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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

ABSTRACT: Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection.

SUBMITTER: Zhang Q

PROVIDER: S-EPMC7857407 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

Zhang Qian Q Bastard Paul P Liu Zhiyong Z Le Pen Jérémie J Moncada-Velez Marcela M Chen Jie J Ogishi Masato M Sabli Ira K D IKD Hodeib Stephanie S Korol Cecilia C Rosain Jérémie J Bilguvar Kaya K Ye Junqiang J Bolze Alexandre A Bigio Benedetta B Yang Rui R Arias Andrés Augusto AA Zhou Qinhua Q Zhang Yu Y Onodi Fanny F Korniotis Sarantis S Karpf Léa L Philippot Quentin Q Chbihi Marwa M Bonnet-Madin Lucie L Dorgham Karim K Smith Nikaïa N Schneider William M WM Razooky Brandon S BS Hoffmann Hans-Heinrich HH Michailidis Eleftherios E Moens Leen L Han Ji Eun JE Lorenzo Lazaro L Bizien Lucy L Meade Philip P Neehus Anna-Lena AL Ugurbil Aileen Camille AC Corneau Aurélien A Kerner Gaspard G Zhang Peng P Rapaport Franck F Seeleuthner Yoann Y Manry Jeremy J Masson Cecile C Schmitt Yohann Y Schlüter Agatha A Le Voyer Tom T Khan Taushif T Li Juan J Fellay Jacques J Roussel Lucie L Shahrooei Mohammad M Alosaimi Mohammed F MF Mansouri Davood D Al-Saud Haya H Al-Mulla Fahd F Almourfi Feras F Al-Muhsen Saleh Zaid SZ Alsohime Fahad F Al Turki Saeed S Hasanato Rana R van de Beek Diederik D Biondi Andrea A Bettini Laura Rachele LR D'Angio' Mariella M Bonfanti Paolo P Imberti Luisa L Sottini Alessandra A Paghera Simone S Quiros-Roldan Eugenia E Rossi Camillo C Oler Andrew J AJ Tompkins Miranda F MF Alba Camille C Vandernoot Isabelle I Goffard Jean-Christophe JC Smits Guillaume G Migeotte Isabelle I Haerynck Filomeen F Soler-Palacin Pere P Martin-Nalda Andrea A Colobran Roger R Morange Pierre-Emmanuel PE Keles Sevgi S Çölkesen Fatma F Ozcelik Tayfun T Yasar Kadriye Kart KK Senoglu Sevtap S Karabela Şemsi Nur ŞN Rodríguez-Gallego Carlos C Novelli Giuseppe G Hraiech Sami S Tandjaoui-Lambiotte Yacine Y Duval Xavier X Laouénan Cédric C Snow Andrew L AL Dalgard Clifton L CL Milner Joshua D JD Vinh Donald C DC Mogensen Trine H TH Marr Nico N Spaan András N AN Boisson Bertrand B Boisson Bertrand B Boisson-Dupuis Stéphanie S Bustamante Jacinta J Puel Anne A Ciancanelli Michael J MJ Meyts Isabelle I Maniatis Tom T Soumelis Vassili V Amara Ali A Nussenzweig Michel M García-Sastre Adolfo A Krammer Florian F Pujol Aurora A Duffy Darragh D Lifton Richard P RP Zhang Shen-Ying SY Gorochov Guy G Béziat Vivien V Jouanguy Emmanuelle E Sancho-Shimizu Vanessa V Rice Charles M CM Abel Laurent L Notarangelo Luigi D LD Cobat Aurélie A Su Helen C HC Casanova Jean-Laurent JL

Science (New York, N.Y.) 20200924 6515

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 ...[more]

PMID: 32972995

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Project description:Patients with inborn errors of immunity (IEI) in Argentina were encouraged to receive licensed Sputnik, AstraZeneca, Sinopharm, Moderna, and Pfizer vaccines, even though most of the data of humoral and cellular responses combination on available vaccines comes from trials conducted in healthy individuals. We aimed to evaluate the safety and immunogenicity of the different vaccines in IEI patients in Argentina. The study cohort included adults and pediatric IEI patients (n = 118) and age-matched healthy controls (HC) (n = 37). B cell response was evaluated by measuring IgG anti-spike/receptor binding domain (S/RBD) and anti-nucleocapsid(N) antibodies by ELISA. Neutralization antibodies were also assessed with an alpha-S protein-expressing pseudo-virus assay. The T cell response was analyzed by IFN-γ secretion on S- or N-stimulated PBMC by ELISPOT and the frequency of S-specific circulating T follicular-helper cells (TFH) was evaluated by flow cytometry.No moderate/severe vaccine-associated adverse events were observed. Anti-S/RBD titers showed significant differences in both pediatric and adult IEI patients versus the age-matched HC cohort (p < 0.05). Neutralizing antibodies were also significantly lower in the patient cohort than in age-matched HC (p < 0.01). Positive S-specific IFN-γ response was observed in 84.5% of IEI patients and 82.1% presented S-specific TFH cells. Moderna vaccines, which were mainly administered in the pediatric population, elicited a stronger humoral response in IEI patients, both in antibody titer and neutralization capacity, but the cellular immune response was similar between vaccine platforms. No difference in humoral response was observed between vaccinated patients with and without previous SARS-CoV-2 infection.In conclusion, COVID-19 vaccines showed safety in IEI patients and, although immunogenicity was lower than HC, they showed specific anti-S/RBD IgG, neutralizing antibody titers, and T cell-dependent cellular immunity with IFN-γ secreting cells. These findings may guide the recommendation for a vaccination with all the available vaccines in IEI patients to prevent COVID-19 disease.

Project description:BackgroundPatients with inborn errors of immunity (IEI) are at increased risk of severe coronavirus disease-2019 (COVID-19). Effective vaccination against COVID-19 is therefore of great importance in this group, but little is known about the immunogenicity of COVID-19 vaccines in these patients.ObjectivesWe sought to study humoral and cellular immune responses after mRNA-1273 COVID-19 vaccination in adult patients with IEI.MethodsIn a prospective, controlled, multicenter study, 505 patients with IEI (common variable immunodeficiency [CVID], isolated or undefined antibody deficiencies, X-linked agammaglobulinemia, combined B- and T-cell immunodeficiency, phagocyte defects) and 192 controls were included. All participants received 2 doses of the mRNA-1273 COVID-19 vaccine. Levels of severe acute respiratory syndrome coronavirus-2-specific binding antibodies, neutralizing antibodies, and T-cell responses were assessed at baseline, 28 days after first vaccination, and 28 days after second vaccination.ResultsSeroconversion rates in patients with clinically mild antibody deficiencies and phagocyte defects were similar to those in healthy controls, but seroconversion rates in patients with more severe IEI, such as CVID and combined B- and T-cell immunodeficiency, were lower. Binding antibody titers correlated well to the presence of neutralizing antibodies. T-cell responses were comparable to those in controls in all IEI cohorts, with the exception of patients with CVID. The presence of noninfectious complications and the use of immunosuppressive drugs in patients with CVID were negatively correlated with the antibody response.ConclusionsCOVID-19 vaccination with mRNA-1273 was immunogenic in mild antibody deficiencies and phagocyte defects and in most patients with combined B- and T-cell immunodeficiency and CVID. Lowest response was detected in patients with X-linked agammaglobulinemia and in patients with CVID with noninfectious complications. The assessment of longevity of immune responses in these vulnerable patient groups will guide decision making for additional vaccinations.

Dataset Information

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19.

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