Published on 16.12.2021
(*) Inserm, Université de Paris, Institut Pasteur, Hospices civils de Lyon (HCL), Centre International de Recherche en Infectiologie (CIRI), Université Paris Est Créteil (UPEC), Établissement français du sang
Between 2020 and 2021, the teams of Prof. Jean-Laurent Casanova (University of Paris) and Laurent Abel, co-directors of the Laboratory of Human Genetics of Infectious Diseases, have highlighted in the journals Science and Science Immunology* that about a quarter of severe forms of COVID-19 are due to immunological or genetic defects leading to a malfunction of type I interferons (IFNs), the first immunological barrier against viral infections. The majority of these defects are related to the abnormal presence of autoantibodies directed against type I IFNs and neutralising their action. This work has been selected by the journal Nature in its top 10 major discoveries of 2020 across all scientific disciplines. It paves the way for further studies on severe pneumonia, but also on other clinical phenotypes following exposure to SARS-CoV-2. They also form the basis for the RHU 5 programme "COVIFERON", which follows a bed-to-lab and lab-to-bed approach.
An ambitious project with 4 major objectives:
1) To decipher the genetic and immunological basis of the different clinical forms of COVID-19 using state-of-the-art genetic and immunological approaches. "We will also study how these discoveries, particularly with regard to autoantibodies, can help to understand other viral diseases such as severe influenza, viral encephalitis, shingles and adverse reactions to live attenuated viral vaccines", predicts Prof. Jean-Laurent Casanova.
2) To develop, in partnership with bioMérieux, ready-to-use diagnostic tests for the accurate and large-scale detection of autoantibodies against type I IFNs, which could allow the rapid assessment of the risk of severe disease in subjects infected with SARS-CoV-2, or even before infection. These tests will be validated and implemented by Cerba HealthCare and its Cerballiance network of medical laboratories. "We will thus be able to integrate these innovations into routine diagnostics and provide clinicians and patients more quickly with the tools for broad screening that will help optimise prevention and adapt the management and treatment of people at risk," explains Jérôme Sallette, Scientific Director of Cerba HealthCare. These tests could also make it possible to detect and manage people at risk of other viral diseases, or to anticipate the adverse effects of live attenuated viral vaccines (for example, the yellow fever vaccine before a trip, or the chickenpox vaccine after the age of 50).
We will explore how these findings can help to understand other viral diseases such as severe influenza, viral encephalitis, shingles and adverse reactions to live attenuated viral vaccines
3) To promote the use of these tests in the context of transfusion to assess the presence of these autoantibodies in blood donors and to understand their possible impact on blood products and on the safety of transfused patients, in partnership with the Établissement Français du Sang (EFS)
4) To propose new preventive and therapeutic approaches. The use of IFN-β - another antiviral protein from the same family as IFN type I - shortly after infection is particularly promising because anti-IFN type I autoantibodies do not generally neutralise IFN-β. "We will thus create a prospective cohort of subjects with impaired IFN type I immunity, whether the cause is genetic or autoimmune, for long-term follow-up. A pilot precision medicine clinical trial will also be offered to them if they are infected with SARS-CoV-2 or other viruses," explains Prof. Jean-Laurent Casanova.
An international consortium and private partners
To achieve these objectives, this multidisciplinary and translational research project will rely on a strong and synergistic combination of assets:
- Unique cohorts including the main national COVID-19 cohorts and the international Covid Human Genetic Effort consortium (www.covidhge.com), which has recruited patients worldwide in record time, mobilising more than 400 research centres in 38 countries. But also French blood donors through the EFS.
- Scientific excellence and leading expertise in the identification of patients with inborn errors of immunity and autoantibodies underlying severe viral infections, but also in research and clinical trials of viral infections (including COVID-19).
- A leading position of private partners in the development of relevant immunological tests and their validation and large-scale implementation by Cerba HealthCare.
 X-linked recessive TLR7 deficiency in 1% of men under 60 years with life-threatening COVID-19, T. Asano et al, Science Immunology, 2021.
 Autoantibodies neutralizing type I IFNs are present in ~ 4% of uninfected individuals over 70 years and account for ~ 20% of COVID-19 deaths, P. Bastard et al., Science Immunology, 2021
 Inborn errors of type I IFN immunity in patients with life-threatening COVID-19, Q. Zhang et al., Science, 24 septembre 2020