Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs
Authors: Bastard Paul , Vazquez Sara E. , Liu Jamin , Laurie Matthew T. , Wang Chung Yu , Gervais Adrian , Le Voyer Tom , Bizien Lucy , Zamecnik Colin , Philippot Quentin , Rosain Jérémie , Catherinot Emilie , Willmore Andrew , Mitchell Anthea M. , Bair Rebecca , Garçon Pierre , Kenney Heather , Fekkar Arnaud , Salagianni Maria , Poulakou Garyphallia , Siouti Eleni , Sahanic Sabina , Tancevski Ivan , Weiss Günter , Nagl Laurenz , Manry Jérémy , Duvlis Sotirija , Arroyo-Sánchez Daniel , Paz Artal Estela , Rubio Luis , Perani Cristiano , Bezzi Michela , Sottini Alessandra , Quaresima Virginia , Roussel Lucie , Vinh Donald C. , Reyes Luis Felipe , Garzaro Margaux , Hatipoglu Nevin , Boutboul David , Tandjaoui-Lambiotte Yacine , Borghesi Alessandro , Aliberti Anna , Cassaniti Irene , Venet Fabienne , Monneret Guillaume , Halwani Rabih , Sharif-Askari Narjes Saheb , Danielson Jeffrey , Burrel Sonia , Morbieu Caroline , Stepanovskyy Yurii , Bondarenko Anastasia , Volokha Alla , Boyarchuk Oksana , Gagro Alenka , Neuville Mathilde , Neven Bénédicte , Keles Sevgi , Hernu Romain , Bal Antonin , Novelli Antonio , Novelli Giuseppe , Saker Kahina , Ailioaie Oana , Antolí Arnau , Jeziorski Eric , Rocamora-Blanch Gemma , Teixeira Carla , Delaunay Clarisse , Lhuillier Marine , Le Turnier Paul , Zhang Yu , Mahevas Matthieu , Pan-Hammarström Qiang , Abolhassani Hassan , Bompoil Thierry , Dorgham Karim ,   COVID HGE Consortium,   French COVID Study Group,   COMET Consortium, Gorochov Guy , Laouenan Cédric , Rodríguez-Gallego Carlos , Ng Lisa F. P. , Renia Laurent , Pujol Aurora , Belot Alexandre , Raffi François , Allende Luis M. , Martinez-Picado Javier , Ozcelik Tayfun , Imberti Luisa , Notarangelo Luigi D. , Troya Jesus , Solanich Xavier , Zhang Shen-Ying , Puel Anne , Wilson Michael R. , Trouillet-Assant Sophie , Abel Laurent , Jouanguy Emmanuelle , Ye Chun Jimmie , Cobat Aurélie , Thompson Leslie M. , Andreakos Evangelos , Zhang Qian , Anderson Mark S. , Casanova Jean-Laurent , DeRisi Joseph L. 
Published: June 2022

Life-threatening “breakthrough” cases of critical COVID-19 are attributed to poor or waning antibody (Ab) response to SARS-CoV-2 vaccines in individuals already at risk. Preexisting auto-Abs neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; their contribution to hypoxemic breakthrough cases in vaccinated people is unknown. We studied a cohort of 48 individuals (aged 20 to 86 years) who received two doses of a messenger RNA (mRNA) vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Ab levels to the vaccine, neutralization of the virus, and auto-Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal Ab response to the vaccine. Among them, 10 (24%) had auto-Abs neutralizing type I IFNs (aged 43 to 86 years). Eight of these 10 patients had auto-Abs neutralizing both IFN-α2 and IFN-ω, whereas two neutralized IFN-ω only. No patient neutralized IFN-β. Seven neutralized type I IFNs at 10 ng/ml and three at 100 pg/ml only. Seven patients neutralized SARS-CoV-2 D614G and Delta efficiently, whereas one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only type I IFNs at 100 pg/ml neutralized both D614G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating Abs capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a notable proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population.