Scientists at Yale School of Medicine are participating in an unprecedented and comprehensive study of the effects of COVID-19 on patients. The study, “IMmunoPhenotyping Assessment in a COVID-19 Cohort” (IMPACC), is a collaboration among the National Institute of Allergy and Infectious Disease (NIAID) and 15 biomedical research centers across the country. Its goal is to evaluate why the SARS-CoV-2 virus has made some people sicker than others, what influences the length of illness, and other factors important to understanding the ongoing pandemic and preparing for possible future pandemics. Researchers have recruited more than 1,000 volunteer patients who have been hospitalized with COVID-related illness. The patients are donating blood and tissue samples that will be rigorously analyzed to establish patterns that can explain both similarities and differences among those who contract the virus. Those patients are also being followed for up to a year after hospital discharge, to capture any longer-term impacts of the viral infection.
While other, smaller studies have uncovered invaluable data about important aspects of the virus and the pandemic, this research and the resources that have gone into it promise to produce the most enlightening insights yet, according to Ruth R. Montgomery, PhD, professor of medicine and of epidemiology (microbial diseases) and associate dean for scientific affairs. “It is a tour de force of organization to have created this research consortium so rapidly during an ongoing pandemic,” Montgomery says. “It reflects significant advances in combining the newest analytic tools in ways that allow a large consortium of scientists to generate and analyze data both efficiently and with high accuracy.”
A key to producing meaningful and accurate results has been to standardize sample-collection methods among the various institutions, and then transport the collected samples to central “core” laboratories, to avoid variations that can occur when multiple labs do their own analyses. Two such cores are based at Yale, including whole exome sequencing and SNP (single nucleotide polymorphism) genotyping at the Yale Center for Genome Analysis (YCGA) to uncover genetic variants that may contribute to severe COVID-19 disease. Another is the Cytometry by Time of Flight (CyTOF) facility at Yale, which Montgomery leads. That core is analyzing as many as 50 parameters in airway cells from patients to define how the disease affects individual cells in the lung.
Another effort by the IMPACC group will examine T cell immune responses to the SARS-CoV-2 virus in the patient volunteers. A substudy at Yale will be the investigation of immunosuppressed patients with autoimmune diseases to determine whether their B cell responses are compromised. “We know that in our Interventional Immunology Clinic at Yale, only 22% of patients receiving B cell depletion therapy generate antibodies against the SARS-CoV-2 virus after vaccination,” says David A. Hafler, MD, chair and William S. and Lois Stiles Edgerly Professor of Neurology and professor of immunobiology. “Determining whether they are mounting an adequate T cell response will be critical in deciding whether a third booster may be required.”
Work at cores located at other institutions includes genetic sequencing of immune cells, and of SARS-CoV-2 virus samples taken from various patients, to see whether certain samples differ genetically from others in ways that include the virus’s ability to infect patients’ cells or evade attack by antibodies. Cores are also analyzing patient serum, for clues to how different patients’ immune systems might produce inflammation as well as other unique reactions to the virus. Examination of antibody samples in these cores may also define how well a patient can clear the virus and be protected against reinfection. Additional cores are generating proteomic and metabolomic data. Proteomics measures the totality of proteins in a cell, tissue, or organism, and metabolomics assesses substances created through the body’s metabolic processes. “Omics” are types of experiments that make comprehensive measurements for specific types of molecules.
It is an enormous amount of data, and a major part of the project will be to correlate the sets of medical, biological, and genetic data with each other, and with variables that include sex, length and severity of illness, and other aspects of the volunteers’ medical histories. The analysis of IMPACC data sets is being coordinated by a data analysis working group, which is co-led by computational immunologist Steven H. Kleinstein, PhD, professor of pathology and of immunobiology. According to Kleinstein, “Each assay will first be analyzed on its own to identify correlates of COVID-19 disease severity and progression, but a unique strength of this study is the ability to then integrate data gathered over an extended time from multiple systems-level immune profiling assays, to get a more complete picture of the dynamic interaction of the virus and immune response.”
Leying Guan, PhD, assistant professor of biostatistics, is carrying out multi-omic modeling that combines data from all of the assays to map functional subtypes of human immune responses to clinical trajectories. All of these analyses will take advantage of a centralized computing infrastructure with massive cloud computing resources. The researchers hope this data analysis will create even greater truths than are known already about how the virus behaves and how it can be stopped.
Recruitment for IMPACC began at Yale in May 2020, during the first wave of COVID-19 in Connecticut; inpatient recruitment concluded in March 2021 during the second wave. The Yale IMPACC center, the Yale COVID-19 Biorepository, and many others stepped in during the most uncertain days of the pandemic to screen and recruit patients and to process samples from participants with COVID-19 at Yale New Haven Hospital. “The success of IMPACC at Yale is a tribute to the dedication and courage of this remarkable team of laboratory and clinical researchers,” says Albert Shaw, MD, PhD, professor of medicine (infectious diseases).
“We have learned a lot about this terrible virus in less than two years since it was first identified, including what was needed to develop effective vaccines in an extraordinarily short time,” Montgomery says. “But to truly subdue COVID-19, and guard against any other pandemic that may come next, comprehensive knowledge about SARS-CoV-2 will be essential. I am confident this study will educate us all.”
In addition to Montgomery, Hafler, Kleinstein, Guan, and Shaw, Yale scientists participating in the IMPACC project include Chris Cotsapas, PhD, professor of neurology and of genetics, laboratory investigators Subhasis Mohanty, PhD, Haowei Wang, PhD, Khadir Raddassi, PhD, William Ruff, PhD, Xiaomei Wang, MD, and Yujiao Zhao, PhD; and clinical coordinator Allison Nelson, RN, and nurse researchers Dimitri Duvilaire, RN, Maxine Kuang, RN, and Denise Shepherd, RN.
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