MRC CIC successful applicants 2020

PI

PI Institution

Co-Is and institutions

Title

Project Summary

Award Amount

Dr Anita Milicic

Jenner, Oxford

Prof. Adrian Hill, the Jenner Institute, NDM, Oxford, Prof. Eleanor Stride, IBME, Dept. of Engineering, Oxford

In vivo evaluation of a single-dose malaria vaccine delivered inside microfluidics-generated polymer microcapsules

Single‐dose immunisation would circumvent many of the challenges facing global vaccination coverage, and has been a long‐standing ambition in vaccine development. It involves the booster dose being encapsulated for a delayed in vivo release and administered together with the first (priming) vaccine. Using a novel microfluidcs‐based system we have manufactured microcapsules that contain a model antigen, and demonstrated delayed burst release in vitro after 4 weeks. This project will test the encapsulated antigen in mice, with the aim to demonstrate successful vaccine delivery in vivo following encapsulation. Single‐dose immunisation will be applied to our leading viral vectored malaria vaccines.

£49,139.55

Dr Emily Adams

LSTM

Dr Tom Fletcher, Dr Joe Fitchett (Mologic, Bedfordshire), Dr Annelyse Duvoix (Mologic, Bedfordshire), Dr Ana Isabel Cubas Atienzar (LSTM), Prof Luis Cuevas (LSTM)

Development of monoclonal antibodies towards an antigen test for Crimean-Congo Haemorrhagic Fever

We aim to develop monoclonal antibodies that specifically bind with antigens of Crimean Congo Haemorrhagic Fever (CCHF) towards the development of an antigen detection test for CCHF.
The development of these antibodies is a crucial first step towards the development of rapid, lateral flow based antigen diagnostics. These will be developed as screening tests for rapid diagnosis at the point of care.

The antibodies will be developed by LSTM in collaboration with our commercial partner Mologic, a company leading the development of rapid diagnostics (https://mologic.co.uk/) with a focus on low-resource settings with Public Health England.

£44,691.89

Dr Joseph Turner

LSTM

Giancarlo Biagini, LSTM.  Andrew Owen, James Stewart, University of Liverpool

A humanised mouse model of CoV2 respiratory disease for therapeutics development

We have recently established a humanised mouse model of SARS-CoV2 (K18-hACE2 mice) that exhibits sustained viral replication and acute respiratory pathology, with poor survival outcome dependent on inoculate dose. This project will characterise the inflammatory cell and cytokine milieu both in the lung microenvironment and systemically following infection. We will determine whether repurposed anti-viral therapies with or without combined anti-inflammatory treatment (e.g. dexamethasone) can modify viral titre or lung disease. Further, we will comparatively test experimental COVID combination therapies identified in the LSTM/UoL preclinical screening pipeline for their ability to perturb viral load and/or lung hyper-inflammation in humanised ACE2 mice.

£71,825.17

Dr Martino Bardelli

Jenner, Oxford

Dr Kirsty McHugh (Department of Biochemistry, University of Oxford), Prof Richard J Pleass (LSTM)

AAV-vectored delivery of engineered monoclonal antibodies as a prophylactic strategy against blood-stage malaria. 

A significant challenge in the development of malaria vaccines is the lack of effective antigen formulations that induce and maintain the very high concentrations of effective antibodies required to achieve protective immunity. Using long-lived potent monoclonal antibodies (mAbs) as prophylactics could provide an alternative route to accelerate malaria control and elimination programmes. Maximising mAb potency will be central to the success of this approach. We propose a proof-of-concept study that combines a proprietary antibody Fc-engineering platform with a vectored immunoprophylaxis (VIP) strategy to deliver previously characterised mAbs against two leading malaria targets (PfRH5 and PvDBP) to neutralise blood-stage Plasmodium parasites of humans.

£38,574.51

Dr Michael Delves

LSHTM

Prof Matthew Fuchter (Imperial College), Dr Javier Gamo (Glaxosmithkline)

Hit-to-lead optimisation of DDD01034957 as a novel antimalarial

DDD01034957 is a molecule with antimalarial properties that possesses a chemical scaffold unique from all other antimalarials currently under development. Initial study has revealed this hit molecule to be fast acting and active against many drug resistant parasite strains. We propose a hit-to-lead programme to optimise the activity and pharmacokinetic properties of DDD01034957 to support the onward application for an MRC DPFS award.

£47,275.00

Dr Nadina Wand

PHE

Professor Roger Hewson (PHE)

Rapid portable isothermal detection of Crimean-Congo Haemorrhagic Fever Virus infection using a novel CRISPR nucleic acid diagnostic method, SHERLOCK

Development of rapid point-of-care diagnostic tools for the detection of Crimean-Congo Haemorrhagic fever virus in patient samples is identified as a priority in the WHO R&D CCHF roadmap for the prevention and control of this high-consequence pathogen in affected countries. We propose to apply a CRISPR-enzyme based diagnostic approach, SHERLOCK, in conjunction with our previously developed RPA assay, to detect CCHF nucleic acid, resulting in a highly sensitive assay appropriate for low-resource settings or a mobile field laboratory in remote regions, where disease burden is most significant and rapid results can lead to important gains in patient management.

£48,757.54

Dr Robert Moon

LSHTM

Colin Sutherland (LSHTM); Paul Bowyer (NIBSC)

Antigen orthologue replacement: Development of species-specific reference panels for evaluation of malaria rapid diagnostic tests.

Rapid diagnostic tests (RDTs) are widely used for malaria diagnosis, and in many settings are the only available laboratory test. RDT often deploy pan-specific monoclonal antibodies against parasite LDH to identify all malaria species, but test performance is highly variable for  Plasmodium ovale curtisi and P. ovale wallikeri. Systematic evaluation of new and existing RDT is hampered by lack of WHO international reference standards for these species. This proposal will generate a panel of transgenic P. knowlesi parasites expressing PoLDH antigen variants as a renewable resource for assessment of RDT performance and development of new test antigens.

£47,215.87

Dr Rosemary Lees

LSTM

Bart Kahr, Michael D. Ward (New York University), Jessica Williams, Hilary Ranson (LSTM)

Can a simple change of crystallisation state restore or enhance the efficacy of pyrethroid insecticides for vector control?

Contact adulticides kill infectious disease vectors at the interface between a crystalline particle and mosquito tarsi. Recently the pyrethroid insecticide deltamethrin was shown to be 12 times more bioavailable when formulated as a second crystalline structure (polymorph) not previously identified, against an insecticide-susceptible Anopheles species from the USA. African malaria vectors have developed multiple pyrethroid resistance mechanisms, including barriers to penetration.  This project will address a key milestone in the translation from proof of concept to new insecticide formulations by evaluating the bioefficacy and rate of penetration of crystalline forms of public health insecticides against African malaria vector populations.

£43,653.74

Dr Thomas Edwards

LSTM

Emily Adams, Lisa Baldwin, Luis Cuevas (LSTM). Antonia Sagona (University of Warwick), Jenifer Mason (Liverpool University Hospital Foundation Trust), Mark Sutton (Public Health England)

Recombinant bacteriophages for direct detection of bacterial blood stream infections

Rapid detection of bacterial pathogens directly from blood remains one of the greatest challenges in diagnostic microbiology. Current strategies rely on blood culture, which takes 24-48 hours, and identifying drug resistance requires further phenotypic tests, delaying targeted therapy and the overuse of empirical antibiotics. Alternative molecular techniques are usually insufficiently sensitive.
We propose to use recombinant fluorescent bacteriophages to provide a signal for the detection of bacteria directly from blood. This approach can rapidly detect low concentrations of bacteria, enable AMR detection,  and by skipping the culture step, provide same day diagnosis.

£39,797.99

Prof Giancarlo Biagini

LSTM

Prof. Steve Ward, Dr Grant Hughes (LSTM), Dr Roger Hewson (PHE)

Defining the principles of a universal combination drug strategy against emerging viruses significant to human health

Proactive efforts towards the development of new antivirals will be essential to containing and eradicating future viral pandemics.  As part of pandemic preparedness efforts, it is therefore imperative that the a priori discovery and development of drugs, including new drug combinations, against viruses with pandemic potential is attempted.  Drug combination strategies offer a number of advantages to monotherapies including the potential to achieve greater efficacy, the potential to increase the therapeutic index of drugs and the potential to reduce the emergence of drug resistance.  We have recently shown that the combination of Remdesivir (RDV)-Ivermectin (IVM) results in a synergistic interaction with improved in vitro antiviral activity against SARS-CoV-2.  We hypothesise that the mechanism underpinning the synergistic interaction is translatable to other important viral pathogens, notably RNA viruses, including important arboviruses.  In this study we propose to test this hypothesis and determine whether RDV and related C-adenosine nucleoside analogs have a synergistic antiviral effect when combined with known RNA polymerase inhibitors against important emerging viruses including Rift Valley fever (RVF), Zika (ZIKV), Chikungunya (CHIKV) and tick-borne encephalitis (TBEV) viruses.  We anticipate that the data established in this study will form the basis of future drug combination discovery and development programmes for global pandemic preparedness.

£37,347.25

Prof Jayne Sutherland

LSHTM

Prof Graham Ball (Intelligent OMICS & Nottingham University)

Optimisation of a host biosignature in sputum for development of a rapid lateral flow test for tuberculosis

Tuberculosis (TB) is still a major global health problem with 1.5 million deaths per year, which is likely to increase due to the effects of SARS-CoV-2 on access to testing and treatment. We have identified and patented a biosignature comprised of host markers in sputum samples which meets the WHO product profile for a Triage test for TB. With CiC funding, we aim to optimise this signature, determine its global applicability, and for identifying treatment response. If successful we will apply for follow-on funding for development of a rapid, lateral flow-based triage test for TB for use in basic health clinics.

£47,275.00

Prof Simon Draper

Jenner, Oxford

Dr Rob Moon (London School of Hygiene and Tropical Medicine), Dr Lloyd King (Jenner Institute, University of Oxford), Dr Jee-Sun Cho (Jenner Institute, University of Oxford)

Development of a next-generation Plasmodium vivax vaccine for Blood-Stage Malaria

The identification and assessment of novel Plasmodium vivax vaccine antigens, is a significant challenge due to a lack of in vitro culture systems for testing vaccine efficacy for this human parasite. To overcome this, we developed a novel assay platform to screen vaccine-induced functional antibodies, using culture adapted P. knowlesi parasites, modified to express P. vivax candidate vaccine antigens. This powerful new system will be used to investigate the potential of the PvEBP antigen as a next-generation vaccine candidate for P. vivax. PvEBP binds reticulocytes, is conserved and naturally-acquired antibodies to this antigen strongly correlate with protection against clinical malaria.

£46,185.78

Prof Steve Ward

LSTM

Prof P. M. O’Neill (University of Liverpool), Dr W. D. Hong (University of Liverpool), Dr S. Leung (University of Liverpool) and Dr D. Soldati-Favre (University of Geneva)

Optimisation of the Antimalarial and DMPK Properties of A Series of Plasmepsin IX/X Beta-hydroxyethylamine Based Inhibitors.

Plasmepsin IX and X are aspartic proteases that play crucial roles in erythrocyte invasion and egress of the malarial parasite. Targeting these enzymes can effect both treatment and chemoprotection against malaria infection. An early lead series of beta-hydroxyethylamines that targets plasmepsin IX/X, demonstrates potent antimalarial activity in vitro and in vivo, but sub-optimal DMPK properties restricting the progression of the series. This project sets out to demonstrate that key DMPK characteristics of this series can be optimised, whilst maintaining the antimalarial activity and the selectivity against plasmepsin IX/X(over other plasmepsins), as a rationale for onward development

£36,023.55