The role of type 1 interferon in severe forms of Covid-19: lead also likely in vaccines

Despite two doses of the mRNA vaccine against Covid-19, patients infected with Sars-CoV-2 develop severe forms of the disease. To explain the mechanisms at work, researchers from the Human Genetics Laboratory of Infectious Diseases*, headed by Professors Jean-Laurent Casanova and Laurent Appel, put forward the hypothesis of an immune deficiency.

Published in Science Immunology, their study follows previous research that highlighted genetic (5% of cases) and immunological (14% of cases) disorders that impair immunity controlled by the type of interferon. 1 (IFN 1), a group of 17 proteins that produce the first immune barrier against viruses. Thus, these abnormalities may be the cause of about 20% of the serious lung diseases associated with Covid. When immunostained, these abnormalities are associated with the presence of autoantibodies directed against IFN 1, which impairs its antiviral action.

Anti-IFN1 autoantibodies increase with age

This discovery, published in October 2020, was confirmed by other work that revealed very rare genetic variants associated with IFN 1, which are also associated with severe forms of Covid. Moreover, the presence of autoantibodies directed against IFN 1, very rare before the age of 65 (0.2 to 0.5%), increases with age: from 4% between 70 and 79 years to 7% between 80 and 85 years. This development partly explains why age is a major risk factor for severe forms of Covid-19.

In this new study, the researchers looked at cases of severe forms, who were hospitalized after infection with the delta variant, despite following a full regimen with an mRNA vaccine. They thus recruited 48 patients aged 20 to 86 years who developed an acute to critical form after infection that occurred two to four months after mRNA vaccination.

The first step was to measure the level of antibodies directed against SARS-CoV-2 in these patients to ensure that they responded well to the vaccination. Six patients had a response to the vaccine “defective”associated with HIV infection, the presence of lymphoma or the intake of immunosuppressive therapies were excluded from the analysis.

Dangerous forms but no death

The researchers then searched the remaining 42 participants for the presence of anti-IFN-1 autoantibodies. They found it in ten (24%) of those (ages 43 to 86). In the general population, autoantibodies to IFN-1 were detected in 20% of cases of deceased unvaccinated patients. But among the subjects of the study, no deaths were recorded, which indicates the effectiveness of vaccination on mortality, despite the development of a severe form.

In-depth molecular studies have enabled researchers to identify the subtypes of the autoantibodies involved, particularly alpha2 antibodies and/or omega antibodies. Eight of these 10 patients had autoantibodies that neutralize both IFN-alpha2 and IFN-omega, while two neutralized only IFN-omega. There is no patient neutralizing IFN-beta”the authors detail, emphasizing that the severity of responses can vary according to the variables.

These findings could make it possible to adapt prevention and management strategies for these patients. The authors therefore recommend testing for the presence of IFN-1 autoantibodies in vaccinated patients in hospital after infection.

*The Human Genetics Laboratory of Infectious Diseases is located in Paris (Imagine Institute/University of Paris/Inserm) and New York (Howard Hughes Medical Institute, Rockefeller University).

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