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  1. Preparedness Research

FDA and global partners to analyze coronavirus samples

Effort to help inform development of SARS-COV-2 diagnostics, vaccines, and therapeutics

Image
Creative rendition of SARS-CoV-2 virus particles. (Note: not to scale.) Credit: NIAID
Caption
Creative rendition of SARS-CoV-2 virus particles. (Note: not to scale.) Credit: NIAID

Background | Project description | Update - August 2021 | Project outcomes | Additional reading | Publications | Related links

Performer: University of Liverpool
Project leader: Julian Hiscox, PhD
Initial contract value: $5,402,198
Contract modification value: $3,510,074 (August 2021)
Project dates: September 2020 – September 2025

View a July 2021 FDA Grand Rounds lecture about this research: SARS-CoV-2 Host-Pathogen Interaction, Vaccines & Variants of Concern - webcast (1 hour, 6 minutes) - about this lecture

Background

The emergence of SARS-CoV-2 in 2019 and the associated COVID-19 pandemic, and prior SARS-CoV and MERS-CoV outbreaks, demonstrate the significant threat posed by coronaviruses. Several vaccines and antiviral therapies are being utilized against SARS-CoV-2, but there is an urgent need to support development and evaluation of additional medical countermeasures (MCMs).

Project description

In this Medical Countermeasures Initiative (MCMi) regulatory science project, the University of Liverpool (ULIV) and international partners will analyze SARS-CoV-2 (including variants of concern, such as the Delta variant), SARS-CoV, and MERS-CoV clinical samples, collected through global partnerships, to better understand coronavirus evolution and virulence, characterize host-pathogen interactions and immunity, and identify biomarkers of disease progression and severity. Through the sequence analysis of current and ongoing collection of samples from humans and animals, this project will help inform the real-time performance of molecular-based diagnostics (e.g., genetic drift that may evade the current molecular diagnostic tests).

This project also has the potential to provide a better understanding of vaccine and therapeutic targets, including biomarkers of protection, potential development of antiviral resistance, and host-directed therapeutics for a broad range of coronaviruses. The pattern of severe disease in COVID-19 is similar to both MERS and SARS, particularly with regard to an enhanced and overt host inflammatory response. This will be investigated and compared in human and animal models. Identification of potentially common pathways would provide necessary information for development of host-directed MCMs.

The project will also examine in vitro models of coronavirus infection, including microphysiological systems (MPS) such as human organs-on-chips, to elucidate how these models compare to in vivo responses in animal models and humans. Ultimately, these in vitro models will result in enhanced MCM screening methods.

Collaborators include:

Update - August 2021

In August 2021, FDA modified this contract to expand characterization of SARS-CoV-2 (including variants of concern) pathogenesis and disease severity in humans and animal models. These studies may inform development and evaluation of the safety and effectiveness of medical countermeasures for COVID-19, including diagnostics, therapeutics, and vaccines.

Project outcomes

During this project, the University of Liverpool and national and international partners listed above, will perform RNA sequencing and immunological analysis of samples from patients who were infected with SARS-CoV-2, SARS-CoV, and MERS-CoV during the COVID-19 pandemic and outbreaks in 2003-2004 (SARS-CoV) and MERS-CoV (since 2012). The project will use a biobank of diverse samples from humans with these infections and compare their response to relevant animal models and in vitro systems being used to develop MCMs.

Major objectives of this project include:

  • Characterizing viral genetics during infection and identifying whether sites targeted by diagnostics and therapeutics are under selection pressure. This will also assess whether the major drivers in evolution are mutation and/or recombination; the latter is a natural byproduct of coronavirus RNA synthesis.
  • Assessing the host response to mild and severe coronavirus infection and identifying any commonalities and differences. This will correlate observations in humans with findings from relevant animal models used in the development of MCMs. Here machine learning approaches will be used to interrogate the large datasets generated and identify patterns.
  • Further characterizing the properties of SARS-CoV-2 and MERS-CoV in cell culture with a specific focus on cell lines and systems used for screening candidate MCMs.
  • Developing and evaluating MPS models of coronavirus infection to support MCM evaluation. 
  • In vitro characterization and assessment of SARS-CoV-2 variants of concern and comparison to data obtained from nonclinical and clinical studies.

The primary planned outcomes of this project are to:

  1. Identify viral evolution in longitudinal samples (nasal aspirates/blood/plasma) taken from patients with MERS-CoV and SARS-CoV-2 using Illumina, PacBio, and Oxford Nanopore-based technologies.
  2. Identify host biomarkers and immune responses through gene and protein expression patterns, using RNAseq, long read sequencing, proteomics, machine learning, digital cell quantification, cytometry, and multiplex tissue imaging in longitudinal samples taken from patients with SARS-CoV, MERS-CoV, and SARS-CoV-2 with metadata including clinical information on disease progression and outcomes.
  3. Characterization of in vitro host pathogen interactions and comparison to in vivo responses for SARS-CoV, MERS-CoV, and SARS-CoV-2. This will range from using traditional continuous cell culture models for benchmarked high-throughput analysis to three-dimensional culture from clinical samples to emerging technologies such as organs-on-chips and marrying with approaches including CODEX.
  4. Characterization of SARS-CoV-2 variants of concern to understand potential impact on the safety and performance of COVID-19 MCMs.

This project is funded through the MCMi Regulatory Science Extramural Research program, and is supported through partnership with the Office of Biodefense Research Resources, and Translational Research, Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH).

Additional reading

Moore SC, Penrice-Randal R, Alruwaili M, et al. Amplicon based MinION sequencing of SARS-CoV-2 and metagenomic characterisation of nasopharyngeal swabs from patients with COVID-19. MedRxiv [preprint]. 2020 Mar 8. DOI: 10.1101/2020.03.05.20032011 - full text (open access)

Davidson AD, Williamson MK, Lewis S, et al. Characterisation of the transcriptome and proteome of SARS-CoV-2 using direct RNA sequencing and tandem mass spectrometry reveals evidence for a cell passage induced in-frame deletion in the spike glycoprotein that removes the furin-like cleavage site. Genome Medicine. 2020 Mar 24. DOI: 10.1186/s13073-020-00763-0 - full text (open access)

Daly JL,  Simonetti B,  Antón-Plágaro C, et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge BioRxiv [preprint]. 05 Jun 2020. DOI: 10.1101/2020.06.05.134114 - full text (open access)

Ryan KA, Bewley KR, Fotheringham SA, et al. Dose-dependent response to infection with SARS-CoV-2 in the ferret model: evidence of protection to re-challenge. BioRxiv [preprint]. 29 May 2020. DOI: 10.1101/2020.05.29.123810 - full text (open access)

Publications

  • Moore, S. C., Kronsteiner, B., Longet, S., et al. (2023). Evolution of long-term vaccine-induced and hybrid immunity in healthcare workers after different COVID-19 vaccine regimens. In Med (Vol. 4, Issue 3, pp. 191-215.e9). Elsevier BV. https://doi.org/10.1016/j.medj.2023.02.004
  • Legebeke J, Lord J, Penrice-Randal R, et al., Evaluating the immune response in treatment-naive hospitalised patients with influenza and COVID-19. Frontiersin. (epub ahead of print) DOI: 10.3389/fimmu.2022.853265
  • Ogbe A, Pace M, Bittaye M, et al., Durability of ChAdOx1 nCov-19 vaccination in people living with HIV. JCI Insight Feb 22:e:157031. DOI: 10.1172/jci.insight.157031 (open access)
  • Zhou J, Peacock TP, Brown JC, et al. Mutations that adapt SARS-CoV-2 to mink or ferret do not increase fitness in the human airway. [Epub ahead of print]. Cell Rep. 2022 Jan 19:110344. DOI: 10.1016/j.celrep.2022.110344.. PMID: 35093235; PMCID: PMC8768428 - full text (open access)
  • Payne, R., Longet, S., Austin, J. et al. Immunogenicity of standard and extended dosing intervals of BNT162b2 mRNA vaccine. Cell, 2021 in press. Early access 16 Oct 2021. https://doi.org/10.1016/j.cell.2021.10.011 (open access)
  • Wang, B., Goh, Y.S., Prince, T. et al. Resistance of SARS-CoV-2 variants to neutralization by convalescent plasma from early COVID-19 outbreak in Singapore. npj Vaccines 6, 125; 2021 October 25. DOI: https://doi.org/10.1038/s41541-021-00389-2  - full text
  • Payne, R., Longet, S., Austin, J. et al.  Sustained T Cell Immunity, Protection and Boosting Using Extended Dosing Intervals of BNT162b2 mRNA Vaccine. [Epub ahead of print]. Cell. 2021 Jul 21. DOI: 10.2139/ssrn.3891065 – full text
  • Aljabr, W., Alruwaili, M., Penrice-Randal, R. et al. Amplicon and Metagenomic Analysis of Middle East Respiratory Syndrome (MERS) Coronavirus and the Microbiome in Patients with Severe MERS. [Epub ahead of print]. mSphere. 2021 Jul 21:e0021921. DOI:  https://doi.org/10.1128/mSphere.00219-21 - full-text
  • Hiscox, J., Khoo, S., Stewart, J. et al.  Shutting the gate before the horse has bolted: is it time for a conversation about SARS-CoV-2 and antiviral drug resistance? Journal of Antimicrobial Chemotherapy; 2021 June 18. DOI: https://doi.org/10.1093/jac/dkab189 - full text
  • Tomic, A., Skelly, D., Ogbe, A. et al. Divergent trajectories of antiviral memory after SARS-Cov-2 infection. Research Square [preprint]; 2021 June 15. DOI: https://doi.org/10.21203/rs.3.rs-612205/v1 - full-text 
  • Legebeke, J., Lord, J., Penrice-Randal, R. et al. Distinct immune responses in patients infected with influenza or SARS-CoV-2, and in COVID-19 survivors, characterised by transcriptomic and cellular abundance differences in blood. medRxiv [preprint]; 2021 May 15. DOI: https://doi.org/10.1101/2021.05.12.21257086 - full-text
  • Seehusen, F., Clark, J. J., Sharma, P., et al. (2022). Neuroinvasion and Neurotropism by SARS-CoV-2 Variants in the K18-hACE2 Mouse. In Viruses (Vol. 14, Issue 5, p. 1020). MDPI AG. https://doi.org/10.3390/v14051020
  • Peacock, T., Penrice-Randal, R., Hiscox, J. et al. SARS-CoV-2 one year on: Evidence for ongoing viral adaptation. Journal of General Virology; 2021 April 15. DOI: https://doi.org/10.1099/jgv.0.001584 
  • Prince, T., Dong, X., Penrice-Randal, R., et al. (2022). Analysis of SARS-CoV-2 in Nasopharyngeal Samples from Patients with COVID-19 Illustrates Population Variation and Diverse Phenotypes, Placing the Growth Properties of Variants of Concern in Context with Other Lineages. In B. Lee (Ed.), mSphere (Vol. 7, Issue 3). American Society for Microbiology. https://doi.org/10.1128/msphere.00913-2
  • Angyal, A., Longet, S., Moore, S. C., et al. (2022). T-cell and antibody responses to first BNT162b2 vaccine dose in previously infected and SARS-CoV-2-naive UK health-care workers: a multicentre prospective cohort study. In The Lancet Microbe (Vol. 3, Issue 1, pp. e21–e31). Elsevier BV. https://doi.org/10.1016/s2666-5247(21)00275-5
  • Russell, C. D., Valanciute, A., Gachanja, N. N., et al. (2022). Tissue Proteomic Analysis Identifies Mechanisms and Stages of Immunopathology in Fatal COVID-19. In American Journal of Respiratory Cell and Molecular Biology (Vol. 66, Issue 2, pp. 196–205). American Thoracic Society. https://doi.org/10.1165/rcmb.2021-0358oc
  • Salzer, R., Clark, J., Vaysburd, M. et al. Single-dose immunisation with a multimerised SARS-CoV-2 receptor binding domain (RBD) induces an enhanced and protective response in mice. FEBS Letters; 2021 July 31. DOI: https://doi.org/10.1002/1873-3468.14171
  • Skelly, D., Harding, A., et al.Vaccine-induced immunity provides more robust heterotypic immunity than natural infection to emerging SARS-CoV-2 variants of concern. Research Square. [preprint] 2021 Feb 9 DOI: 10.21203/rs.3.rs-226857/v1
  • Clark, J. J., Sharma, P., Bentley, E. G. et al. Naturally-acquired immunity in Syrian Golden Hamsters provides protection from re-exposure to emerging heterosubtypic SARS-CoV-2 variants B.1.1.7 and B.1.351. bioRxiv [preprint]; 2021 March 10. DOI: https://doi.org/10.1101/2021.03.10.434447 - full text
  • Dong, X., Penrice-Randal, R., Goldswain, H. et al. Identification and quantification of SARS-CoV-2 leader subgenomic mRNA gene junctions in nasopharyngeal samples shows phasic transcription in animal models of COVID-19 and aberrant patterns in humans. bioRxiv [preprint]; 2021 March 03. DOI: https://doi.org/10.1101/2021.03.03.433753 - full text
  • Song, E., Zhang, C., Israelow, B., et al. (2021). Neuroinvasion of SARS-CoV-2 in human and mouse brai>
  • Salguero, F.J., White, A.D., Slack, G.S. et al. Comparison of rhesus and cynomolgus macaques as an infection model for COVID-19. Nature Communications. 2021 Feb. 24 DOI: 10.1038/s41467-021-21389-9
  • Dorward, D. A., Russell, C. D., Um, I. H., et al. (2021). Tissue-Specific Immunopathology in Fatal COVID-19. In American Journal of Respiratory and Critical Care Medicine (Vol. 203, Issue 2, pp. 192–201). American Thoracic Society. https://doi.org/10.1164/rccm.202008-3265oc
  • Clark, J. J., Penrice-Randal, R., Sharma, P., et al. (2020). Sequential infection with influenza A virus followed by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) leads to more severe disease and encephalitis in a mouse model of COVID-19. Cold Spring Harbor Laboratory. [preprint]; https://doi.org/10.1101/2020.10.13.334532
  • Nasir, J. A., Kozak, R. A., Aftanas, P., et al. (2020). A Comparison of Whole Genome Sequencing of SARS-CoV-2 Using Amplicon-Based Sequencing, Random Hexamers, and Bait Capture. In Viruses (Vol. 12, Issue 8, p. 895). MDPI AG. https://doi.org/10.3390/v12080895
  • Dong, X., Goldswain, H., Penrice-Randal, R., et al. (2021). Rapid selection of P323L in the SARS-CoV-2 polymerase (NSP12) in humans and non-human primate models and confers a large plaque phenotype. Cold Spring Harbor Laboratory. [preprint]; https://doi.org/10.1101/2021.12.23.474030
  • Bentley, E. G., Kirby, A., Sharma, P., (2021). SARS-CoV-2 Omicron-B.1.1.529 Variant leads to less severe disease than Pango B and Delta variants strains in a mouse model of severe COVID-19. Cold Spring Harbor Laboratory. https://doi.org/10.1101/2021.12.26.474085 [preprint]; 2021 Dec 28. doi: https://doi.org/10.1101/2021.12.26.474085 
  • Longet, S., Hargreaves, A., Healy, S., et al. (2022). mRNA vaccination drives differential mucosal neutralizing antibody profiles in naïve and SARS-CoV-2 previously-infected individuals. In Frontiers in Immunology (Vol. 13). Frontiers Media SA. https://doi.org/10.3389/fimmu.2022.953949 
  • Gupta, K., Toelzer, C., Williamson, M. K., et al. (2022). Structural insights in cell-type specific evolution of intra-host diversity by SARS-CoV-2. In Nature Communications (Vol. 13, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41467-021-27881-6 
  • Penrice-Randal, R., Dong, X., Shapanis, A. G., et al. (2022). Blood gene expression predicts intensive care unit admission in hospitalised patients with COVID-19. In Frontiers in Immunology (Vol. 13). Frontiers Media SA. https://doi.org/10.3389/fimmu.2022.988685 
  • Poh, X. Y., Tan, C. W., Lee, I. R., et al. (2022). Antibody Response of Heterologous vs Homologous Messenger RNA Vaccine Boosters Against the Severe Acute Respiratory Syndrome Coronavirus 2 Omicron Variant: Interim Results from the PRIBIVAC Study, a Randomized Clinical Trial (SARS-CoV-2). In Clinical Infectious Diseases. Oxford University Press (OUP). https://doi.org/10.1093/cid/ciac345 
  • Ugolini, C., Mulroney, L., Leger, A., et al. (2022). Nanopore ReCappable sequencing maps SARS-CoV-2 5′ capping sites and provides new insights into the structure of sgRNAs. In Nucleic Acids Research (Vol. 50, Issue 6, pp. 3475–3489). Oxford University Press (OUP). https://doi.org/10.1093/nar/gkac144 
  • Shankar, S., Beckett, J., Tipton, T., et al. (2022). SARS-CoV-2-Specific T Cell Responses Are Not Associated with Protection against Reinfection in Hemodialysis Patients. In Journal of the American Society of Nephrology (Vol. 33, Issue 5, pp. 883–887). American Society of Nephrology (ASN). https://doi.org/10.1681/asn.2021121587 
  • Carroll, M. (2022). Serological evidence of zoonotic filovirus exposure among bushmeat hunters in Guinea. Research Square Platform LLC. [preprint]  https://doi.org/10.21203/rs.3.rs-1347502/v1
  • Khoo, S. H., FitzGerald, R., Saunders, G., et al. (2022). Molnupiravir versus placebo in unvaccinated and vaccinated patients with early SARS-CoV-2 infection in the UK (AGILE CST-2): a randomised, placebo-controlled, double-blind, phase 2 trial. In The Lancet Infectious Diseases. Elsevier BV. https://doi.org/10.1016/s1473-3099(22)00644-2 
  • Renia, L., Goh, Y. S., Rouers, A., et al. (2022). Lower vaccine-acquired immunity in the elderly population following two-dose BNT162b2 vaccination is alleviated by a third vaccine dose. In Nature Communications (Vol. 13, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41467-022-32312-1 
  • Donovan-Banfield, I., Penrice-Randal, R., Goldswain, H., et al. (2022). Characterisation of SARS-CoV-2 genomic variation in response to molnupiravir treatment in the AGILE Phase IIa clinical trial. In Nature Communications (Vol. 13, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41467-022-34839-9

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