Immune response markers might predict COVID-19 outcomes

COVID-19 unit at a UW Medicine hospital
Randy Carnell
A nurse cares for a patient in a COVID-19 unit at a UW Medicine hospital.

Researchers have identified five immune response markers which, collectively created “antibody signatures” that could correctly classify both COVID-19 patients who recovered and those who did not survive the disease.

Their study is published in the Cell Press journal, Immunity. The senior authors are Galit Alter, group leaded at the Ragon Institute of Massachusetts General Hospital, MIT and Harvard, and professor of medicine at Harvard Medical School, and Helen Chu, associate professor of medicine, Division of Allergy and Infectious Diseases. She is also a physician at UW Medicine.

Chu’s team was responsible for the enrollment, specimen collection, and management of the clinical work in this study. They collected samples from hospitalized COVID-19 patients in the earlier months of the coronavirus pandemic in the Seattle area. The study used samples from 22 individuals, 12 of whom recovered, and 10 of whom died.

Alter’s team in the greater Boston area used her systems serology technique, an approach that relies on 60-plus assays to create a detailed profile of the immune response, to compare the immune responses of those who had survived to those who had not.

“Any given feature tells only a small part of the story. By looking at the overall profile of the immune response, we can begin to truly understand how the immune system responds to COVID-19 and then use that knowledge to prevent the worst outcomes of this disease,” said Alter.

The virus that causes COVID-19, SARS-CoV-2, has two main proteins that provoke a response from the humoral immune system, which is responsible for antibody production. They are the spike (S) protein and the nucleocapsid (N) protein.

“Most vaccine candidates in development are designed to elicit antibodies against spike antigen, which is the response we observed with individuals who survived natural infection,” Chu said. The N protein is produced at significantly higher levels in the virus than the S protein, but previous studies have shown that an immune response to the N protein does not provide protection against the pandemic coronavirus, SARS-CoV-2.

Alter’s lab compared the immune responses from the recovered individuals to the deceased. Her lab found that patients who had recovered had a humoral immune response that responded mostly to S protein, while patients who died had a shift in immunodominance such that that they had a stronger immune response to the N protein.

“The shift in immunodominance was only apparent after comparing robust, detailed profiles of the immune response from different groups of patients,” Alter said.

This immunodominance shift could be detected by measuring five immune response markers: IgM and IgA1 responses to S protein and antibody-dependent complement deposit, IgM, and IgA2 response to N protein.

With these five markers, researchers built a model that could correctly classify clinical samples as belonging to deceased or convalesced individuals. To verify this model, 40 clinical COVID-19 samples from Boston, 20 from convalesced individuals and 20 from deceased patients, were assayed.

The results showed the same S protein to N protein shift in immunodominance in deceased individuals compared to convalesced ones. Furthermore, in the samples analyzed, this immunodominance shift was more predictive of recovery or death than demographic factors such as age or sex.

“Finding these early antibody signatures also may have implications for assessing COVID-19 vaccine candidates to ensure they produce an immune response similar to that of individuals who survive natural infection,” Chu said.

How these predictive immune markers may be influenced by risk factors of COVID-19, time course of infection, or severity of disease is yet to be determined. Nonetheless, this study provides a potential way to identify patients at high risk for mortality based on individual immune responses and may drive help rational vaccine design.

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