Understanding immune response and disease immunopathology can help refine development of treatments and vaccines for better disease management.
Fluidigm platforms for both microfluidics and CyTOF® technology, which powers mass cytometry and Imaging Mass Cytometry™, are enabling immune response studies in COVID-19 patients. These platforms are designed to identify prognostic and mechanistic biomarkers that can be used to guide the development of effective vaccines and direct treatment of COVID-19 disease.
Fluidigm technology is being used in three National Clinical Trial (NCT) COVID-19 studies:
- IMPACC Clinical Study
- COntAGIouS Trial
- Prospective Natural History Study of Smoking, Immune Cell Profiles, Epigenetics and COVID-19
- Mesenchymal Stem Cell for Acute Respiratory Distress Syndrome Due for COVID-19
- Systematic Assessment of SARS-CoV-2 Neurotropic Capacity in Modestly and Critically Ill Patients, and Patients Who Died From COVID-19
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID); 10 participating institutions in North America
“This surveillance study will collect detailed clinical, laboratory, and radiographic data in coordination with biologic sampling of blood and respiratory secretions and viral shedding in nasal secretions in order to identify immunophenotypic and genomic features of COVID-19-related susceptibility and/or progression. The aim: for the results obtained from this study to assist in generating hypotheses for effective host-directed therapeutic interventions, to help to prioritize proposals for such interventions, and/or optimize timing for administration of host-response directed therapeutics.”
Sponsor: Universitaire Ziekenhuizen Leuven
“The COntAGIouS trial (COvid-19 Advanced Genetic and Immunologic Sampling; an in-depth characterization of the dynamic host immune response to coronavirus SARS-CoV-2) proposes a transdisciplinary approach to identify host factors resulting in hyper-susceptibility to SARS-CoV-2 infection, which is urgently needed for directed medical interventions.”
“The overall aim of this prospective study is to provide an in-depth characterization of clinical and immunological features of patients hospitalized in UZ Leuven because of SARS-CoV-2 infection. Assessed characteristics will be compared between severe and non-severe COVID-19 patients, and between COVID-19 positive and negative (‘control’) patients.”
Sponsor: National Institute of Environmental Health Sciences (NIEHS)
“This study is a prospective, longitudinal, observational, single-center, exploratory study to collect samples and data that will enable explorations of the interaction between smoking, immune system characteristics and Coronavirus Disease 2019 (COVID-19). This study will collect baseline samples and data prior to COVID-19 infection required to explore these interactions prospectively. Early evidence in the COVID-19 pandemic suggests that smokers have higher risk for morbidity and mortality associated with COVID-19 infection. We have identified smoking-associated altered epigenetics, transcription and changes in immune cell profiles. We propose that the immune system senescence associated with prior smoking is a susceptibility factor in COVID-19 morbidity.”
Sponsor: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran
“Acute Respiratory Distress Syndrome (ARDS) is the main cause of death from COVID-19. One of the main mechanisms for ARDS is the violent storm of cytokines and chemokines, which cause uncontrolled fatal systemic inflammation by the immune system on the body, with additional multiple organ failure. ...
“The objective of this study is to describe the clinical changes secondary to IV administration of allogeneic MSC, in patients with bilateral COVID-19 pneumonia complicated by severe ARDS…”
Sponsor: University Hospital, Basel, Switzerland
“This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19 in pathogenesis and brain stem dysfunction in critically ill patients. … “Primary endpoints of this project are the multidimensional integration of the analysis from the procedures described above and assessment of the correlation between the gained clinical data (MRI, mental/neurological state), the body fluid proteomic and mass-cytometric analysis (CSF and Plasma proteomics, peripheral blood mass cytometry) and the CODEX analysis of defined brain regions on autopsy specimens.”
Therapeutic Interventions Webinar
Profiling of COVID-19 Patient Immune Responses
Ruth Montgomery, PhD
Professor of Internal Medicine
Director, Yale CyTOF Facility
Associate Dean for Scientific Affairs
“Single cell immune profiling of dengue virus patients reveals intact immune responses to Zika virus with enrichment of innate immune signatures.” Zhao, Y. et al. PLOS Neglected Tropical Diseases 14 (2020): e0008112.
Therapeutic Interventions Publications
- “Emergence of low-density inflammatory neutrophils correlates with hypercoagulable state and disease severity in COVID-19 patients.” | Morrissey, S. et al. medRxiv (2020): doi.org/10.1101/2020.05.22.20106724v1.
- “Transplantation of ACE2– mesenchymal stem cells improves the outcome of patients with COVID-19 pneumonia.” Leng, Z. et al. Aging and Disease 11 (2020): 216–228.
- “Down-regulated gene expression spectrum and immune responses changed during the disease progression in COVID-19 patients.” Ouyang, Y. et al. Clinical Infectious Diseases (2020): ciaa462.
- “Impaired type I interferon activity and exacerbated inflammatory responses in severe COVID-19 patients.” Hadjadj, J. et al. medRxiv (2020): doi.org/10.1101/2020.04.19.20068015.
- “High-dimensional immune profiling by mass cytometry revealed immunosuppression and dysfunction of immunity in COVID-19 patients.” Wang, W. et al. Cellular & Molecular Immunology (2020): doi.org/10.1038/s41423-020-0447-2.
- “Identification of human immune cell subtypes most vulnerable to IL-1b-induced inflammatory signaling using mass cytometry.” Kothari, H. et al. bioRxiv (2020): doi.org/10.1101/2020.04.19.047274
Mass cytometry has been used to monitor immune responses during vaccine development and testing for years, and it will be useful in SARS-CoV-2 vaccine development as well. Here we spotlight reference materials that outline the current use of CyTOF technology in this area.
Multiple research groups around the world employ mass cytometry to investigate many aspects of vaccine development and efficacy. Two reviews1,2 provide excellent background on this topic. The Brodin1 article emphasizes the importance of a systems immunology approach to monitoring vaccine responses, especially when sample volume is limited, as in pediatric samples. In Reeves et al.2, the potential of mass cytometry to capture the complex and often unanticipated immune cell interactions and responses to candidate vaccines is highlighted by review of multiple publications and comparison to other technologies.
Other publications show how mass cytometry has helped researchers investigate the impact of vaccine schedule on immune response3,4, including deep profiling of specific immune cell populations5,6, use of immune profiles to predict vaccine response7 and identification and deep profiling of antigen-specific T cells using metal-labeled HLA tetramers8,9. Of key importance in vaccine research are papers on high-dimensional data analytic approaches10–12 (read the article).
In addition, mass cytometry is being used as a readout in five ongoing clinical trials of vaccine response as well as in one additional completed trial (Table 1).
Machine learning and infectious disease: how we can better understand vaccine efficacy at the patient level
Adriana Tomic, PhD,
University of Oxford
|Clinical Trial Name||Sponsor/ Collaborator||Start Date||Phase||NCT Number|
|CVD 38000: Study of Responses to Vaccination with Typhoid and/or Cholera||University of Maryland||2018||4||03705585|
|Blood Donor CVD 5000||University of Maryland||2004||4||03971669|
|CVD 37000: Immunity and Microbiome Studies at Intestinal and Systemic Sites in Ty21a Vaccinated Adults||University of Maryland||2013||4||03970304|
|Study of a New MVA Vaccine for Hepatitis C Virus||ReiThera Srl/ University of Oxford, Oxford University Hospitals, University Hospital Birmingham||2010||1||01296451|
|High Dose Flu Vaccine in Treating Children Who Have Undergone Donor Stem Cell Transplant||Vanderbilt-Ingram Cancer Center/ National Cancer Institute||2016||2||02860039|