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.
(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 are generating a new adenoviral vectored vaccine using the same technology as the MERS vaccine which has completed phase I 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 likely to our best chance at a new prophylactic approach. Other variant vaccines – RNA/DNA and protein are being sponsored by CEPI. They hope to get seed material for the full GMP manufacture by the end of March, using the capacity in our clinical biomanufacturing facility as well as working with an external partner. Professor Lambe will lead the biomedical studies. We have agreement from Rocky Mountain Laboratories (RML) and Commonwealth Scientific and Industrial Research Organisation (CSIRO) to do the animal challenge studies, and we may then be in a position to do clinical trials in Oxford in June in conjunction with Professor Andy Pollard, Department of Paediatrics. Consideration will be made for an aerosol variant. It was decided that the NDM should provide an underwrite of £1m to get the contracts with our 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 (Radcliffe Department of Medicine) has a collaborator in Thailand who has cloned some plasmablasts for antibody sequencing; he will work with Elma Tchillian (Pirbright) in isolating monoclonal antibodies to the Spike protein; and he will be working with Professor Mark Howarth in the Department of Biochemistry in Oxford to make a protein aggregate vaccine based on the spike protein, but this will take time.
(v) Professor Tao Dong - Protective Immune Response, Broader collaborations and other projects in China
Professor Dong has long term collaborations in China at Beijing You’an and Ditan Hospitals, the largest infectious diseases hospitals in Beijing. She has staff who are studying the immune responses and cloning antibodies; she is also coordinating to obtain the permission from China to ship the plasmids. The Head of Division, Professor Gavin Screaton and Professor Dong are speaking with their Chinese Embassy contacts to determine supportive responses, and offer expert access from Oxford is requested. In addition Professor Dong has agreed with Professor Cao Xuetao, as Directors of the CAMS Oxford Institute, to prioritise projects for nCoV. https://www.camsoxford.ox.ac.uk
(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.