Performer: Public Health England (PHE)
Project leader: Miles W. Carroll, PhD
Initial contract value: $3.2 million
Contract modification value: $250,000 (March 2020)
Project dates: September 2015 - March 2021
In the course of responding to the 2014-2015 West African Ebola epidemic, regulatory authorities worldwide are working together to facilitate the rapid development and availability of medical countermeasures to detect, treat and prevent Ebola virus disease (EVD). In addition to policy and legal agreements and information sharing, these collaborations include regulatory science research.
Regulatory science helps FDA and other regulators learn if investigational medical products will help or harm patients, or have no effect. Scientists investigate these questions by developing tools, methods and standards to assess if these medical products are safe, and if they work.
Reference databases are an important part of regulatory science research because they provide standardized data that researchers can share and use to help develop new medical countermeasures. Regulators can use these databases to help assess safety and efficacy of these products.
Similarly, correlates of protection are measurable signs that a person is protected against a disease. For example, the presence of antibodies against a virus is often considered a correlate of protection.
In this Medical Countermeasures Initiative (MCMi) regulatory science project, Public Health England (PHE), will research issues that are key to understanding and predicting if—and how—vaccines and therapeutics to prevent and treat EVD will show efficacy.
PHE will establish correlates of protection to support potential licensure of new EVD vaccines, and analyze blood samples collected from patients with Ebola to create a reference database. The reference database will demonstrate biomarkers of disease progression in humans.
This project builds on previous studies by the European Mobile Laboratory (EMLab) and its associated research project (EVIDENT) in Guinea, Liberia and Sierra Leone, funded by the European Commission (EC).1 Collaborators include Laboratoire National de Santé Publique, Conakry, Guinea; Laboratoire des Fièvres Hémorragiques en Guineé, Université Gamal Abdel Nasser de Conakry, Guinea; the Bernhard-Nocht Institute for Tropical Medicine, Hamburg, Germany; The Phillips University of Marburg, Germany; and the University of Liverpool, Southampton and Bristol UK.
Sample collection and initial testing will be conducted at existing EMLab and EVIDENT facilities, and new facilities will be established in collaboration with Guinean partners in Conakry and Guéckédou, Guinea. High-resolution testing will be completed in the UK and Germany.
Image: Professor Miles Carroll arrives at an EVIDENT facility in Guinea with research equipment. (Credit: EVIDENT)
During this project, PHE, with University of Liverpool, will perform RNA sequencing analysis of up to 400 RNA samples from patients who became infected with EVD and survived or died during the 2014-2015 epidemic in West Africa.2 Deliverables include:
- Access to a cryopreserved biobank (under the ownership of the Guinean authorities) of up to 100 blood and plasma samples from volunteer Guinean Ebola survivors, from 1 month to 4 years after they have recovered from EVD. Up to four samples may be taken from each volunteer, at various time points.
- In-depth analysis of humoral and cellular response to naturally acquired immunity to EVD at various time periods including 1-14 months, and up to 2, 3 and 4 years post-infection.
- Reports comparing results from various tests on plasma from vaccinated volunteers and EVD survivors, to gauge differences in immunity between Ebola survivors and those who have received a vaccine.
Ultimately, this research will help identify a unique set of biomarkers of EVD, and expected disease outcomes. These tools will provide reference points for the development of new treatments and vaccines for Ebola, and help regulatory agencies evaluate the efficacy of urgently needed new medical products to treat and prevent EVD.
In March 2020, FDA modified this contract with PHE, including collaborators at the University of Liverpool (UoL) to apply technology used for the Ebola project to gather important information about COVID-19 infection. PHE and UoL are developing reagents and new methods to sequence the SARS-CoV-2 virus to create profiles of coronavirus for the rapid characterization of these viruses in humans and animal models. Ultimately, this study may support development and evaluation of medical countermeasures for COVID-19, including rapid diagnostics, therapeutics, and vaccines, and inform FDA evaluation of these products.
This project was funded through the MCMi Regulatory Science Extramural Research program
Carroll M, Matthews D, Hiscox J, et al. Temporal and spatial analysis of the 2014–2015 Ebola virus outbreak in West Africa. Nature. 2015 Aug 6;524:97-101. DOI: 10.1038/nature14594
Dowall S, Matthews D, Garcia-Dorival I, et al. Elucidating variations in the nucleotide sequence of Ebola virus associated with increasing pathogenicity. 2014 Nov 22;15(11):540. DOI: 10.1186/s13059-014-0540-x
2 Data will be compared to a control group of samples from United Kingdom residents with West African ancestry.
- Williamson, M., Hamilton, F., Hutchings, S. et al. Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual. medRxiv [preprint]; 2021 June 4. DOI: https://doi.org/10.1101/2021.05.31.21257591 - full text
- Angyal, Adrienn, Longet, Stephanie, et al. T-Cell and Antibody Responses to First BNT162b2 Vaccine Dose in Previously SARS-CoV-2-Infected and Infection-Naive UK Healthcare Workers: A Multicentre, Prospective, Observational Cohort Study. Lancet [Preprint] 2021 Mar 25. DOI: https://doi.org/10.2139/ssrn.3812375
- Daly, J. L., Simonetti, B., Klein, K. et al. Neuropilin-1 is a host factor for SARS-CoV-2 infection. Science; 2020 November 13. DOI: 10.1126/science.abd3072 – full text
- Almuqrin, A., Davidson, A. D., Williamson, M. K. et al. SARS-CoV-2 candidate vaccine ChAdOx1 nCoV-19 infection of human cell lines reveals a normal low range of viral backbone gene expression alongside very high levels of SARS-CoV-2 S glycoprotein expression. Research Square; 2020 October 20. DOI: 10.21203/rs.3.rs-94837/v1 – full text
- Moore, S. C., Penrice-Randal, R., Alruwaili, M. et al. Amplicon-Based Detection and Sequencing of SARS-CoV-2 in Nasopharyngeal Swabs from Patients With COVID-19 and Identification of Deletions in the Viral Genome That Encode Proteins Involved in Interferon Antagonism. Viruses; 2020 October 14. DOI: 10.3390/v12101164 – full text
- Nasir, J. A., Kozak, R. A., Aftanas, P. et al. A Comparison of Whole Genome Sequencing of SARS-CoV-2 Using Amplicon-Based Sequencing, Random Hexamers, and Bait Capture. Viruses; 2020 August 15. DOI: 10.3390/v12080895 – full text
- Tipton, T. R. W., Hall, Y., Bore, J. A. et al. Characterisation of the T-cell response to the ebolavirus glycoprotein amongst survivors of the 2013-16 West Africa epidemic. Nature Communications; 2021 February 19. https://www.nature.com/articles/s41467-021-21411-0 - full text
- Davis, C., Tipton, T., Sabir, S. et al. Post-exposure prophylaxis with rVSV-ZEBOV following exposure to a patient with Ebola virus disease relapse in the UK: an operational, safety and immunogenicity report. Clinical Infectious Diseases; 2020 December 01. https://doi.org/10.1093/cid/ciz1165 - full text
- Steeds, K., Hall, Y., Slack, G.S. et al. Pseudotyping of VSV with Ebola virus glycoprotein is superior to HIV-1 for the assessment of neutralising antibodies. Scientific Reports; 2020 August 31. https://www.nature.com/articles/s41598-020-71225-1 - full text
- Speranza, E., Ruibal, P., Port, J. R. et al. T-Cell Receptor Diversity and the Control of T-Cell Homeostasis Mark Ebola Virus Disease Survival in Humans. The Journal of Infectious Diseases; 2018 December 15. https://doi.org/10.1093/infdis/jiy352 - full text
- Carroll, M. W., Haldenby, S., Rickett, N. Y. et al. Deep Sequencing of RNA from Blood and Oral Swab Samples Reveals the Presence of Nucleic Acid from a Number of Pathogens in Patients with Acute Ebola Virus Disease and Is Consistent with Bacterial Translocation across the Gut. mSphere; 2017 Aug 23. DOI: 10.1128/mSphereDirect.00325-17 – full text
- Donal T. Skelly, Adam C. Harding, 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
- Bosworth, A., Rickett, N.Y., Dong, X. et al. Analysis of an Ebola virus disease survivor whose host and viral markers were predictive of death indicates the effectiveness of medical countermeasures and supportive care. Genome Med 13, 5 (2021). https://doi.org/10.1186/s13073-020-00811-9 - full text (open access)
- Dorward, D., Russell, C., Hwa Um, I. , et al. Tissue-specific Immunopathology in Fatal COVID-19. PubMed. [preprint] 2020 Nov 20 DOI: 10.1164/rccm.202008-3265OC – full text (open access)
- Clark, J., Penrice-Randal, R., Sharma, P., et al. 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. bioRxiv. [preprint] 2020 Oct 13 DOI: 10.1101/2020.10.13.334532 - full text (open access)
- Thom, R., Tipton, T., Strecker, T., et al. Longitudinal antibody and T cell responses in Ebola virus disease survivors and contacts: an observational cohort study. The Lancet Infectious Diseases. 2020 Oct 13. DOI: 10.1016/S1473-3099(20)30736-2 - full text (open access)
- Dong, X., Munoz-Basagoiti, J., Rickett, N., et al. Variation around the dominant viral genome sequence contributes to viral load and outcome in patients with Ebola virus disease. Genome Biol 21, 238 (2020). https://doi.org/10.1186/s13059-020-02148-3 - full text (open access)
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Also see related press release from the University of Liverpool
Shona C Moore, Rebekah Penrice-Randal, Muhannad Alruwaili, et al. Amplicon based MinION sequencing of SARS-CoV-2 and metagenomic characterisation of nasopharyngeal swabs from patients with COVID-19. MedRxiv; 2020 Mar 8. DOI: 10.1101/2020.03.05.20032011 - full text (open access)
Andrew D. Davidson, Maia Kavanagh Williamson, Sebastian Lewis, et al. Characterisation of the transcriptome and proteome of SARS-CoV-2 reveals a cell passage induced in-frame deletion of the furin-like cleavage site from the spike glycoprotein. Genome Med 12, 68 (2020). https://doi.org/10.1186/s13073-020-00763-0 - full text (open access)
- Ebola Preparedness and Response Updates from FDA
- Supporting Field Laboratory Testing of Ebola Antibodies in Sierra Leone
- Decoding Ebola: Next-Generation Sequencing of the Ebola Genome for the FDA ARGOS Database
- Survivor Studies: Better Understanding Ebola's After-Effects to Help Find New Treatments
- EVIDENT project (EU)
- Coronavirus Disease 2019 (COVID-19)