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Since the beginning of the Covid-19 pandemic, many researchers have focused on a crucial question: why do some patients infected with SARS-CoV-2 have no symptoms while others develop pneumonia and even death?
This question has been the subject of rigorous research within the framework of an international collaboration led by teams from Inserm, Université Paris Cité and AP-HP at the Human Genetics of Infectious Diseases Laboratory, in its two branches: at the Institut Imagine, located at the Hôpital Necker-Enfants malades AP-HP, and at the Rockefeller University in New York. This work has led to publications showing that about 20% of severe pneumopathies following SARS-CoV-2 infection are explained by genetic (5% of cases) and immunological (14% of cases) abnormalities that weaken the immune response carried by type I interferons.
Type 1 interferonsType 1 interferons (IFN 1) are a group of 17 proteins that are usually produced rapidly by the body's cells in response to a viral infection and whose main effect is to inhibit viral replication in infected cells. There are several types, divided into several families: alphas, betas, omegas, kappas and epsilons. On the other hand, autoantibodies occur when antibodies attack an individual's own body cells. In some patients with severe forms of Covid-19, autoantibodies directed against type 1 interferons have been found. These autoantibodies neutralize the action of IFN 1 and thus prevent the body from defending itself against the virus. |
Covid-19 mRNA vaccines are very effective in preventing severe manifestation of the disease, including reducing the risk of pneumonitis, as shown by numerous studies. However, in very rare cases, some vaccinated individuals may become infected with SARS-CoV-2 and develop severe forms of the disease, requiring hospitalization.
With the knowledge acquired on immunological deficiencies associated with an increased risk of severe Covid-19, the research teams led by Prof. Jean-Laurent Casanova and Dr. Laurent Abel, co-directors of the Human Genetics of Infectious Diseases Laboratory, have attempted to better understand this phenomenon.
Anti-IFN-1 autoantibodies
In their study, the investigators enrolled 48 patients aged 20 to 80 years who had developed a severe to critical form of delta variant infection, despite a complete mRNA vaccination.
The first step was to verify that the vaccine had been effective in these participants, i.e. that the body had responded by producing a good level of anti-SARS-CoV-2 antibodies. The idea was to rule out severe forms that might have developed after vaccine failure, in order to isolate and identify other factors. For various reasons (HIV infection, presence of lymphoma, immunosuppressive treatments, etc.), six patients had a defective vaccine response and were therefore excluded from the study.
Next, the scientists built on their previous work and looked for the presence of anti-interferon type 1 (IFN-1) autoantibodies in the remaining 42 patients. Different tests were performed to measure the level of anti IFN-1 autoantibodies and their neutralizing effect.
Analysis of the data indicated that 24% of the 42 patients had antibodies that were able to neutralize type 1 interferons. Apart from this feature, these patients had no other immunological deficiencies and no history of severe viral infection.
Interestingly, although these patients developed a severe form of Covid-19, none resulted in death. However, in the unvaccinated population, the death rate of those with type 1 anti-interferon autoantibodies is 20%. It can therefore be assumed that vaccination had an effect even if it did not prevent the development of the disease.
Testing patients to identify risks
In order to go further in the understanding of the underlying biological mechanisms, in-depth molecular studies finally allowed the researchers to identify the subtypes of autoantibodies concerned, showing that they were mainly anti-alpha2 and/or anti-omega autoantibodies.
These results therefore help explain why some vaccinated individuals with high levels of antibodies against SARS-CoV-2 may nevertheless develop severe forms of the disease. Although this phenomenon remains very rare, it is nonetheless important to acquire solid knowledge on the subject in order to adapt prevention and patient management strategies.
The authors of the study recommend testing for the presence of anti-IFN-1 autoantibodies in vaccinated patients hospitalized with SARS-CoV-2 infection. They will continue their work in order to better understand why these anti-IFN-1 autoantibodies develop in certain patients, particularly by looking at genetic factors.
Rigorous communication in the service of scienceIf this study concerns very rare forms of severe Covid-19 occurring in vaccinated people, which concern only a small number of patients, it seemed important to relay these results in a rigorous and transparent way, faithful to Inserm's approach in favor of reliable scientific information, so that these results could not be subject to misinterpretation or manipulation by conspiracy mongers. |
Sources:
DOI : https://www.science.org/doi/10.1126/sciimmunol.abp8966
Researcher contact
Pr Jean-Laurent Casanova E-mail : casanova@mail.rockefeller.edu
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