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Survivor Studies: Better Understanding Ebola's After-Effects to Help Find New Treatments

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U.S. Public Health Service officers celebrate as a Liberian man adds his handprint to a “survivors’ wall.” Each patient who overcame Ebola after treatment at the USPHS mobile hospital outside Monrovia was given a set of clothes and essentials and invited to mark their recovery with a handprint. (Photo: FDA)
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U.S. Public Health Service officers celebrate as a Liberian man adds his handprint to a “survivors’ wall.” Each patient who overcame Ebola was invited to mark their recovery with a handprint.

This project has been completed, and this page is no longer being updated. For new project updates, visit MCM Regulatory Science.

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 | Publications

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 - June 2022

Background

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.

Ebola Project Description

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.

Zika Project Description

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. 

New Technologies Including Quantum Barcoding

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. 

Update – March 2020 (COVID-19)

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.

Collaborations

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.

Project Outcomes

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.

1 http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/case-counts.html  

2 http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/survivors.html

Additional Reading

  • Clark, D. V., Kibuuka, H., Millard, M., et al. (2015). Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. In The Lancet Infectious Diseases (Vol. 15, Issue 8, pp. 905–912). Elsevier BV. https://doi.org/10.1016/s1473-3099(15)70152-0
  • Nanyonga, M., Saidu, J., Ramsay, A., et al. (2015). Sequelae of Ebola Virus Disease, Kenema District, Sierra Leone. In Clinical Infectious Diseases (Vol. 62, Issue 1, pp. 125–126). Oxford University Press (OUP). https://doi.org/10.1093/cid/civ795.
  • Qureshi, A. I., Chughtai, M., Loua, T. O., et al. (2015). Study of Ebola Virus Disease Survivors in Guinea: Table 1. In Clinical Infectious Diseases (Vol. 61, Issue 7, pp. 1035–1042). Oxford University Press (OUP). https://doi.org/10.1093/cid/civ453

 

Publications

  • Jiang, S., Mukherjee, N., Bennett, R. S., et al. (2021). Rhesus Macaque CODEX Multiplexed Immunohistochemistry Panel for Studying Immune Responses During Ebola Infection. In Frontiers in Immunology (Vol. 12). Frontiers Media SA. https://doi.org/10.3389/fimmu.2021.729845 
  • Jiang, S., Chan, C. N., Rovira-Clavé, X., et al. (2022). Combined protein and nucleic acid imaging reveals virus-dependent B cell and macrophage immunosuppression of tissue microenvironments. In Immunity (Vol. 55, Issue 6, pp. 1118-1134.e8). Elsevier BV. https://doi.org/10.1016/j.immuni.2022.03.020
  • Kelly, J. D., Hoff, N. A., Spencer, D., et al. (2018). Neurological, Cognitive, and Psychological Findings Among Survivors of Ebola Virus Disease From the 1995 Ebola Outbreak in Kikwit, Democratic Republic of Congo: A Cross-sectional Study. In Clinical Infectious Diseases (Vol. 68, Issue 8, pp. 1388–1393). Oxford University Press (OUP). https://doi.org/10.1093/cid/ciy677
  • Kotliar, D., Lin, A. E., Logue, J., et al. (2020). Single-Cell Profiling of Ebola Virus Disease In Vivo Reveals Viral and Host Dynamics. In Cell (Vol. 183, Issue 5, pp. 1383-1401.e19). Elsevier BV. https://doi.org/10.1016/j.cell.2020.10.002
  • Lee, I. T., Nakayama, T., Wu, C.-T., et al. (2020). ACE2 localizes to the respiratory cilia and is not increased by ACE inhibitors or ARBs. In Nature Communications (Vol. 11, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s41467-020-19145-6
  • Modak, S., Sehgal, D., & Valadi, J. (2019). Applications of Artificial Intelligence and Machine Learning in Viral Biology. In Global Virology III: Virology in the 21st Century (pp. 1–39). Springer International Publishing. https://doi.org/10.1007/978-3-030-29022-1_1
  • McElroy, A. K., Akondy, R. S., Mcllwain, D. R., et al. (2020). Immunologic timeline of Ebola virus disease and recovery in humans. In JCI Insight (Vol. 5, Issue 10). American Society for Clinical Investigation. https://doi.org/10.1172/jci.insight.137260
  • O’Huallachain, M., Bava, F.-A., Shen, M., et al. (2020). Ultra-high throughput single-cell analysis of proteins and RNAs by split-pool synthesis. In Communications Biology (Vol. 3, Issue 1). Springer Science and Business Media LLC. https://doi.org/10.1038/s42003-020-0896-2
  • Bjornson-Hooper, Z. B., Fragiadakis, G. K., Spitzer, M. H., et al. (2022). A Comprehensive Atlas of Immunological Differences Between Humans, Mice, and Non-Human Primates. In Frontiers in Immunology (Vol. 13). Frontiers Media SA. https://doi.org/10.3389/fimmu.2022.867015
  • Fragiadakis, G. K., Bjornson-Hooper, Z. B., Madhireddy, D., et al. (2022). Variation of Immune Cell Responses in Humans Reveals Sex-Specific Coordinated Signaling Across Cell Types. In Frontiers in Immunology (Vol. 13). Frontiers Media SA. https://doi.org/10.3389/fimmu.2022.867016
  • Feyaerts, D., Hédou, J., Gillard, J., et al. (2022). Integrated plasma proteomic and single-cell immune signaling network signatures demarcate mild, moderate, and severe COVID-19. In Cell Reports Medicine (Vol. 3, Issue 7, p. 100680). Elsevier BV. https://doi.org/10.1016/j.xcrm.2022.100680

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