Bastard, P.Vazquez, S. E.Liu, J.Laurie, M. T.Wang, C. Y.Gervais, A.Voyer, T. L.Bizien, L.Zamecnik, C.Philippot, Q.Rosain, J.Catherinot, E.Willmore, A.Mitchell, A. M.Bair, R.Garçon, P.Kenney, H.Fekkar, A.Salagianni, M.Poulakou, G.Siouti, E.Sahanic, S.Tancevski, I.Weiss, G.Nagl, LManry, J.Duvlis, S.Arroyo-Sánchez, D.Artal, E. P.Rubio, L.Perani, C.Bezzi, M.Sottini, A.Quaresima, V.Roussel, L.Vinh, D. C.Reyes, L. F.Garzaro, M.Hatipoglu, N.Boutboul, D.Tandjaoui-Lambiotte, Y.Borghesi, A.Aliberti, A.Cassaniti, I.Venet, F.Monneret, G.Halwani, R.Sharif-Askari, N. S.Danielson, J.Burrel, S.Morbieu, C.Stepanovskyy, Y.Bondarenko, A.Volokha, A.Boyarchuk, O.Gagro, A.Neuville, M.Neven, B.Keles, S.Hernu, R.Bal, A.Novelli, A.Novelli, G.Saker, K.Ailioaie, O.Antolí, A.Jeziorski, E.Rocamora-Blanch, G.Teixeira, C.Delaunay, C.Lhuillier, M.Turnier, P. L.Zhang, Y.Mahevas, M.Pan-Hammarström, Q.Abolhassani, H.Bompoil, T.Dorgham, K.Consortium, C.Group, F.Consortium, C.Gorochov, G.Laouenan, C.Rodríguez-Gallego, C.Ng, L. F. P.Renia, L.Pujol, A.Belot, A.Raffi, F.Allende, L. M.Martinez-Picado, J.Özçelik, TayfunImberti, L.Notarangelo, L. D.Troya, J.Solanich, X.Zhang, S.Puel, A.Wilson, M. R.Trouillet-Assant, S.Abel, L.Jouanguy, E.Ye, C. J.Cobat, A.Thompson, L. M.Andreakos, E.Zhang, Q.Anderson, M. S.Casanova, J.DeRisi, J. L.2024-03-112024-03-112022-06-14https://hdl.handle.net/11693/114497Life-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.enCC BY 4.0 DEED (Attribution 4.0 International)https://creativecommons.org/licenses/by/4.0/Article10.1126/sciimmunol.abp89662470-9468