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  1. MCM Regulatory Science

Cellular signaling and immune correlates for SARS-CoV-2 infection

Research to help inform the development and FDA review of COVID-19 medical countermeasures for all

Illustration of SARS-CoV-2, which causes COVID-19
Illustration of SARS-CoV-2, which causes Coronavirus Disease 2019 (COVID-19)

Background | Project description | Project outcomes | Additional reading | Publications

Performer: Stanford University School of Medicine
Project leader: Garry P. Nolan, PhD
Initial contract value: $1.55 million
Contract modification value: $500,000 (September 2021)
Contract Modification value: $700,000 (June 2023)
Project dates: October 2020 – September 2024


Following the Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) outbreaks in 2002 and 2012, respectively, the Coronavirus Disease 2019 (COVID-19) pandemic—caused by SARS-CoV-2—is the third deadly human outbreak in less than 20 years caused by a zoonotic coronavirus jumping the species barrier.

To help mitigate this public health emergency, the scientific community needs to better understand the pathogenesis of and immune response to SARS-CoV-2 and other coronaviruses. Generating knowledge databases to inform medical countermeasure (MCM) development against SARS-CoV-2 and other coronaviruses is critical to the COVID-19 response, and to preparedness for future outbreaks.

Project description

In this Medical Countermeasures Initiative (MCMi) regulatory science project, Stanford University School of Medicine will conduct research to help explain the host factors contributing to coronavirus immune responses, to further the ability to more rapidly predict patient outcomes, and to address unmet needs in patient care.

Researchers will use innovative analytical tools to perform an in-depth analysis of existing tissue samples from previously conducted clinical and nonclinical studies. They will profile circulating immune signatures of coronavirus infection and complete cutting-edge COVID-19 pathology tissue imaging, leveraging novel tools to define the characteristics of tissue viral reservoirs (cell types or areas of the body where the virus persists), and learning more about how SARS-CoV-2 affects different systems in the body.

The project will identify immune correlates of protection, which could potentially help identify and inform development of new coronavirus MCMs, such as drug and vaccine candidates. The project will also help enhance understanding and use of immune correlates for the regulatory review of MCMs.

SARS-CoV-2-infected lung tissue, imaged using viralMIBI. (Image: Stanford)
SARS-CoV-2-infected lung tissue, imaged using viralMIBI. Blue indicates cell nucleus, magenta and yellow indicate immune cell infiltration, dark orange indicates tissue structural protein, and green indicates SARS-CoV-2 viral RNA. (Image: Stanford)

Collaborators include:

  • UK Health Security Agency (formerly Public Health England)
  • Integrated Research Facility at the National Institutes of Health (NIH)
  • California National Primate Research Center at UC Davis
  • Erasmus University Medical Center
  • Wisconsin National Primate Research Center (WNPRC)
  • Harvard Medical School Center for Virology and Vaccine Research
  • University of Pittsburgh Graduate School of Public Health
  • University of Liverpool (UK)
  • University of California San Francisco
  • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán (INCMNSZ) (Mexico)
  • Inflammation in COVID-19 – Exploration of Critical Aspects of Pathogenesis (ICECAP) consortium
  • University Hospital Basel & Cantonal Hospital of Liestal, Switzerland
  • (Contract Option A Modification): FDA Office of Minority Health and Health Equity

Project outcomes

During this project, the Stanford University School of Medicine will perform tissue imaging and analysis of samples from existing clinical and nonclinical SARS-CoV-2 studies. The primary outcomes of this project are:

  1. To conduct multiplexed single-cell analysis of blood samples using CyTOF mass cytometry—a technology that combines flow cytometry and mass spectrometry to simultaneously measure dozens of features located on and in cells—to identify circulating immune cell responses related to stage of disease and severity of outcome following coronavirus infection. Parallel assessments of cases in humans and nonhuman primates (NHPs) will shed light on similarities and differences across species.
  2. To perform multiplexed antibody-based imaging of respiratory and immune tissues collected from COVID-19 patients or during NHP coronavirus challenge studies being conducted and funded outside of this project, using CO-Detection by indEXing (CODEX). The team will use computational tools to extract single-cell data from CODEX images to precisely identify cell types responding to coronavirus infection, and the spatial relationships of these cells contributing to effective or ineffective immune responses.
  3. To apply a new technique merging multiplexed antibody-based protein measurements with viral RNA detection to analyze coronavirus infection. This method, called viral Multiplexed Ion Beam Imaging (viralMIBI), will also be applied to tissues from previous clinical and nonclinical studies to gain a deeper understanding of the relationships between presence of viral RNA and viral and host proteins during coronavirus infections. 
  4. (September 2021 – Contract Option A) Identify biomarkers and immune correlates of protection in nonclinical and clinical studies, to elucidate the diversity of responses across clinical populations, including race, ethnicity, sex, and age to aid the development and evaluation of medical countermeasures for all.
  5. (June 2023 – Contract Option B) Complete sample analysis for identification of biomarkers and immune correlates of protection and initiate interim analysis of collected data from BASE/Option A studies.

This project was funded through the MCMi Regulatory Science Extramural Research program, in collaboration with FDA's Office of Minority Health and Health Equity

Additional reading

  • Angelo, M., Bendall, S. C., Finck, R., et al. (2014). Multiplexed ion beam imaging of human breast tumors. In Nature Medicine (Vol. 20, Issue 4, pp. 436–442). Springer Science and Business Media LLC. https://doi.org/10.1038/nm.3488
  • Goltsev, Y., Samusik, N., Kennedy-Darling, J., et al. (2018). Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging. In Cell (Vol. 174, Issue 4, pp. 968-981.e15). Elsevier BV. https://doi.org/10.1016/j.cell.2018.07.010 
  • Keren, L., Bosse, M., Thompson, S., et al. (2019). MIBI-TOF: A multiplexed imaging platform relates cellular phenotypes and tissue structure. In Science Advances (Vol. 5, Issue 10). American Association for the Advancement of Science (AAAS). https://doi.org/10.1126/sciadv.aax5851 
  • Schürch, C. M., Bhate, S. S., Barlow, G. L., et al. (2020). Coordinated Cellular Neighborhoods Orchestrate Antitumoral Immunity at the Colorectal Cancer Invasive Front. In Cell (Vol. 182, Issue 5, pp. 1341-1359.e19). Elsevier BV. https://doi.org/10.1016/j.cell.2020.07.005


  • 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 
  • 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 
  • Nakayama, T., Lee, I. T., Jiang, S., et al. (2021). Determinants of SARS-CoV-2 entry and replication in airway mucosal tissue and susceptibility in smokers. In Cell Reports Medicine (Vol. 2, Issue 10, p. 100421). Elsevier BV. https://doi.org/10.1016/j.xcrm.2021.100421 
  • 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
  • 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

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