By Rachel Tompa, Ph.D. / Allen Institute

Nearly eight months into the worst public health crisis of our lifetimes, and scientists are still grappling with one of the most basic questions about COVID-19: Why do some people infected with the novel coronavirus die, while others recover with few symptoms — or even no symptoms at all?

A new study underway in Seattle aims to answer that — and related questions — by tracking the details of individuals’ immune responses as they are infected with, and recover from, SARS-CoV-2. Headquartered at Fred Hutchinson Cancer Research Center, the study is enrolling Seattle-area adults newly infected with the novel coronavirus. Research teams at Fred Hutch and the Allen Institute for Immunology, a division of the Allen Institute, are delving into the molecular and cellular details of how these patients’ immune systems are responding to the virus, both shortly after infection and in the weeks and months following.

A deep dive into COVID-19 immunology

Researchers around the world have pivoted to study the novel coronavirus, but most scientific studies to date have focused on severely ill patients. The new Seattle study will instead focus on people with mild-to-moderate symptoms.

“Data have shown that the virus is far more widespread in the population than we initially thought,” said Tom Bumol, Ph.D., Executive Vice President and Director of the Allen Institute for Immunology. “To capture the complete scientific story of this pandemic, we need to study the biology of all infections, not just the most severe.”

That complete picture could ultimately help shape communities’ response to COVID-19. If scientists can understand the “successful” immune responses that accompany a mild or moderate case of the virus, and which aspects of those responses fail in severe illness, they might be able to better treat or prevent the more serious and deadly cases.

“We don’t yet know what a normal, healthy, effective response to this coronavirus looks like,” said Troy Torgerson, M.D., Ph.D., Director of Experimental Immunology at the Allen Institute for Immunology. “If we can understand all of the moving parts that constitute a healthy immune response, that will be very informative for vaccine developers and researchers who are trying to develop better therapies — especially in cases where the immune response itself contributes to COVID19 illness.”

The research team will use the newly established deep immune system profiling pipeline at the Allen Institute for Immunology, in collaboration with viral immunology experts at the Fred Hutch, to capture a detailed survey of patients’ immune systems as close to infection as possible. The researchers will then follow the same patients, studying samples taken in the weeks and months after infection. Following the same patient over time will help the researchers zero in on the aspects of the immune response specific to the novel virus and that volunteer’s unique outcome.

Samples studied through the Allen Institute for Immunology’s adaptive pipeline, which is now being used to interrogate COVID-19.

They’ll compare the data from patients with mild or moderate infections to samples from uninfected people and those with more severe infections, to understand which immune changes in people with mild infections could be considered successful, or beneficial, responses. They’re planning to do these deep dives for about 50 patients with mild or moderate infections and are also hoping to follow the immune responses in some of those patients over the next few years, to better understand the long-term immune reactions to the virus — including understanding how long natural immunity lasts. Understanding whether immunity to the virus wanes or is durable is an important unknown to address to help guide vaccine development — more than 100 vaccine initiatives are currently underway around the world.

The Institute’s immune-profiling pipeline was built to study any immune-related disease or condition, assessing and integrating several different types of scientific data gleaned from a single blood or tissue sample and comparing samples from the same person over weeks or months as their disease progresses, stabilizes or resolves. Along with medical data from the patients, the researchers also use emerging single-cell technologies that allow them to view the immune system through several lenses, capturing information about the types of immune cells present, their genetic and environmental states, and a corresponding set of immune proteins and other molecules present in the blood. The researchers will integrate these experimental data with medical data gathered from the patients to get a more complete picture of the biology of COVID-19.

Since the Allen Institute for Immunology’s launch in December 2018, the researchers have been working to establish the pipeline and begin studies of the healthy human immune system as well as certain autoimmune diseases and cancers. It was an existing collaboration with Fred Hutch to study the blood cancer multiple myeloma that led to the COVID-19 collaboration. The SARS-CoV-2 study is led by Julie McElrath, M.D., Ph.D., Senior Vice President and Director of Fred Hutch’s Vaccine and Infectious Disease Division. Other research teams at the Hutch are using the same patient samples to study particular cells or molecules known to be specifically induced by SARS-CoV-2 itself.

“Fred Hutch has a long history of collaborating with other like-minded organizations to develop cures and therapies for both cancer and infectious diseases,” said McElrath, who also holds the Joel D. Meyers Endowed Chair at the Hutch. “We’re optimistic that the collective immune profiling expertise between Fred Hutch and the Allen Institute will lead to new discoveries and insights into the prevention and control of COVID-19.”