The Nuffield Department of Medicine is supporting global efforts in tackling nCoV
Introduction – objectives
On 30th January 2020 the World Health Organisation declared the outbreak of novel coronavirus (2019-nCoV) a Public Health Emergency of International Concern.
This international global health emergency requires an immediate and coordinated international response.
The Nuffield Department of Clinical Medicine is supporting global efforts in tackling nCoV. It is prioritising collaborative projects for front line actions. This site’s primary purpose is to provide signposting to projects.
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(i) Professor Peter Horby – clinical characterisation and clinical trials
Professor Horby has been collaborating with the World Health Organization (WHO) and investigators at the Chinese Academy of Medical Sciences and China CDC via ISARIC and ERGO since the 2nd January. ISARIC has launched a number of international resources made available free of charge, through which investigators retain full control of all data and samples.
Main activities are:
a.) Development and dissemination of a nCoV electronic Case Record Form (eCRF) and hosting of the WHO Global 2019-nCoV Clinical Data Platform.
b.) Development and dissemination of a nCoV Clinical Characterisation Protocol (CCP) which is a flexible research protocol enabling collection of data and biological samples by investigators who wish to run their own observational studies. Several studies are already underway using the protocol and other are planned. The aim of all these resources is to reach more precise and robust conclusions faster to inform local and international public health responses and patient care. These resources have been made available free of charge and investigators retain full control of all data and samples.
c.) Clinical trials. Peter and his team have contributed to randomised controlled trials being conducted in China of lopinavir/ritonavir and of remdesivir in patients hospitalised with 2019-nCoV.
After discussion it was agreed that support of this work should be a Medical Sciences divisional priority (MSD).
(ii) Professor Sarah Gilbert – Vaccine Development
Professor Gilbert and Professor Teresa Lambe have generated a new adenoviral vectored vaccine using the same technology as the MERS vaccine, which has completed a phase I clinical trial in the UK (NCT03399578), is currently undergoing phase I trials in Saudi Arabia and recently showed good single dose efficacy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5643297/). It was unanimously agreed that a vaccine is likely to be our best chance at a new prophylactic approach. Other variant vaccines – RNA/DNA and protein are being sponsored by CEPI.
The team have developed and manufactured the ChAdOx1 nCoV-19 vaccine in our clinical biomanufacturing facility and with the support of an external partner, Advent, have produced enough doses for use in Phase I, II and III clinical trials.
Professor Lambe is leading the biomedical studies and is collaborating with NIH Rocky Mountain Laboratories (RML), Commonwealth Scientific and Industrial Research Organisation (CSIRO), and the Pirbright Institute to complete the animal challenge studies. Following sufficient data from the preclinical studies and previous clinical trials using the ChAdOx1 technology, the newly developed vaccine entered clinical trials in April, in collaboration with Professor Andrew Pollard, Department of Paediatrics. The vaccine has now reached Phase II/III clinical trials and the programme is aiming to recruit 10,000 participants across multiple trial sites in the UK to assess the efficacy of the vaccine.
This work has been generously supported to allow the trial to progress rapidly, and it was decided that the NDM should provide an underwrite of £1m to get the contracts with GMP partners in Italy in place to accelerate the work.
(iii) Professors Dave Stuart and Yvonne Jones – Structure, Drug Screens and Tools
Professor Stuart is collaborating with Zihe Rao who with the group in Shanghai has already determined the crystal structure of the 2019-nCoV Mpro. The Chinese Synchrotron has been in a routine shut-down and so he is currently prioritising work at Diamond to accommodate nCoV activity. The group in Shanghai have screened a number of licensed drugs against the proteinase, and will go onto the fragment-based screening, XChem, developed at Diamond Light Source in collaboration with the Structural Genomics Consortium. We are committed to generating a lot of protein crystals locally, given we are unlikely to receive samples from China. In addition, we intend to work on the nCoV spike protein with the aim of mapping neutralising, and other antibodies, to the spike glycoprotein via cryo-EM structures. It was again agreed that consideration should be given to supporting these activities from MSD funds.
(iv) Professor Alain Townsend - Neutralising Antibodies and Protein Vaccines
Professor Townsend with Pramila Rijal and Tiong (Jack) Tan (Radcliffe Department of Medicine) has three related projects 1) Sub-unit Vaccine for Covid-19: Working with Mark Howarth, the Centre for Process Innovation, Ingenza and FUJIFILM Diosynth Biotechnologies, the group is developing a Virus Like Particle sub-unit vaccine. This has shown promising results in vaccination trials in mice and pigs (with the Pirbright Institute), inducing a high titre neutralising antibody response in both species. Efforts to produce the vaccine in Pichia yeast are proceeding. If successful, this will be a very inexpensive vaccine based on a technology radically different to the self amplifying RNA vaccine (Imperial), and the Recombinant Adenovirus vaccine (Jenner) funded by HMG. 2) Human Monoclonal Antibodies to SARS-2: our long-term collaborator Dr Arthur Huang has now isolated 32 antibdoies to the Spike Protein that we are characterising in collaboration with Prof David Stuart. Several are powerfully neutralising and bind to non-overlapping epitopes on the Receptor Binding Domain that could form the basis for a therapeutic cocktail. 3) A Point of Care Haemagglutination Test for antibodies: With Dr Etienne Joly (Toulouse), we have designed a test based on a simple reagent that detects antibodies to the Receptor Binding Domain of SARS-2 Spike protein that does not require any specialised equipment, and is read by eye. It requires a finger-prick sample of blood, takes one hour to perform, and is read at the point of care. In collaboration with Dr Derrick Crook and Dr Philippa Matthews we have established that our HA test has a Sensitivity of ~90% and Specificity 98.5% for detecting antibodies in test set of sera from PCR positive donors and pre-Covid negative control donors. We hope that it will be useful for Nations that lack access to ELISA readers, and are seeking collaborators for field testing.
(v) Professor Tao Dong - Protective Immune Response, Broader collaborations and other projects in China
Professor Don’s group had long term interest in studying the Antigen specific T cells in acute and chronic virus infection, in particular their roles in protection or disease pathogenesis. She has established collaborative networks in China especially with the two largest infectious disease hospitals in Beijing. Since the start of the pandemic, the group has been working with colleagues in oxford and in China, testing samples taken from COVID-19 positive patients, taken at different time points in their illness and trying to understand why some people with a COVID-19 infection are able to fight it off successfully, while others get really ill. The team believes understanding the immune response to COVID-19 is going to be key to defeating it. They recently found broad and strong SARS-Cov-2 specific immune responses in the patients recovered from COVID-19, and identified clusters of target antigens in the virus can be seen by the T cells (doi: https://doi.org/10.1101/2020.06.05.134551). As result of this work Professor Dong’s group, with other immunologists, are developing a diagnostic cocktail consisting the T cell antigen peptides identified, which they think will complimentary to the antibody test at early stage of infection. Other findings from her group including: Longitudinal COVID-19 profiling associates IL-1Ra and IL-10 with disease severity and RANTES with mild disease which was published in JCI Insight early this month (10.1172/jci.insight.139834); Interferon-induced transmembrane protein-3 genetic variant rs12252-C is associated with disease severity in COVID-19 published in Journal of Infectious Disease (10.1093/infdis/jiaa224) and Clinical and epidemiological features of COVID-19 family clusters in Beijing, China. published in Journal of infection (10.1016/j.jinf.2020.04.018).
In addition, Professor Dong has agreed with Professor Cao Xuetao, as Directors of the CAMS Oxford Instituteand chief scientist for the COI core support funded by CAMS Innovation fund, priories 7 COVID-19 research projects early this year. (https://www.camsoxford.ox.ac.uk/news/coi-prioritising-funding-support-to-the-current-crisis-caused-by-ncov-2019).
Professor Dong has also coordinated a large donation of PPE to Oxford university and hospitals by one our partner University in China Nankai university, including 150,000 N95 and surgical masks and 20,000 nasal swab kits in early April.
Professor Dong also served as panel member for UKRI/NIHR COVID-19 Rapid-Response Initiative and UKRI/NIHR Rolling call Highlight Notice for Covid-19 virus (SARS-CoV-2) research
(vi) Professors Gavin Screaton and Guy Thwaites – Samples, Data and Neutralising Antibodies
Professor Screaton is experienced in looking at the neutralising antibody responses to Dengue and Zika and well placed to take similar studies for nCoV forward. It is inevitable that the Oxford Clinical Research Unit in Vietnam, OUCRU, will have access to samples and data. Accessing that will have to be managed but is within the capability of the Unit. NDM will support equipping OUCRU for cell sorting if required.
(vii) Professors Derrick Crook & Tim Peto – UK Hospital Setting; Sample Access, BioAid
Professor Crook is assessing the testing landscape at it emerges in the UK. Any potential cases are tested by PHE hand-in-hand with the local NHS service. PHE during this early phase are understandably reluctant to support independent testing of samples. This will change soon once national protocols become well embedded. Locally, we have ethics approval for testing surplus sample and will transparently undertake testing if cases arise in Oxford.
(viii) Professors Christophe Fraser, John Todd, Miles Carroll – Pathogen Evolution and Sequencing.
The Wellcome Centre for Human Genetics (WHG) with Christophe Fraser’s group in the Big Data Institute, have designed and tested high-throughput sequencing tool for 2019-nCoV, based on their SARS experience. The WHG has recently established a major collaboration with the Chinese sequencing company, BGI, which has just announced urgent release of its latest ultra-high-throughput sequencer and a 2019-nCoV RT PCR kit. Miles Carroll who recently joined NDM on partial secondment from Public Health England will assist in getting samples. Establishing safe local protocols is going to be a priority. A number of groups in Oxford are contributing to the disease modelling, development of anti-viral agents, structural determination of key nCoV proteins, vaccine development and identification of therapeutic monoclonal antibodies against the virus.
(ix) Professor Emily Chan – Oxford Visiting Professor
Serving as a global and regional platform for research, education, and community knowledge transfer in the areas of disaster and humanitarian medicine, CCOUC has been responding to COVID-19 outbreak by engaging in various research, education, and community knowledge transfer initiatives with local and international academic partners since early February 2020. Relevant resources, tools, projects, and information can be found in this site