Researchers at the Ragon Institute of MGH, MIT and Harvard, and the University of Washington (UW) School of Medicine, have identified five immune response markers that, collectively, were able to distinguish between those COVID-19 patients who convalesced from the infection, and those who didn’t survive the disease. The researchers used a systems serology technique to generate a detailed profile of SARS-Co-2-specific humoral—antibody generating—responses in hospitalized patients, which they validated in a second patient cohort. The findings indicated that individuals who survived COVID-19 infection and those who died exhibited antibody responses that were primarily directed against different SARS-CoV-2 proteins.

“Any given feature tells only a small part of the story,” said co-lead scientist Galit Alter, PhD, group leader at the Ragon Institute and professor of medicine at Harvard Medical School. “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.”

The results could help in the development of COVID-19 vaccine candidates, suggested co-lead researcher Helen Chu, MD, associate professor of medicine, division of allergy and infectious diseases, and UW Medicine physician. “Finding these early antibody signatures 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.”

The investigators reported on their study in Immunity, in a paper titled, “Distinct early serological signatures track with SARS-CoV-2 survival.

It’s still not clear why some individuals infected with SARS-CoV-2 recover from infection and others die, the authors noted. “While the rapid spread of SARS-CoV-2, even during the asymptomatic phase of this infection, is alarming, more harrowing is our inability to predict disease trajectories among symptomatic individuals.” And without any therapeutics or vaccines as countermeasures, there is “an urgent need” to start mapping how immunity to the virus starts to develop. This knowledge will not only help to guide patient care, but could help to direct the development of future immune-based strategies against the disorder.

For their study, the researchers profiled how the immune responses of hospitalized SARS-CoV-2 infected patients evolved, to see if they could define antibody features that were predictive of disease outcome. A team headed by Chu collected samples from a cohort of 22 hospitalized SARS-CoV-2 patients, 12 of whom recovered, and 10 of whom died.

Alter’s team then applied her systems serology technique—which is an approach that relies on more than 60 assays to create a detailed profile of the immune response—to compare the immune responses of those individuals who had survived, with the responses of individuals who died from COVID-19.

SARS-CoV-2 has two main proteins that trigger humoral immune system responses. They are the spike (S) protein and the nucleocapsid (N) protein. The N protein is produced at significantly higher levels in the virus than the S protein is, but previous studies have shown that an immune response to the N protein does not provide protection against coronaviruses related to SARS-CoV-2.

Using her systems serology technique, which creates a detailed profile of the humoral immune response, Alter’s lab compared the immune responses from the recovered individuals to those of deceased patients. They found that those who had recovered exhibited a humoral immune response that responded mostly to S protein, while deceased individuals had a shift in immunodominance such 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. Using these five markers, researchers were able to build a model that could correctly classify clinical samples as belonging to deceased or convalesced individuals.

“Despite inter-individual heterogeneity, distinct antibody signatures resolved individuals with different outcomes,” the investigators wrote. “While no differences in SARS-CoV-2-specific IgG levels were observed, spike–specific humoral responses were enriched among convalescent individuals, whereas functional antibody responses to the nucleocapsid were elevated in deceased individuals. These data point to early diverging humoral immune responses that may mark more effective immunity and suggest that functional antibodies directed against S protein might be beneficial for SARS-CoV-2 disease trajectory.”

In order to verify this model, another 40 clinical COVID-19 samples—20 from convalesced individuals and 20 from deceased patients—from a different hospital were evaluated. The results showed the same S protein to N protein shift in immunodominance in samples from the deceased individuals, compared with those from convalesced patients.

Importantly, in the samples analyzed, this immunodominance shift was more predictive of recovery or death than were demographic factors, such as age or sex. “Thus, a minimal set of SARS-CoV-2 humoral profiles, rather than demographic information, appear to significantly resolve individuals who later went on to die from those who recover,” the team noted. “… these findings suggest that a consistent overall shift in S:N immunity early in SARS-CoV-2 infection may have a protective role and aid in recovery from severe disease.”

How these predictive immune markers may be influenced by risk factors of COVID-19, time course of infection, or severity of disease isn’t yet known. However, the study provides a potential approach to identifying at-risk patients, based on individual immune responses, and may help in the design and development of anti-COVID-19 vaccines, the scientists suggested. “Whereas this study only attempted to understand the humoral disparities between convalescent and deceased individuals in a cohort of severely infected individuals, further studies may attempt to define humoral profiles able to further classify individuals across the clinical trajectory spectrum ranging from asymptomatic to severe disease.”

And while the team noted several limitations to their studies, they concluded, “These results demonstrate that early antigen-specific and qualitative features of SARS-CoV-2-specific antibodies, point to differences in disease trajectory, highlighting the potential importance of functional antigen-specific humoral immunity to guide patient care and vaccine development.

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