Most research on immunity to the SARS-CoV-2 virus and the development of the COVID-19 vaccine has focused on antibody responses to ear protein and other viral surface proteins. But antibodies that recognize the virus’s internal proteins could also be important for immunity and disease outcomes, according to a new study led by researchers at the University of Pittsburgh, the Georgia Institute of Technology and Emory University.
In the study, now online at Cell Reports, the team performed the most comprehensive analysis to date of COVID-19 antibodies in a small set of patients with severe disease. They found that antibody profiles of internal viral proteins, including those preserved through coronaviruses, predicted which patients survived or died as well as the corresponding profiles for surface proteins, suggesting that they target others. Parts of the virus beyond the spike protein could be important in improving COVID. -19 vaccines and therapies.
The new aspect of this study is that we performed a very deep profile of SARS-CoV-2 antibodies and analyzed many different aspects of these antibodies. Everyone has focused on peak 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-author, assistant professor of immunology and computational and systems biology at Pitt School of Medicine
When the immune system finds a virus, it produces antibodies that help neutralize and eliminate the infection. Each antibody specifically recognizes only one antigen, often a viral protein. Most research on COVID-19 immunity has focused on the ear and other surface proteins, which form the outer layer of the virus, but beyond these so-called “canonical antigens,” SARS-CoV- 2 has about 25 more internal proteins.
To see if immune responses to these non-canonical antigens could predict survival outcomes in patients with severe COVID-19, Das partnered with lead authors Aniruddh Sarkar, Ph.D., assistant professor in the Department of Biomedicine at Wallace H. Coulter. Engineering at Georgia Tech and Emory University, and Harinder Singh, Ph.D., professor of immunology and director of the Pitt Systems Immunology Center.
The researchers analyzed blood samples that had been collected from 21 patients who were hospitalized with severe COVID-19 in 2020 -; before vaccination is approved. Seven of these patients died from the disease and the other 14 survived. Using a microscale antibody profile platform developed by Sarkar, the team thoroughly analyzed the antibodies of three canonical and four non-canonical antigens.
According to Sarkar, the platform analyzes three key characteristics of antibodies. One is the specificity of the antigen, or what the antibody binds to. The second is effector function, which is related to the role of antibodies in the immune response. The third characteristic is glycosylation, or the addition of carbohydrate molecules to the antibody, which dramatically affects the function of the antibodies.
“By simultaneously profiling these three characteristics, we can gain a much deeper understanding of a given antibody than just looking at antibody titers,” Sarkar explained.
The researchers found that no antibody feature could differentiate patient survival outcomes. But when they analyzed the global antibody profiles -; whether canonical or non-canonical -; they noticed clear differences between survivors and non-survivors.
“We were surprised to find evidence so compelling that antibodies targeting canonical and non-canonical antigens were equally predictive of survival outcomes,” Singh said. “Our results suggest that non-canonical antibodies may play a role in the recovery from a serious disease, although more research is needed to demonstrate causality and identify mechanisms.”
Most vaccines against COVID-19 and monoclonal antibodies -; The artificial antibodies used to treat COVID-19 have become less effective with the advent of delta and omicron variants because mutations in the ear help the virus to avoid detection. According to Singh, far fewer mutations have been accumulated in the virus’s internal proteins, suggesting that increasing vaccines or therapies to target these non-canonical antigens could lead to more robust immunity against emerging variants of concern.
When the team restricted their analysis to antibodies against non-canonical antigens conserved among coronaviruses -; including those that cause the common cold and other respiratory infections -; in patients with COVID-19, they could still distinguish between survivors and non-survivors. These antibodies were also found in nine healthy pre-pandemic control subjects, suggesting that coronavirus exposure in addition to SARS-CoV-2 could induce antibody responses related to favorable outcomes in severe COVID-19.
According to Das, these findings could inform the development of pan-coronavirus vaccines.
In the ongoing work, the team is using its platform to analyze antibodies in vaccinated people with innovative infections compared to unvaccinated individuals. They are also interested in understanding whether different antibodies have different roles in protection against COVID-19 over time.
They also plan to expand the platform to understand antibodies in other contexts, including rejection of organ transplants and other infectious diseases.
Source:
Magazine reference:
Peddireddy, SP, et al. (2022) Antibodies targeting conserved non-canonical antigens and endemic coronaviruses are associated with favorable outcomes in severe COVID-19. Cell reports. doi.org/10.1016/j.celrep.2022.111020.