ sugar baits

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.

 £ 28,843.52

Emily Adams

Liverpool School of Tropical Medicine

Luis Cuevas - LSTM
Thomas Edwards - LSTM
Christopher Parry - LSTM
Guoliang Fu – GeneFirst

Novel Probe Technology for Multiplex Molecular Diagnostics

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.

 £ 40,713.08

Giancarlo Biagini

Liverpool School of Tropical Medicine

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

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

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.

 £ 45,480.11

Alister Craig

Liverpool School of Tropical Medicine

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

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

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.

 £ 42,500.60

Nicholas Feasey

Liverpool School of Tropical Medicine

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

Pharmacokinetics of azithromycin and ciprofloxacin in the management of typhoid fever

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.

 £ 40,374.78

Sarah Gilbert

The Jenner Institute, University of Oxford

Dr. Sarah Sebastian (Jenner Institute, University Of Oxford)

Development and testing of MVA VerOx

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.

 £ 46,598.47

Gareth Lycett

Liverpool School of Tropical Medicine

Rosemary Lee (LITE); Dave Malone (IVCC)

In vivo screening of resistance breaking compounds

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.

 £ 31,166.92

David Moore

London School of Hygiene & Tropical Medicine

Kate Gaskell (LSHTM)

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

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.

 £ 35,478.21

Mark Paine

Liverpool School of Tropical Medicine

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

Development of smart materials for insect vector control

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.

 £ 43,802.56

Christine Rollier

The Jenner Institute, University of Oxford

 

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

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

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.

 £ 49,860.49

Mark Taylor

Liverpool School of Tropical Medicine

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)

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

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.

 £ 46,598.47

Steve Ward

Liverpool School of Tropical Medicine

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)

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

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.

£ 50,984.32

Sam Willcocks

London School of Hygiene & Tropical Medicine

Prof Brendan Wren (LSHTM); Dr Mark (Gardner, Salvensis)

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

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.

 £ 46,598.47