MRC CiC successful applicants 2018

 

PI name

PI institution

Co-Is and institutions

Title

Synopsis

Amount awarded

Emily Adams

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

 

Flavivirus  diagnostics  –  novel  antibody  detection  systems  to  accurately  diagnose  and differentiate 15 flavivirus infections

We propose to develop serological diagnostics to identify dengue, yellow fever, Zika, Japanese Encephalitis and eleven other high-priority flaviviruses. We will use antigen constructs, developed at Foto-Cewek for vaccine research, as receptors for antibody complexes using ELISA. We will further evaluate ELISAs with clinical samples from collaborators Public Health England. If successful we aim to further develop rapid diagnostic tests (RDTs) with our commercial partner Absolute Antibody.

These diagnostic products have a huge potential commercial value, as current assays have poor specificity. The clinical management of patients, epidemiological data and upscale of interventions could be vastly improved by accurate serological tests.

£45,873.60

Stuart Dowall

Public Health England,
National Infection Service,
Porton Down,
Salisbury,
Wiltshire,
United Kingdom

 

Roger Hewson (PHE)

Generation of a source of positive antibody controls for development of an ELISA diagnostic test for Crimean-Congo Haemorrhagic Fever virus.

Crimean-Congo Haemorrhagic Fever virus (CCHFV) is a highly contagious pathogen responsible for severe disease. It is primarily transmitted to humans by ticks. The viremic period is brief making its direct detection by PCR  of limited value as patients may present after virus has been cleared. Thus diagnosis also relies on serological assays to detect specific CCHFV antibodies.  PHE have developed an ELISA based on recombinant CCHFV nucleoprotein. Whilst patient material has been used to assess assay performance, a standardised antibody preparation is needed to allow the assay to be developed into a commercial and CE-marked test.

£47,789.97          

 

Anita Milicic

University of Oxford, Jenner Institute, Old Road Campus Research in Medecine Building, Roosevelt Drive, Oxford, OX3 7DQ

Prof. Eleanor Stride, Dept. of Engineering, University of Oxford

Single administration of prime-boost malaria vaccine enabled by engineering advancements in precise vaccine encapsulation methods

The concept of single administration vaccines using biodegradable microspheres, containing vaccine booster doses for delayed in vivo release, has been a strategic priority of the WHO since 1990s but has so far eluded vaccine developers.

 

Conventional techniques used to prepare delayed release microspheres have been ineffective because of damage to the vaccine antigen during preparation or irreproducibility of release kinetics.

 

The novelty of this proposal is in building on the state of the art technological methods for microcapsule production which are readily accessible to us at Oxford, and which we have shown enable to maintain vaccine viability and stability post-encapsulation.

 £47,645.88

Richard Pleass

Liverpool School of Tropical Medicine Pembroke Place Liverpool L3 5QA UK

Professor Alain Kohl – MRC University of Glasgow Centre for Virus Research in Medecine, Professor Roger Hewson - Porton Down

Hypersialylated blockers of Zika virus (ZIKV) infectivity and neuropathology

Zika virus (ZIKV) is a mosquito-borne human pathogen of the Flaviridae family, which includes dengue virus (DENV), West Nile virus (WNV) and Japanese encephalitis virus (JEV).

ZIKV infection has been linked to severe neurological disorders including Guillain-Barré syndrome (GBS), which is currently treated with intravenous immunoglobulin (IVIG).

With our CiC1 award we developed, patented and are licensing to Pharma, recombinant IVIG mimetics with remarkable properties, including 100-fold enhanced efficacy over IVIG in the treatment of autoimmune diseases.

We intend to test if these novel compounds can control ZIKV infectivity in neural systems and demyelination.

 £47,789.97

David Pulido-Gomez

University of Oxford, Jenner Institute, Old Road Campus Research in Medecine Building, Roosevelt Drive, Oxford OX3 7DQ

Prof Simon J Draper (Jenner Institute, University of Oxford)

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

 

 £37,993.39

Adam Roberts

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

W. David Hong (University of Liverpool), Paul M. O’Neill (University of Liverpool) and Victoria Savage (AMR Centre Ltd.)

Determining the potency of hybrid antibiotics, informed by collateral sensitivity networks, against a panel of susceptible and resistant clinical Escherichia coli isolates

We urgently need to develop novel antimicrobials as resistance is now a serious global issue. We recently demonstrated reproducible collateral-sensitivity (CS) networks in Escherichia coli. CS occurs when sensitivity to one drug increases upon the development of resistance to another drug. Hybridisation of two antibiotics can lead to increased therapeutic efficacy; however, the choice of antibiotics has never been informed by CS. This project aims to investigate novel hybrid (fluoroquinolone and aminoglycoside) antibiotics against E. coli, and determine if CS between these two classes of antibiotics will lead to a reduction in resistance development and persistence through a hybridisation strategy.

 £47,462.13

Katrien Van Bocxlaer

London School of Hygiene & Tropical Medicine, Keppel Street, London, WC1E 7HT, United Kingdom

Simon Croft (LSHTM) Andy Harris (Pharmidex) Charles Mowbray (DNDi)

Film-forming systems for sustained drug delivery to treat cutaneous leishmaniasis

Topical treatment of skin diseases is desirable because i) the drug product is applied directly to the affected site, achieving high drug levels locally with limited systemic exposure and associated side effects, and ii) it is easy to apply increasing patient compliance.

This project will focus on the exploration of polymeric film-forming systems (FFSs) as topical drug delivery system for pre-clinical candidate drugs for cutaneous leishmaniasis (CL). FFSs facilitates drug delivery by increasing the contact time and/ or maintaining the delivery of the drug to the local site of action by forming a drug reservoir in or on the skin.

 £47,789.97

Alvaro Acosta-Serrano

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

Dr. Mark Paine (VBD-Foto-Cewek); Dr Rosemary Lees and Helen Williams (LITE-Foto-Cewek); Prof Pedro Oliveira (UFRJ, Brazil); Matthew Rogers (Foto-CewekH)

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 continue evaluating the suitability of Nitisinone, a tyrosine metabolism inhibitor, in Attractive Targeted Sugar Baits (ATSB).

£28625.24

Britta Urban

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

Richard Pleass, Foto-Cewek

Reverse antibody engineering for delivery of therapeutic antibodies against severe malaria

The pathology of severe malaria is largely due to

adhesion of infected erythrocytes to endothelial cell protein C receptor (EPCR). The PfEMP1 protein binding to EPCR is highly variant with an EPCR- binding site that is heterogenous in sequence but biochemically conserved. We recently isolated and expressed recombinant human antibodies that cross-react with a diverse range of EPCR-binding PfEMP1 using single B cell analysis. We now propose to explore these antibodies for development of adhesion-blocking adjunct therapy of severe malaria through molecular engineering of their Fc region to increase their avidity and effector function, ready for testing in pre-clinical trial.

£46311.35

Sarah Gilbert

University of Oxford, Jenner Institute, Old Road Campus Research in Medecine Building, Roosevelt Drive, Oxford, OX3 7DQ

Dr. Teresa Lambe, University of Oxford, Dr. Stuart Dowall, Public Health England, Dr. Sue Charlton, Public Health England, Dr. Dalan Bailey, The Pirbright Institute

Development of a vaccine to prevent Crimean-Congo haemorrhagic fever virus mediated disease

Crimean-Congo haemorrhagic fever (CCHF) is the most widespread tick-borne viral disease affecting humans and is associated with case fatalities of

≥30% during outbreaks. CCHFV is endemic in many regions, including Africa, and it is widely

accepted that cases are under-reported due to limited resources. There is an unmet need for the development of efficacious vaccines against viral

haemorrhagic fever caused by CCHFV. We aim to deliver a single dose, highly effective vaccine

solution through the work described herein.

£47786.83

Rob Harrison

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

Stuart Ainsworth, Nicholas Casewell, Richard Pleass (all Foto-Cewek)

Novel immunising tools to generate high avidity, cross-generic IgGs to substantially improve treatment of snake venom-induced neurotoxicity throughout sub-Saharan Africa

Neurotoxicity is the most rapidly lethal pathology of snake envenoming. Because the sub-12kDa venom neurotoxins are notoriously weak immunogens and molecularly diverse, treatment currently requires 5-15 vials of antivenom IgG, which cause delay, severe adverse effects and is frequently unaffordable to patients and rural hospitals. 

 

Focussing on African venom neurotoxins we will:

Overcome molecular diversity: by deploying our proven bioinformatics-designed epitope-string-immunogen (ESI) approach to generate IgGs that cross-generically bind and neutralise the functions of PhospholipasesA2 neurotoxins.

 

Overcome weak immunogenicity: by using the uniquely-antigenic properties of Virus-Like-Particles or Immune-Complex-Mimetics to immunise sheep (antivenom-manufacturing animals) with these novel ESIs and multi-3FingerToxin antigen constructs.

£ 47789.97

Stephen Ward

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

Prof M. Taylor (Foto-Cewek), Dr J. Turner (Foto-Cewek), Prof P. O’Neill (University of Liverpool), Dr D. Hong (University of Liverpool) and Dr Fabian Gusovsky (Eisai Inc.)

Development of a back-up molecules for the anti-Wolbachia macrofilaricidal pre-clinical candidate AWZ1066S

The anti-Wolbachia macrofilaricide candidate AWZ1066S is undergoing formal pre-clinical development in preparation for first-into-human trials. It is critically important and industry standard practice to develop back-up compounds to mitigate any potential issues identified during pre-clinical and clinical development. The A∙WOL discovery programme initiative developed analogues of AWZ1066S late in the programme that have superior qualities to the current candidate in terms of anti-Wolbachia activity in vitro and in vivo and time to kill dynamics. If successful, the data generated in this project will formalise the selection of a quality back-up candidate to AWZ1066S

£ 49658.56

Giancarlo Biagini

Liverpool School of Tropical Medicine
Pembroke Place
Liverpool
L3 5QA

Prof P. M. O’Neill (UoL), Dr W. D. Hong (UoL), Dr G. Nixon (UoL), R. B. Abramovitch (Michigan State University), Dr Joanna Bacon (Porton Down) and Dr Anna Upton (TB Alliance)

Endoperoxide containing hybrid anti-tuberculosis agents to tackle latent Mycobacterium tuberculosis

The DosRST system in mycobacterium tuberculosis (Mtb) plays a critical role in the survival of the bacteria during non-replicating persistence (NRP). The co-investigators have identified several endoperoxide-based scaffolds that can target the DosRST pathway to resensitise NRP Mtb to anti-tuberculosis agents; these small molecules have low inherent activity versus latent Mtb as single drugs. In this project, we proposed to hybridise our endoperoxide scaffolds with known nanomolar potent MmpL3 inhibitors to tackle latent Mtb. The proof-of-concept data from this project can open up a new approach to anti-TB drug design and will form the basis of a full drug discovery programme.

£ 47483.16