In an article published in Nature Communications, researchers from Benaroya Research Institute (BRI) and Yale University confirm that COVID-19 immunization does not drive the development of new autoantibodies. While safe overall, mRNA-based COVID-19 vaccines are associated with rare vaccine-related adverse events. These events coupled with observations that acute SARS-CoV-2 infection is associated with increased autoantibodies brought into question whether COVID-19 vaccination also promotes the development of autoantibodies, particularly in patients with preexisting autoimmune disease.

Researchers used rapid extracellular antigen profiling, an autoantibody screening approach developed by Aaron Ring, MD, PhD, at Yale to characterize self- and viral-directed antibodies secreted by immune cells before and after SARS-CoV-2 mRNA vaccination. They confirmed that most individuals generated robust virus-specific antibody responses post-vaccination, but that the quality of the response is impaired in autoimmune patients on certain modes of immunosuppression. Additionally, they found that COVID-19 mRNA vaccination was not associated with development of new autoantibody responses and there was no difference in the dynamics of autoantibodies, even in patients with preexisting autoimmune disease or COVID-19 vaccine-related myocarditis.

Through its biorepository, BRI recruited individuals with and without autoimmune disease. Participants were seen for this study before and after their first COVID-19 immunizations. Yale researchers recruited individuals with myocarditis associated with COVID-19 immunization, and a group of health care workers who received the vaccine – about half of whom were seropositive prior to vaccination. 

The results of this work bolster the emerging safety profile of mRNA vaccines and highlights their ability to decouple SARS-CoV-2 immunity from the autoantibody responses observed during acute COVID-19 infection.

In a new study published in the Journal of Allergy and Clinical Immunology led by Benaroya Research Institute (BRI) and Seattle Children’s Research Institute in collaboration with the University of Washington School of Medicine and the University of Wisconsin, researchers discovered why individuals with allergic asthma may have reduced susceptibility to COVID-19 and an important mechanism by which allergic inflammation diminishes SARS-CoV-2 infection, despite well-known susceptibilities to other respiratory viral infections. 

Allergic diseases such as asthma are characterized by type-2 inflammation in the airways. BRI’s Naresh Doni Jayavelu, PhD, and the research team looked at mechanisms whereby type-2 inflammation in the airway surprisingly protects against SARS-CoV-2 in children. The study utilized bronchial airway cells from carefully characterized children with and without asthma obtained from the biorepository of Dr. Jason Debley, investigator at the Center for Immunity and Immunotherapies at Seattle Children’s Research Institute. The Debley Lab team then used the cells to conduct SARS-CoV-2 infection experiments in their biosafety level 3 (BSL-3) facility using an organotypic ex vivo airway epithelial model system. Results demonstrated that viral replication was lower in airway epithelial cells from children with allergic asthma compared to their healthy counterparts, and that increasing the level of type-2 inflammation in the epithelium could dramatically impair viral replication. 

“This was a highly collaborative research effort that revealed important molecular and clinical insights by which people with allergic asthma are likely protected from SARS-CoV-2 infection,” said Dr. Jayavelu. “Early epidemiologic studies reported conflicting findings on the association of asthma with COVID-19 adverse outcomes. However, now we are seeing that it is other pulmonary disease (such as COPD) that confer risk for worse COVID-19, but surprisingly allergy and allergic asthma can confer unexpected protection.”

The findings also illustrate a notable mechanism of intrinsic protection against SARS-CoV-2. 

“To my knowledge, this is perhaps the most compelling demonstration of a mechanism of intrinsic protection against SARS-CoV-2. We know antibody responses after vaccine or natural infection are protective, but this mechanism protects in the absence of prior exposure to the virus,” said Matthew Altman, MD, BRI affiliate investigator and co-author on the study. 

Since the study findings are based on in vitro cell culture experiments, Dr. Jayavelu and Dr. Altman are now investigating to what degree type-2 inflammation decreases viral replication and severe disease in a large observational cohort that was enrolled at the beginning of the pandemic to more fully understand the clinical impact of their results. 

This research was funded by the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, and other sources. It builds on a previous study that set the groundwork for a hypothetical mechanism of protection. For more information on BRI and its asthma research, visit benaroyaresearch.org.

Studies in the lab of Estelle Bettelli, PhD, at Benaroya Research Institute (BRI) demonstrate that disease modifying therapies (DMTs) used to treat individuals with multiple sclerosis significantly change immune responses generated by COVID-19 vaccines.

Illustrates better understanding of cellular mechanisms involved in viral resistance; screening method used can be applied to other dangerous pathogens

Discoveries from the Benaroya Research Institute at Virginia Mason (BRI) have identified a new cellular protection pathway that targets a common vulnerability in several different pandemic viruses, and collaborators at Case Western Reserve University, Boston University School of Medicine and MRI Global have shown that this pathway can protect cells from infection by Ebola virus and coronaviruses, like SARS-CoV-2. Published today in Science, these new findings provide a better understanding of cellular mechanisms involved in viral resistance that can inform future treatments and therapies for viral infectious diseases.

The research illuminates a completely new role for the two genes identified and a unique approach to inhibiting virus fusion and entry into human cells—getting us one step closer to the next generation of antiviral therapies. Researchers used a transposon-mediated gene-activation screen to search for new genes that can prevent infection by Ebola virus. This new screening strategy—that serves as a blueprint for uncovering resistance mechanism against other dangerous pathogens— found that the gene MHC class II transactivator (CIITA) induces resistance in human cell lines by activating the expression of a second gene, CD74. One form of CD74, known as p41, disrupts the processing of proteins on the coat of the Ebola virus protein by cellular proteases called Cathepsins. This prevents entry of the virus into the cell and infection. CD74 p41 also blocked the Cathepsin-dependent entry pathway of coronaviruses, including SARS-CoV-2.

"Uncovering these new cellular protection pathways is incredibly important for understanding how we disrupt or change the virus infection cycle to elicit better protection against viruses like Ebola or SARS-CoV-2." said Adam Lacy-Hulbert, PhD, Principal Investigator, BRI and lead author on the study. "And our new strategy helps us find mechanisms that have eluded conventional genetic screens."

The findings illustrate a new role for genes previously thought to be involved in more conventional T cell and B cell mediated immune responses. For example, CIITA was understood as important for communication between immune cells, but it had not previously been seen as a way for cells to defend themselves against viruses.

"As a virologist, I am excited not just about what this means for Ebola virus, but about the broader implications for other viruses," said Anna Bruchez, PhD, Instructor in Pathology, Case Western Reserve University and co-author on the study. "Many viruses, including coronaviruses, use cathepsin proteases to help them infect cells. Fortunately, when SARS-CoV-2 emerged, I had recently moved to Case Western, and was able to use their specialized BSL3 laboratories to show the CD74 pathway also blocked endosomal entry by this virus. Thus, this anti-viral mechanism has evolved to work against many different viruses."

"We really don’t understand the cellular mechanisms that block viral infections which has limited our ability to effectively respond to pandemics, including this year’s coronavirus," said Lynda M. Stuart, MD, PhD, Deputy Director, Bill & Melinda Gates Foundation, BRI Affiliate Investigator and co-author on the study. "We really need therapies that can block all viruses, including unknown future pathogens. To do that we need to find common pathways that viruses target and then develop approaches to block those vulnerabilities. Our work demonstrates one way in which cells can be modified to do this, and we hope that our insights will open up new avenues for scientists developing therapies and interventions to treat viral infectious diseases that impact millions of lives around the world."

For more information on this discovery and its implications to better understand viral resistance, see the paper: MHC class II transactivator CIITA induces cell resistance to Ebola virus and SARS Coronavirus in Science.

For more information on the Benaroya Research Institute at Virginia Mason, visit www.benaroyaresearch.org

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