ISARIC 4C

About

ISARIC4C Consortium leadership

  • Kenneth Baillie (j.k.baillie@ed.ac.uk)
  • Calum Semple (M.G.Semple@liverpool.ac.uk)
  • Peter Openshaw (p.openshaw@imperial.ac.uk)

Management

  • Recruitment, sample tracking and ethical approvals: Hayley Hardwick (H.E.Jelleyman@liverpool.ac.uk)
  • MTAs, IDAMAC and Consortium Management: Wilna Oosthuyzen(Wilna.Oosthuyzen@ed.ac.uk)

Objectives and Resources

Each Work Package has a lead and deputy who will be responsible for resource allocation and leadership

Each deliverable has a single consortium member who will be responsible for ensuring delivery

WP1. Coordination (Baillie, Semple, Openshaw(co-leads), Russell, Ho, Docherty, Noursadeghi, Law)

  • Coordinate timely delivery across consortium(Baillie).[WEEKS 0-78]
    • DELIVERABLE: Extend existing collaboration agreement. Baillie.[WEEKS 0-2]
    • DELIVERABLE: Coordinate rapid delivery across all WPs. Baillie.[WEEKS 0-78]
    • DELIVERABLE: Database for sharing results. Law.[WEEKS 0-10]
    • DELIVERABLE: Browser interface for sharing results. Docherty.[WEEKS 4-20]
    • DELIVERABLE: Completion of proposed analyses in public domain. Baillie.[WEEKS 0-78]
    • DELIVERABLE: Anonymise clinical data to prevent personal disclosures. Doherty.[WEEKS 0-1]
    • DELIVERABLE: Submission to WHO sharepoint. Law.[WEEKS 0-78]
  • Lead Recruitment of 1300 confirmed cases (Semple).[WEEKS 0-78]
    • DELIVERABLE: Recruit 300 cases at TIER2(4 serial samples). Semple.[WEEKS 0-40]
    • DELIVERABLE: Recruit 1000 cases at TIER1(1 sample). Semple.[WEEKS 30-60]
    • DELIVERABLE: Provide additional research nurse support flexibly to sites. Semple.[WEEKS 3-55]
    • DELIVERABLE: Establish and review 4-month contracts with sites for reserach nurse support. Semple.[WEEKS 3-55]
    • DELIVERABLE: Establish distrubution of samples to consortium and partners. Semple.[WEEKS 0-78]
    • DELIVERABLE: Recruit and distribute samples in Scotland. Ho.[WEEKS 0-40]
  • Lead Recruitment 1000 suspected cases(Noursadeghi).[WEEKS 0-52]
    • DELIVERABLE: Establish BioAid clone as substudy of ISARIC CCP. Noursadeghi.[WEEKS 0-4]
    • DELIVERABLE: Recruit 1000 suspected cases at presentation. Noursadeghi.[WEEKS 0-52]

WP2. Viral transmission (Barclay(lead), Dunning(deputy), Zambon, Ho, Hiscox)

  • Idenfity sites and duration of viral shedding(Hiscox)[WEEKS 0-40]
    • DELIVERABLE: PCR on SAM strips, Urine + stool. Hiscox.[WEEKS 0-40]
  • Quantify Aerosol spread in hospitalised cases(Barclay)[WEEKS 0-15]
    • DELIVERABLE: Aerosol transmission study. Barclay.[WEEKS 0-15]
    • DELIVERABLE: Quantify the effect of high-flow nasal oxyen on viral aerosolisation. Barclay.[WEEKS 0-15]

WP3. Pathogen characteristics and evolution (Hiscox(lead), Thomson(deputy), Zambon, Rambaut, Bogaert)

  • Identify viral sequence correlates with severe disease(Hiscox, Thomson, Zambon)[WEEKS 0-40]
    • DELIVERABLE: Deep MinION sequencing for metagenomics on 80 respiratory (SAM) samples. Hiscox/Thomson.[WEEKS 0-8]
    • DELIVERABLE: Amplicon MinION sequencing for metagenomics on 300 respiratory (SAM) samples. Hiscox/Thomson.[WEEKS 4-40]
    • DELIVERABLE: Analysis of viral selection during infection. Thomson.[WEEKS 12-45]
  • Map and track viral transmission and evolution(with PHE).(Rambaut)[WEEKS 0-78]
    • DELIVERABLE: Analysis of viral transmission and evolution. Rambaut.[WEEKS 0-78]
  • Detect bacterial/viral/fungal coinfection(Hiscox, Bogaert)[WEEKS 0-40]
    • DELIVERABLE: Microbiome sequencing in respiratory samples. Bogaert/Hiscox.[WEEKS 10-40]

WP4. Clinical characterisation (Semple(lead), Baillie(deputy), Openshaw, Summers, Docherty, Russell, Dunning, Ho, Cooke)

  • Define dynamics of viral production disease.(Docherty)[WEEKS 0-40]
    • DELIVERABLE: Collate, integrate and interpret viral shedding data. Docherty.[WEEKS 0-40]
    • DELIVERABLE: Synthesise viral load data in clinical context. Semple.[WEEKS 0-40]
  • Create prognostic scores(Ho, Noursadeghi)[WEEKS 0-24]
    • DELIVERABLE: Clincal prognostic score. Ho.[WEEKS 0-24]
    • DELIVERABLE: Molecular prognostic score. Noursadeghi.[WEEKS 20-48]
  • Determine role of nonpulmonary organ injury(Docherty)[WEEKS 0-24]
    • DELIVERABLE: Clinical lab tests on serial samples (U&E, LFT(AST), HSTrop, Ferritin, Trigs, CRP, Procalcitonin, D-dimer, LDH, BNP, CK, Amylase). Baillie.[WEEKS 0-40]
    • DELIVERABLE: Quantify clinical severity for every case + timepoint. Doherty.[WEEKS 6-12]
    • DELIVERABLE: Analyse and report clinical description. Doherty.[WEEKS 6-12]

WP5. Integrative analysis of disease mechanisms (Baillie(lead), Meynert(deputy), Thomson, Hiscox, Openshaw, Russell, Klenerman, Sancho Shimizu)

  • RNAseq quantitation of systemic viral RNAemia and host transcriptome.(Thomson/Meynert)[WEEKS 0-40]
    • DELIVERABLE: Whole blood RNA extraction and storage. Baillie.[WEEKS 0-60]
    • DELIVERABLE: Host/viral RNAseq. Baillie.[WEEKS 8-10]
    • DELIVERABLE: Host/viral RNAseq. Baillie.[WEEKS 18-20]
    • DELIVERABLE: Host/viral RNAseq. Baillie.[WEEKS 28-30]
    • DELIVERABLE: Host/viral RNAseq. Baillie.[WEEKS 38-40]
    • DELIVERABLE: Align viral reads from whole blood RNAseq. Thomson.[WEEKS 4-40]
    • DELIVERABLE: Upload viral reads to ENA. Meynert.[WEEKS 12-40]
    • DELIVERABLE: Upload host reads to ENA. Meynert.[WEEKS 12-40]
    • DELIVERABLE: Align and quantify viral reads. Meynert.[WEEKS 12-40]
    • DELIVERABLE: Align and quantify host reads. Meynert.[WEEKS 12-40]
  • Integrate consortium data to estimate tolerance and resistance.(Russell)[WEEKS 0-40]
    • DELIVERABLE: Define integrated tolerance and resistance patterns. Russell.[WEEKS 4-40]
    • DELIVERABLE: Differential expression analysis. Parkinson.[WEEKS 11-42]
  • Identify patient subgroups/trajectories.(Baillie)[WEEKS 0-60]
    • DELIVERABLE: Unsupervised clustering of disease trajectories. Baillie.[WEEKS 0-40]
  • Detect genetic associations with severe disease.(Meynert)[WEEKS 0-60]
    • DELIVERABLE: Cell pellet DNA extraction and storage. Baillie.[WEEKS 0-60]
    • DELIVERABLE: Genome-wide array genotyping. Baillie.[WEEKS 15-18]
    • DELIVERABLE: Genome-wide array genotyping. Baillie.[WEEKS 35-38]
    • DELIVERABLE: GWAS analyses. Meynert.[WEEKS 20-44]
    • DELIVERABLE: Link with known eQTL. Meynert.[WEEKS 0-40]
    • DELIVERABLE: WGS. Baillie.(£606 - 27% unit cost for seq)[WEEKS 20-30]
    • DELIVERABLE: Identify high-consequence variants in WGS. Sancho Shimizu.[WEEKS 30-45]

WP6. Immunology (Openshaw(lead), Klenerman(deputy), Thwaites, Zambon, Ijaz, Thomson, Turtle, Dunning, Solomon, Stuart)

  • Describe and characterise the host immune response.(Openshaw)[WEEKS 12-22]
    • DELIVERABLE: Cytokine and proteomic analyses in respiratory specimens. Openshaw.[WEEKS 12-30]
    • DELIVERABLE: Cytokine analyses in blood. Openshaw.[WEEKS 12-30]
    • DELIVERABLE: Proteomic analyses in 60 blood samples. Semple.[WEEKS 12-22]
  • Determine effects of prior immunity to coronaviruses on susceptibility.(Thomson, Zambon, Ijaz)[WEEKS 0-40]
    • DELIVERABLE: Serological tests for prior exposure to coronaviruses. Ijaz.[WEEKS 6-18]
    • DELIVERABLE: NGS Serological tests for prior exposure to all resp viruses. Thomson.[WEEKS 12-22]
    • DELIVERABLE: Integrate clinical, transcriptomic, NGS serology and neutralisation assays to determine ADE effect. Ballie.[WEEKS 30-40]
  • Describe B&T cell responses in a subset of patients(Klenerman)[WEEKS 4-16]
    • DELIVERABLE: Obtain PBMCs from a subset of acute cases. Turtle.[WEEKS 4-16]
    • DELIVERABLE: T-cell functional assays. Klenerman.[WEEKS 4-16]
  • Identify antigens targeted by neutralising antibodies.(Stuart)[WEEKS 0-26]
    • DELIVERABLE: Determine structure of antibody-binding sites. Stuart.[WEEKS 0-40]
  • Identify nasal cell populations supporting viral replication(Thwaites)[WEEKS 8-14]
    • DELIVERABLE: Single-cell (nucelar) sequencing on 20 nasopharyngeal (SAM) samples. Thwaites.[WEEKS 8-14]
  • Identify circulating immune cell subpopulations associated with severe disease.(Klenerman)[WEEKS 0-20]
    • DELIVERABLE: Single-cell (nuclear) sequencing on 60 selected frozen cell pellet samples. Klenerman.[WEEKS 8-14]

WP7. Diagnostics and immunotherapeutics (Mentzer, Ijaz, Zambon(co-leads), Pollakis, Noursadeghi, Klenerman)

  • Obtain large-volume convalescent samples from 8 patients.(Mentzer)[WEEKS 0-10]
    • DELIVERABLE: Select 8 patients and arrange transfer to Oxford. Mentzer.[WEEKS 0-4]
    • DELIVERABLE: Obtain 8x200mls convalescent plasma and PBMCs. Mentzer.[WEEKS 0-4]
  • Distribute serum and PBMCs to PHE and external groups(Semple, Mentzer)[WEEKS 0-60]
    • DELIVERABLE: Cyropreserve and distribute convalescent PMBC as instructed by IDAMAC. Mentzer.[WEEKS 0-10]
    • DELIVERABLE: Store and distribute convalescent plasma as instructed by IDAMAC. Mentzer.[WEEKS 0-10]
    • DELIVERABLE: Provide samples to define international reference standard. Mentzer.[WEEKS 0-1]
  • Establish open-access platform for large-scale diagnostic evaluation.(Mentzer)[WEEKS 0-52]
    • DELIVERABLE: Platform for comparisons of diagnostics. Mentzer.[WEEKS 8-65]
    • DELIVERABLE: Validate oral fluid test for population serology. Tedder.[WEEKS 20-32]
  • CL2 SARS-CoV-2 virus neutralization assay(Pollakis/Paxton)[WEEKS 0-52]
    • DELIVERABLE: Produce retroviral pseudo-virus, optimize for infectivity. Pollakis.[WEEKS 0-6]
    • DELIVERABLE: Determine best target cell for infection and sensitive readout. Pollakis.[WEEKS 4-8]
    • DELIVERABLE: Selection of high neutralizing sera for relative quantification of responses. Paxton.[WEEKS 8-20]
    • DELIVERABLE: Develop SARS-CoV-2-specific neutralization protocol. Paxton.[WEEKS 8-20]
    • DELIVERABLE: Convalescent sera neutralizing response measurements and cross-validation with serology assays. Paxton/Pollakis.[WEEKS 20-52]
    • DELIVERABLE: Upscaling of neutralization assay for high throughput. Pollakis.[WEEKS 20-34]
    • DELIVERABLE: High throughput neutralization measurement on all samples. Pollakis.[WEEKS 35-48]

WP8. Facilitating translation to local clinical guidelines (Alex(lead), Bach(deputy), Grover, Baillie, Russell)

  • AI-driven guideline/protocol sharing system for local clinicians.(Alex, Bach)[WEEKS 0-30]
    • DELIVERABLE: Collate, compare and present local clinical guidelines. Russell.[WEEKS 0-10]
    • DELIVERABLE: Create AI engine. Alex.[WEEKS 0-30].
    • DELIVERABLE: Create web interface. Bach.[WEEKS 0-20].

WP9. Long-term follow-up (unfunded) (Lone(lead), Semple(deputy), Jenkins, Turtle, Docherty, Baillie, Russell, many others…)

  • Serial serology (Semple, Turtle)
    • DELIVERABLE: Serial serology and immunology follow-up of selected cases. Semple.
  • Clincal follow-up (Lone, Jenkins)
    • DELIVERABLE: Data linkage follow-up of all cases. Lone.
    • DELIVERABLE: Clinical follow-up of selected cases. Jenkins.

ISARIC 4C

ISARIC 4C