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Additional information on the Universities Coronavirus research efforts can be found on the Coronavirus Research pages.

BinCaoWuhan2.jpgDespite the social and economic impact of epidemic infections, historically very little clinical research has been done to find better ways to prevent, diagnose and treat these infections. This is because outbreaks are unpredictable in their timing, location and magnitude, they start and finish quickly, they often occur in resource-poor settings, and the outbreaks themselves disrupt the delivery of healthcare.  The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) aims to address these difficulties and led by NDM’s Professor Peter Horby,  ISARIC is a world-wide, grass-roots consortium of clinical research networks, responsible for a series of initiatives in capacity-building and pandemic preparedness. ISARIC has previously been deployed against a variety of epidemic infections, including pandemic influenza, Ebola, Lassa fever, and plague.

ISARIC’s pre-positioned ‘epidemic’ research protocols were used to publish the first clinical report of COVID19 in Wuhan in January 2020.  ISARIC has most recently provided a platform for leading UK responses to COVID-19, including the UKRI and DHSC funded ISARIC-4C (Coronavirus Clinical Characterisation Consortium), the world’s largest prospective observational COVID-19 study. ISARIC has also supported the UKRI and DHSC funded RECOVERY (Randomised Evaluation of COVid-19 thERapY) Trial which Peter is leading.  The NDM hosts  the ISARIC database.

Access to the ISARIC protocols and ethical frameworks in the UK has been a major reason for the rapidity of our scientific research response and ability to prosecute the pre-clinical development of vaccines and other therapies.

serologyThe NDM has created a high throughput robotic serology testing platform reporting anti-SARS-2 Spike antibody levels in people exposed to the virus (>99% sensitivity and specificity). The diverse project team of clinical and non-clinical staff from the NHS, NDM, Rosalind Franklin Institute and Diamond Light Source has been led by Professors David Stuart and Derrick Crook. It has brought  together our expertise anti-viral humoral immunity, our ability to produce high quality antigens, and our strength in clinical microbiology and infectious diseases.  The NDM has formed a strategic alliance with Thermo Fisher to support the platforms and transition to a capacity of up to 50,000 assays/24hr.

Since 26th April, we have been reporting data to the UK government on SARS-Cov2 immunity in the UK population. This forms part of an Office of National Statistics COVID19 Survey led by Professor Sarah Walker. The platform has been used to survey UK BioBank and 10,000 NHS staff in Oxford. Our reagents and protocols have been shared and used to establish serology screens in our overseas units, notably in Kenya. Going forward, our experience in establishing the assay and ability to generate high quality antigens, provides us with the capacity to respond rapidly to future pandemic threats.

Our team has used our platform to compare routine laboratory and home commercial serology kits and provide validate antigens for the development of lateral flow tests, both at the request of the UK government.

Read about how Oxford ramps up COVID-19 testing capability.

Professor Sarah Gilbert in the NDM’s Jenner Institute had pioneered chimpanzee adenovirus-vectored vaccines against disease including influenza, tuberculosis and prostate cancer. Recently she showed that the ChAdOx1 vector can be used to make vaccines that are protective against Middle East Respiratory Syndrome (MERS), a coronavirus related to SARS-CoV-2 affecting camels and their human contacts. Professor Gilbert and Professor Adrian Hill (Director of the Jenner Institute) are co-founders of an Oxford University spin-out, Vaccitech, based on her viral-vectored vaccines.

In January 2020, Professor Gilbert adapted the ChAdOx1 vector to express the SARS-CoV-2 spike protein, and the NDM agreed to underwrite a £1M contact with an Italian contractor manufacturer, Advent and to accelerate GMP manufacturing of trial doses in its on Clinical Biomanufacturing Facility (led by Professor Cath Green). Animal studies in March 2020 in Rocky Mountain Laboratories in the USA and at the PHE in Porton Down funded by CEPI, UKRI and DHSC, showed the vaccine was safe and protective against virus in the lungs.

On 27th March, the Jenner team started recruitment of 510 human participants for a phase I/II trial; and on the 30th April, AstraZeneca and the University of Oxford signed a deal for the global development and distribution of the vaccine.  Research Trials have continued in the UK, South Africa and Brazil under the leadership of Professor Andy Pollard, with immunological testing in the Jenner laboratories led by Professor Tess Lambe and Professor Gilbert. The NDM transferred the manufacturing processes, which had been led by Dr Sandy Douglas, to AstraZeneca.

Although it can provide a definitive solution to pandemic threat, even the most accelerated vaccination programme takes too long; therefore, our efforts have turned to other solutions to control the spread of infection or the severity of disease.

On 5th March 2020, Christophe Fraser, Professor of Pathogen Dynamics in the NDM, and Dr David Bonsall submitted a paper to Science describing their idea that digital contact tracing with mobile phones could play a role in helping to contain the epidemic spread of the SARS-COV-2 virus. Described by many people as brilliant and inspirational, the concept is theoretically generalisable to the control of any contagious disease.  Professor Fraser’s proposal led to the development of Phone Tracking Apps by the NHS, Google, Apple and government agencies internationally.  The UK government played an important role in making this important UK technological and conceptual advance available to its partners overseas.

Contact tracing apps have been introduced across Europe and other countries. In the UK, on the 5th May 2020 an App developed by NHS-X was trialled on the Isle of Wight. One month later, there was evidence this had reduced transmission on the island but issues with the proximity detection system on iPhones led to it being abandoned. On the 13th August, a second trial using a Google/Apple platform was launched on the lsle of Wight and in the London Borough of Newnham.

The UKRI and DHSC funded RECOVERY (Randomised Evaluation of COVid-19 thERapY) Trial is led by NDM’s Professor Peter Horby, with deputy director Professor Martin Landray from the Nuffield Department of Population Health.

RECOVERY has been widely recognised as a triumph of delivery and speed: its innovative and adaptive multi-arm trial protocol was drafted on 10th March 2020, before WHO declared the pandemic; and its first patient was recruited on 19th March 2020, four days before lockdown in the UK. RECOVERY was rapidly embedded across the NHS, and it has become the largest randomised control trial looking at potential treatments for treatment in COVID-19 in hospitalised patients worldwide.  The 10,000th patient was recruited on 14th May 2020.

On 9th June 2020, RECOVERY provided the first robust evidence that Hydroxychloroquine was not an effective COVID-19 treatment for active disease. Then on 16th June 2020, it reported that dexamethasone was effective in reducing mortality by up to 35% in patients on supplemental oxygen or ventilated. This was the first treatment shown to reduce mortality in COVID-19 disease. It has been calculated that the implementation of dexamethasone, which is cheap, will directly save 10,000’s of lives worldwide.

In August 2020, it was decided that RECOVERY will be extended as RECOVERY-International, starting with NDM’s OUCRU in Vietnam, and it will remain embedded in the NHS as a vehicle for testing new treatments for respiratory infections over coming years.

Since January 2020, staff from NDM’s Structural Biology Division (STRUBI), Diamond and the Rosalind Franklin Institute have worked to create, characterise and distribute a wide variety of SARS-Cov-2 viral proteins for the purposes of drug screens.  This has evolved into a UK wide COVID-19 Protein Production Consortium (CPPC).

Amongst 29 SAR-Cov2 specific proteins, there are several potentially druggable enzymes and proteins inhibiting anti-viral immunity; and several of these could be targeted in all coronaviruses to provide defence against future pandemics. STRUBI scientists working at Diamond solved the structure of the SARS-CoV-2 main protease and completed a large XChem crystallographic fragment screen against it, which was led by Professor Frank von Delft (XChem) The follow up on this initiative was managed externally through an open crowdsourcing and crowd-funding initiative, the COVID Moonshot.  On 11th May, the first biochemical and structural data from Moonshot compounds was released and by the 12th June over 500 compounds had been tested, demonstrating that the design-make-test process was fully in place.

In seeking to target other coronaviral specific enzymes NDM scientists have solved structures for the SARS-Cov-2 viral RNA polymerase (Professor Jonathan Grimes), and papain-like protease, which also inhibits the interferon responses by deubiquitinylating host proteins. In collaboration with partners in ExScientia and the Weizmann Institute, Professor Stuart’s team have screened the 15K Gates’ ReFRAME library of licensed drugs, identifying two potential inhibitors amongst licenced drugs.

Some months prior to the emergence of the COVID-19 pandemic, Professor David Stuart in collaboration with Arthur Huang (Chang Gung Memorial Hospital, Taiwan) piloted a pipeline for comprehensive, atomic level, analysis of neutralising antibody responses in four Hand Foot and Mouth Disease (HFMD) child patients infected during the 2012 EV71 B5 epidemic (unpublished). In brief, some 50% of the antibodies in 4 children were found to be against this virus, and of these ~50% were neutralising. The number of unique antibodies was rather small so a comprehensive structural analysis of the antibodies and their interaction with EV71 was performed for 13 antibodies providing a comprehensive in-depth map of antibody responses, which revealed unexpected insight into focussing of responses in individuals.

This work was a prelude to the activity triggered by the COVID-19 outbreak, which has brought together groups from across the NDM (notably Professors Gavin Screaton, Alain Townsend, David Stuart) to rapidly map out immune responses to SARS-CoV-2. This has linked to work with NDM Professor Jim Naismith, the Director of the RFI, to develop potent nanobodies, and with Professor Peijun Zhang for tomography on whole virus.  The Screaton Lab (WHG) has generated >200 virus specific antibodies with varying isotypes some with sub-nanomolar binding affinities.

The key to future treatment of COVID19 and other coronaviral threats remains in understanding the underlying pathology.  The same is true for many other diseases for which we lack adequate forms of treatment, and the NDM is prioritising new paradigms of molecular pathology that explore disease at the levels of cells and their relationships. The COVID19 outbreak has been an opportunity to develop this capacity further.

The Oxford COVID19 Pathology Project comprises 119 scientists spanning Medical Sciences and Mathematics, Physical and Life Sciences Divisions, and is chaired by NDM’s Professor Paul Klenerman. The consortium has collected over 100 clinical samples from age matched COVID19 patients presenting with mild, severe or critical disease in hospital or mild disease outside hospital, and hospitalised patients with influenza or sepsis, and unaffected controls. This was led by work led by Dr Alex Mentzer, linking to ISARIC, Bio-AID, UK-Gains and our own Oxford Healthcare worker study.

The following work-packages (with lead investigators) will be reported on our database:

  • WP1: Humoral Immunity (Gavin Screaton)
  • WP2: COMBAT: Deep Phenotyping (Julian Knight)
  • WP3: Inflammatory Response and Haematology (Fiona Powrie)
  • WP4: T cell Immunity (Graham Ogg)
  • WP5: Data Integration (Julian Knight, Brian Marsden and John Todd)
  • WP6: Prospective 10,000 Oxford Healthcare Workers Study (Chris Conlon)