Diagnostics and Host Response
Improving diagnostics is central to the delivery of the mission of the UKHSA to respond to infectious diseases, the threats they pose and to inform disease management strategies. Whilst great progress has been made in the use of nucleic acid-based detection strategies, development of serologic approaches have lagged, despite their unique capability to confirm infection in the absence of nucleic acid. Genomic approaches have shown the utility of characterising the host response to inform triage of patients. Further work is required to validate these methodologies, particularly to investigate the predictive power of unique molecular signatures and to correlate these with patient data and improve case management protocols. This Theme brings together a multidisciplinary team to characterise pathogen and host biology and use this information to develop new versatile platforms to diagnose infection and inform case management.
Project 2.1: Determining molecular signatures in acute emerging infections (Covid-19, Ebola and hantavirus disease) and association with outcome
I'ah Donovan-Banfield
PhD Student
University of Liverpool
This project utilises RNA samples obtained from an ongoing phase II clinical trial (AGILE CST-2) to observe minor genomic variants that arise in patients in both treatment arms. The methodology uses established sequencing techniques and bioinformatic analysis pipelines in addition to in-house data visualisation scripts. Any mutations that are enriched in the molnupiravir treatment arm will be further investigated using sub-viral replicons and reverse genetic systems to reveal functionality (if any) of these mutations and whether they may confer resistance.
Project 2.2: Historical genomic analysis to enhance pathogen outbreak sequencing
Professor Miles Carroll
Theme Co-Lead
University of Oxford
Jack Crook
PhD Student
UK Health Security Agency
This project will analyse past, present and emerging strains of viral haemorrhagic fevers (Lassa and CCHF) to try and understand how they evolve and identify sites of hypermutation and markers for increased virulence which may also serve as targets for new interventions. The work will use existing strain collections, NGS, complex bioinformatics analysis and structural modelling. The sample selection is currently being finalised. The PhD student began in October 2020 and their training programme has now started. There will be EBOV & COVID focussed studies in collaboration with Prof. Julian Hiscox at the University of Liverpool.
Project 2.3: Analysis of bush meat hunter sera to address potential spill over events of high consequence viruses in the forested region of Guinea. Modelling risk and preparing for outbreaks
Professor Peter Simmonds
Theme Co-Lead
University of Oxford
Grace Hood
PhD Student
University of Oxford
The project would be based on a cohort of approx. 500 bushmeat hunter serum samples collected in the forests of the Macenta prefecture of Guinea that straddles the border with Liberia. There are another 250 longitudinal samples (2015-2020) from an EVD survivors cohort as well as 1250 serum samples from a WHO EBOV vaccine study based in the Atlantic region of the country. The latter could serve as a control cohort.
The hypothesis is that filovirus spill over events have occurred independent of the 2013-2016 EBOV epidemic. This includes both EBOV Zaire in additional to other known and unknown filoviruses. Within the bushmeat hunter serum collection we already have strong evidence of serological binding to EBOV GP (Nature Comms in review) but many positives do not neutralise EBOV suggesting they are the result of exposure to non-EBOV Zaire but related filovirus.
Project 2.4: Development of multiplex serological diagnostic tests for the differentiation of emerging viruses
Dr Emily Adams
Theme Co-Lead
Liverpool School of Tropical Medicine
Caitlin Thompson
PhD Student
Liverpool School of Tropical Medicine
This project aims to use recombinant protein technology to rapidly develop antigens and monoclonal antibodies to enhance diagnostic capabilities for the emergence of an unknown virus. The project will initially focus on the development of a rapid diagnostic test for Crimean-Congo Haemorrhagic Fever Virus, a World Health Organisation priority disease for research and development, with scope to expand research to other Viral Haemorrhagic Fever Viruses, including flaviviruses. We will work with industry partners such as Mologic to ensure research this is translated to product development and work to enhance research and clinical partnerships overseas to field test new diagnostic tests in endemic countries.
Project 2.5: To characterise the natural history of T-cell responses against emerging viruses
Professor Paul Klenerman
Theme Co-Lead
University of Oxford
Cecilia Jay
PhD Student
University of Oxford
This project is centred around the role of T-cell cross-reactivity in viral immunity, specifically against SARS-CoV-2 and other coronaviruses including the four circulating common cold coronaviruses, SARS and MERS. We have recruited and run T- and B-cell assays on a cohort of families from Oxford, London and Cardiff. Key findings include: greater T-cell responses in older individuals; partially activated cross-reactive T-cells in exposed individuals who do not seroconvert, perhaps as a result of transient infection that is rapidly shut down by pre-existing T-cells; an association of older age with poorer outcomes and greater levels of common-cold-specific IgG following infection.