Impaired Type I IFN Immunity Due to Autoantibodies or a Genetic Defect: a Prospective National Cohort

Not yet recruiting

• Conditions: Immunology; Infectious Diseases; Allergy; Genetic Diseases

• Registration Number: NCT06762002
• Lead Sponsor: Institut National de la Santé Et de la Recherche Médicale, France

Brief Summary

The major role of human genetic factors in the immune response to infections is now well established, particularly for viral infections. In the context of the COVID-19 pandemic, the following results have identified 1) several inborn errors of immunity (IEI) affecting the response or production of type I interferons (type I IFNs) in around 4% of adult patients with severe clinical disease, and 2) the presence of type I IFN-neutralizing autoantibodies (auto-Abs) in around 15% of severe cases, and 20% of deaths. The investigators would like to carry out a longitudinal immunological and clinical follow-up study on a prospective cohort of patients with either a genetic defect affecting the type I IFN-dependent immune response, or anti-IFN-I auto-Abs, to monitor the incidence of infectious and/or autoimmune events in these individuals, the evolution of neutralizing power, and the kinetics of auto-Abs. This should lead to a better understanding of the prevention and management of these patients.

The research design is a national multicenter prospective cohort of adults with 1) anti-IFN-I auto-Abs or 2) IEI- IFN-I, with follow-up from 1 to 4 years. These individuals may be: 1) patients who have or have had clinical disease (related to COVID-19, other viral infections, autoimmune disorders); or 2) "healthy" participants (e.g. blood donors, relatives of an IEI patient).

Follow-up will include:

* yearly visits to the Clinical Investigation Center (CIC) or a clinical department with blood sampling;

* specific visit in case of hospitalization for infectious events or adverse effects of vaccination, exacerbation or new diagnosis of auto-immune disease, new diagnosis of cancer, or SARS-CoV-2 infection whether or not patients are admitted to hospital, with blood sampling.

In addition, a retrospective "passive" follow-up will be implemented through matching with the data from the SNDS (National Health Data System), in order to collect clinical events of and healthcare resource consumption. Moreover, matching with controls adults from the national CONSTANCES cohort, not carrying auto-Abs against type I IFNs nor IEI-IFN-I, will be performed. (ratio 3:1; matching on age (+/- 5 years), gender and geographic region of recruitment). Individuals under long-lasting immunosuppressive or immunomodulatory drugs will not be eligible. Follow-up of controls, which will be carried out as part of the CONSTANCES cohort, will include web-based questionnaires, every 12 months, in addition to linking with SNDS data as already done in this cohort.

Inclusion visit:

After signing the consent form, the following tests will be performed:

* Demographic characteristics (sex, age, country of birth)

* Medical history from participant and family member(s) including infectious and auto-immune diseases, cancers and vaccination status and side effects

* Blood samples for:

* full blood cell count;

* classical autoimmune investigations (anti-nuclear, anti-ENA, native anti-DNA, anti- thyroid antibodies, rheumatoid factor);

* immunophenotyping\*;

* auto-Abs against type I IFNs, other cytokines\*, or other target proteins\* (dosage and neutralization activity);

* Genetic explorations by whole-exome or whole-genome sequencing\*;

* Biobanking (DNA, plasma/sera; cryopreserved peripheral blood mononuclear cells (PBMCs).

* these biological analyses will be carried out as part of dedicated COVIFERON RHU5 workpackages.

In addition, vaccination against SARS-CoV-2 and influenza will be offered to these subjects as a priority, as part of their usual care.

Follow-up visits :

Annual visits to the CIC :

* Medical history since last visit, including infectious, auto-immune and oncologic events, vaccination status and side effects

* Blood samples for:

* full blood cell count;

* classical autoimmune investigation (anti-nuclear, anti-ENA, native anti- DNA, anti-thyroid antibodies, rheumatoid factor);

* immunophenotyping;

* Auto-Abs against type I IFNs, other cytokines, or other target proteins (dosage and neutralization)

* Biobanking (DNA, plasma, cryopreserved peripheral blood mononuclear cells (PBMCs))

Additional specific visit in the event of a clinical event of interest, at any time during follow-up:

* In case of SARS-CoV-2 infection, whatever the severity of the disease: blood sampling for determination and neutralization of type I anti-IFN autoAbs, CBC, and biobanking (plasma and PBMC) and teleconsultation with the CIC in charge of patients, as soon as possible.

* In the event of hospitalization for infectious events or exacerbation or new diagnosis of an auto-immune disease: blood sampling for determination and neutralization of anti-IFN-I autoAbs, CBC, and biobanking (plasma and PBMCs) and collection of the hospitalization report in the case report form on a dedicated page.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2024-11-14
• Status Verified: 2024-12
• Study Start: 2025-01
• Study First Submitted QC: 2025-01-06
• Last Update Submitted: 2025-01-06
• Study First Posted: 2025-01-07
• Last Update Posted: 2025-01-07
• Primary Completion: 2029-01
• Study Completion: 2029-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 500

Inclusion Criteria

• Age >18 years
• History of carrying 1) auto-Abs against type I IFNs or 2) IEI impairing the response to, or the production of, type I IFNs (IFN-I-IEI)
• Affiliated to social security
• Written informed consent

Exclusion Criteria

• Participation to an interventional clinical trial on a pharmacological treatment
• Clinical condition leading to life expectancy less than 1 year
• Subject to a legal protection measure (safeguard of justice, curatorship, tutorship)
• Individuals deprived of freedom

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
primary endpoint n°1 : quantitative dosage of auto-Abs against type I IFNs	year 0, year 1, year 2 and year 3	Method: Quantitative trait will be measured by Gyros using commercially available internal control antibodies.
primary endpoint n°2 : neutralization capacity evaluation of auto-Abs against type I IFNs	year 0, year 1, year 2 and year 3	The neutralization capacity will be performed as previously reported using an in vitro luciferase system in HEK293 cells

Secondary Outcome Measures

Name	Time	Method
Cumulative incidence of clinical events of interest, i.e. infectious events, autoimmune diseases or cancers	Year 0, year 1, year 2 and year 3	Method: annual medical visits, SNDS (PMSI, DCIR). Incidence density rate is defined as the number of newly disease individuals on the sum of time periods for all disease-free individual-at-risk
Clinical and biological factors associated with clinical outcomes	Year 0, year 1, year 2 and year 3	the potential predictor variables will be assessed by bivariate logistic regressions where occurrence of clinical events is the variable to be explained. Factors associated with a p-value less than 0.20 will be included in the multivariate logistic model. Backward selection on pvalue will be applied. Internal validity of the final model will be estimated by cross-validation (Leave-One-Out Cross-Validation method). Discrimination will be assessed by the area under the ROC curve and its 95% confidence interval.
Cumulative incidence of the same clinical events of interest, in control participants who are negative for auto-Abs, matched by age and sex followed through the large CONSTANCES cohort	Year 0, year 1, year 2 and year 3	Cumulative incidence of the same clinical events of interest, in control participants who are negative for auto-Abs, matched by age and sex followed through the large CONSTANCES cohort (Constances database), and its 95% confidence interval: Incidence density rate is defined as the number of newly disease individuals on the sum of time periods for all disease-free individual-at-risk.
Genetic factors associated with the development of auto-Abs against type I IFNs	year 0, year 1, year 2 and year 3	Using gene-level criteria to select candidate variants such as the negative selection level measured by the CoNeS approach.

Trial Locations

Locations (9)

Cic Lille; 🇫🇷 Lille, France

LYON HCL; 🇫🇷 Lyon, France

Cic Montpellier; 🇫🇷 Montpellier, France

Cic Bichat; 🇫🇷 Paris, France

Cic Creteil; 🇫🇷 Paris, France

Cic La Salpetriere; 🇫🇷 Paris, France

Cic Necker; 🇫🇷 Paris, France

Cic St Louis; 🇫🇷 Paris, France

Cic Tours; 🇫🇷 Tours, France