Antibody profiles of internal viral proteins predict severe COVID-19 outcomes

Most research on SARS-CoV-2 virus immunity and COVID-19 vaccine development has focused on antibody responses to the spike protein and other viral surface proteins. But antibodies that recognize the virus’s internal proteins may also be important for immunity and disease outcomes, according to a new study led by University of Pittsburgh, Georgia Institute of Technology and Emory University researchers.

In the study, now online in Mobile Reports, the team conducted the most comprehensive analysis to date of COVID-19 antibodies in a small group of patients with severe disease. They found that antibody profiles of internal viral proteins, including those conserved across coronavirusespredicted which patients survived or died as well as corresponding surface protein profiles, suggesting that targeting other parts of the virus outside of the spike protein could be important for improving COVID-19 vaccines and therapies.

The novel aspect of this study is that we performed a very in-depth profiling of SARS-CoV-2 antibodies and looked at many different aspects of these antibodies. The whole world is focused on the spike protein and receptor binding domain, but this study is the first concrete evidence that specific antibodies against internal proteins are also positively associated with survival in severe COVID-19.”

Jishnu Das, Ph.D., co-senior author, assistant professor of immunology and computational and systems biology in Pitt’s School of Medicine

When the immune system encounters a virus, it produces antibodies that help neutralize and clear the infection. Each antibody specifically recognizes only one antigen, often a viral protein. Most research on immunity to COVID-19 has focused on the spike and other surface proteins, which make up the virus’s outer layer, but outside of these so-called ‘canonical’ antigensSARS-CoV-2 has about 25 other internal proteins.

To see whether immune responses to these non-canonical antigens can predict survival outcomes in patients with severe COVID-19, Das collaborated with co-senior authors Aniruddh Sarkar, Ph.D., assistant professor in the Wallace H. Coulter Department of Biomedical. Engineering at Georgia Tech and Emory University, and Harinder Singh, Ph.D., professor of immunology and director of the Center for Systems Immunology in Pitt.

The researchers analyzed blood samples taken from 21 patients hospitalized with severe COVID-19 in 2020 -; prior to vaccine approval. Seven of these patients died of the disease, and the other 14 survived. Using a microscale antibody profiling platform developed by Sarkar, the team extensively analyzed antibodies against three canonical and four non-canonical antigens.

According to Sarkar, the platform analyzes three key characteristics of antibodies. One is antigen specificity, or what the antibody binds to. The second is effector function, which relates to the role of the antibody in the immune response. The third feature is glycosylation, or the addition of carbohydrate molecules to the antibody, which dramatically affects antibody function.

“By profiling these three features simultaneously, we can gain a much deeper understanding of a given antibody than just looking at antibody titers,” explains Sarkar.

The researchers found that no antibody function could discriminate between patient survival outcomes. But when they analyzed common antibody profiles -; either canonical or non-canonical -; they noted clear differences between survivors and non-survivors.

“We were surprised to find such compelling evidence that antibodies directed against canonical and non-canonical antigens were equally predictive of survival outcomes,” Singh said. “Our findings suggest that non-canonical antibodies may play a role in recovery from serious disease, although more research is needed to prove causation and establish the mechanisms.”

Most COVID-19 vaccines and monoclonal antibodies -; Artificial antibodies used to treat COVID-19 have become less effective with the emergence of delta and omicron variants as peak mutations help the virus avoid detection. Far fewer mutations have accumulated in the virus’s internal proteins, Singh said, suggesting that expanding vaccines or therapies to target these non-canonical antigens could elicit stronger immunity against emerging variants of concern.

When the team limited their analysis to antibodies to non-canonical antigens conserved across coronaviruses -; including those that cause colds and other respiratory infections -; in COVID-19 patients, they were still able to distinguish survivors from non-survivors. These antibodies were also found in nine pre-pandemic healthy control subjects, suggesting that exposure to coronaviruses in addition to SARS-CoV-2 could induce antibody responses associated with favorable outcomes in severe COVID-19.

According to Das, these findings could contribute to the development of pan-coronavirus vaccines.

In ongoing work, the team is using their platform to look at antibodies in vaccinated people with breakthrough infections compared to unvaccinated individuals. They are also interested in understanding whether different antibodies play different roles in protecting against COVID-19 over time.

They also plan to expand the platform to understand antibodies in other contexts, including organ transplant rejection and other infectious diseases.


Reference magazine:

Pedireddy, SP, et al. (2022) Antibodies targeting conserved non-canonical antigens and endemic coronaviruses are associated with favorable outcomes in severe COVID-19. Mobile Reports

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