Study expands to include investigation of Zika virus disease, incorporate new technologies
Background | Ebola Project Description | Zika Project Description | New Technologies Including Quantum Barcoding | Update – March 2020 (COVID-19) | Collaborations | Project Outcomes | Additional Reading
Performer: Stanford University School of Medicine
Project leader: Dr. Garry P. Nolan
Initial contract value: $3,661,908
Contract option exercise: $1,086,000 (August 2017)
Contract modification 1 value: $459,131 (September 2017)
Contract modification 2 value: $989,200 (September 2019)
Contract modification 3 value: $250,000 (March 2020)
Project dates: May 2016 - December 2021
The West African Ebola epidemic of 2014-2015 was the largest-ever Ebola outbreak, claiming more than 11,000 human lives, and forever altering many thousands more. Unlike previous Ebola outbreaks, however, a large number of Ebola patients survived this epidemic.1
For some, surviving wasn’t the end of their challenges. Many of the recent epidemic’s 16,000+ Ebola survivors suffer from chronic, long-term health problems including headaches, joint pain, and eye problems caused by Ebola.2 Scientists do not yet fully understand what causes these after-effects.
In addition to supporting ongoing response to Ebola outbreaks in the Democratic Republic of the Congo (DRC), FDA and government partners are conducting studies in West Africa to better understand how Ebola affects patients who have survived, and to learn how to more effectively treat these patients’ chronic health problems.
In this Medical Countermeasures Initiative (MCMi) regulatory science project, Stanford University will analyze Ebola survivors with and without chronic health problems in an effort to identify factors responsible for driving prolonged disease well after the initial, acute infection.
This project will also explore immunopathology—how the immune system responds to diseases—and how it differs for various chronic post-Ebola signs and symptoms. This new data will provide valuable information to better understand the natural course of Ebola virus disease, and identify possible causes of chronic health problems in survivors.
The team will use a variety of approaches to analyze laboratory specimens, including CyTOF mass cytometry, and will make analysis readily interpretable by researchers around the world.
Other analysis will include conducting Luminex cytokine and metabolomic assays (tests), evaluating clinical metrics, and creating multiplexed ion beam imaging (MIBI) 3D models of solid tissues, to better understand the relationships between tissue cells, immune cells and viral molecules.
In September 2017, FDA modified this contract with Stanford University to apply the technology used for the Ebola project to gather critical information about the nature of Zika virus infection. The potential benefits of this additional study include improved understanding of congenital defects associated with maternal Zika virus infection and animal models of Zika virus infection.
Ultimately, this study may help identify candidate vaccines and treatments, and inform FDA’s evaluation of such products.
In September 2019, FDA partnered with the National Institute of Allergy and Infectious Disease (NIAID), National Institutes of Health (NIH), to expand this project to apply a new method to the study of Ebola and Zika tissue samples. Under this project expansion, the Stanford laboratory will use multiplexed ion beam imaging (MIBI) to identify viral reservoirs—cells or anatomical sites where viruses accumulate and persist—for both Ebola and Zika infection.
In addition, the Stanford laboratory will explore the use of Quantum Barcoding (QBC)—an experimental diagnostic single-cell technology that can rapidly measure multiple targets including RNA, DNA, and proteins—to augment both mass cytometry and water-in-droplet based techniques as the primary means to analyze single cells in laboratory and field stations. At the end of this collaboration, Stanford will deploy QBC to a designated laboratory for onsite testing.
In March 2020, FDA modified this contract with Stanford University to apply the same innovative approaches (including CyTOF mass cytometry, and viralMIBI) used to study Ebola and Zika to better understand viral infection and immune responses to SARS-CoV-2 in non-clinical and clinical studies. Ultimately, this study may aid development and evaluation of medical countermeasures for COVID-19, including rapid diagnostics, therapeutics, and vaccines, and inform FDA evaluation of these products.
This three-year project builds on previous immune system mass cytometry reference work supported by FDA. Collaborators include:
- UCLA Fielding School of Public Health
- European Mobile Laboratory (EMLab)/Public Health England (PHE)
- Centre National de Formation et de Recherche en Santé Rurale de Mafèrinyah (CNFRSR) (National Center for Education and Research in Rural Health, Mafèrinyah, Guinea)
- The Liberian Institute for Biomedical Research (LIBR)
- National Institutes of Health, Integrated Research Facility (IRF)
- U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID), using Zika samples from a collaboration with George Washington University (GWU)
- School of Veterinary Medicine, University of California, Davis
- California National Primate Research Center, University of California, Davis
- National Institute of Allergy and Infectious Diseases (NIAID), NIH
In collaboration with these partners, samples will be collected in Guinea and the Democratic Republic of the Congo, and in Liberia as part of the Partnership for Research on Ebola Vaccines in Liberia (PREVAIL III). Stanford will combine results from tests performed on these samples with data collected at the field research sites to model and find potential causes of chronic after-effects.
For the Zika research, Stanford will work with the University of California, Davis and USAMRIID to analyze existing tissue samples these partners have collected during previous and ongoing studies, including an FDA-funded project.
Ultimately, this research will help the global scientific community better understand the course of Ebola and Zika virus infections—an important factor in finding new treatments—and facilitate the deployment of novel, effective analytical technologies into federal laboratory space. In addition, it will help identify ways we can improve the lives of the thousands of Ebola survivors stricken by chronic Ebola-related health problems, and further progress toward countermeasures to treat and prevent Zika virus disease.
This project was funded through the MCMi Regulatory Science Extramural Research program.
Clark DV, Kibuuka H, Millard M, et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect Dis. 2015 Aug;15(8):905-12. DOI
Nanyonga M, Saidu J, Ramsay A, et al. Sequelae of Ebola Virus Disease, Kenema District, Sierra Leone. Clin Infect Dis. 2016 Jan 1;62(1):125-6. DOI
Qureshi, AI, Chughtai, M, Loua, TO, et al. Study of Ebola Virus Disease Survivors in Guinea. Clin Infect Dis. 2015;61(7), 1035–42. DOI
- Jiang, S., Chan, C., Rovira-Clave, X. et al. Virus-Dependent Immune Conditioning of Tissue Microenvironments. bioRxiv [preprint]; 2021 May 23. DOI: https://doi.org/10.1101/2021.05.21.444548 - full text
- Dorien Feyaerts, Julien Hédou, et al. Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19. BioRxiv [preprint]. 2021 Feb 12. doi: https://doi.org/10.1101/2021.02.09.430269 - full text (open access)
- Ivan T Lee, Tsuguhisa Nakayama, Chien-Ting Wu, Yury Goltsev, Sizun Jiang, Phillip A Gall, Chun-Kang Liao, Liang-Chun Shih, Christian M Schurch, David R McIlwain, Pauline Chu, Nicole A Borchard, David Zarabanda, Sachi S Dholakia, Angela Yang, Dayoung Kim, Tomoharu Kanie, Chia-Der Lin, Ming-Hsui Tsai, Katie M Phillips, Raymond Kim, Jonathan B Overdevest, Matthew A Tyler, Carol H Yan, Chih-Feng Lin, Yi-Tsen Lin, Da-Tian Bau, Gregory J Tsay, Zara M Patel, Yung-An Tsou, Chih-Jaan Tai, Te-Huei Yeh, Peter H Hwang, Garry P Nolan, Jayakar V Nayak, Peter K Jackson. Robust ACE2 protein expression localizes to the motile cilia of the respiratory tract epithelia and is not increased by ACE inhibitors or angiotensin receptor blockers. MedRxiv [preprint]; 2020 May 8. DOI: https://doi.org/10.1101/2020.05.08.20092866 - full text (open access)
- Anita K. McElroy, Rama S. Akondy, David R. Mcllwain, Han Chen, Zach Bjornson-Hooper, Nilanjan Mukherjee, Aneesh K. Mehta, Garry Nolan, Stuart T. Nichol, and Christina F. Spiropoulou. Immunologic timeline of Ebola virus disease and recovery in humans. JCI Insight; 2020 May 21. DOI: https://doi.org/10.1172/jci.insight.137260 - full text (open access)
- Ebola Preparedness and Response Updates from FDA
- Decoding Ebola: Next-Generation Sequencing of the Ebola Genome for the FDA ARGOS Database
- Developing a Toolkit to Assess Efficacy of Ebola Vaccines and Therapeutics
- Supporting Field Laboratory Testing of Ebola Antibodies in Sierra Leone
- Zika Virus Response Updates from FDA
- Companion Studies to Define the Distribution and Duration of Zika Virus in Non-Human Primates
- Turning the Tide on Ebola (FDA Voice blog, March 19, 2015 - ARCHIVED)