Immunovirological and environmental screening reveals actionable risk factors for fatal COVID-19 during post-vaccination nursing home outbreaks
Authors: Cuypers Lize , Keyaerts Els , Hong Samuel Leandro , Gorissen Sarah , Menezes Soraya Maria , Starick Marick , Van Elslande Jan , Weemaes Matthias , Wawina-Bokalanga Tony , Marti-Carreras Joan , Vanmechelen Bert , Van Holm Bram , Bloemen Mandy , Dogne Jean-Michel , Dufrasne François , Durkin Keith , Ruelle Jean , De Mendonca Ricardo , Wollants Elke , Vermeersch Pieter ,   COVID-19 Genomics Belgium Consortium, Wattiez Ruddy , Peeters Michael , Bakelants Kate , Denayer Sarah , Dufrasne François E. , Meex Cécile , Gillet Laurent , Artesi Maria , Hayette Marie-Pierre , Bontems Sébastien , Bours Vincent , Gourzonès Claire , Ek Olivier , Bureau Fabrice , Kabamba Benoit , Gala Jean-Luc , Bearzatto Bertrand , Ambroise Jérôme , Marchant Arnaud , Henin Coralie , Haerlingen Benoit , de Mendonca Ricardo , Delforge Marie-Luce , Vael Carl , Berckmans Lynsey , Selhorst Philippe , Ariën Kevin K. , Van Dooren Sonia , Hinckel Bruno , Imamura Hideo , Janssen Toon , Caljon Ben , Soetens Oriane , Piérard Denis , Demuyser Thomas , Michel Charlotte , Vandenberg Olivier , van den Wijngaert Sigi , Zorzi Giulia , Van Lint Philippe , Verstrepen Walter , Naesens Reinout , Van Lent Sarah , Hilbert Pascale , Brohée Sylvain , Léonard Pierre-Emmanuel , Karadurmus Deniz , Gras Jeremie , Féret Damien , Lambert Barbara , Vankeerberghen Anne , Holderbeke Astrid , De Beenhouwer Hans , Cattoir Lien , Lammens Christine , Xavier Basil Britto , Le Mercier Marie , Coppens Jasmine , Matheeussen Veerle , Goossens Herman , Martens Geert A. , Swaerts Koen , Van Hoecke Frederik , Desmet Dieter , Descheemaeker Patrick , Bogaerts Pierre , Degosserie Jonathan , Denis Olivier , Huang Te-Din , Obbels Dagmar , Valgaeren Hanne , Frans Johan , Smismans Annick , Claus Paul-Emile , Veltman Denise , Goegebuer Truus , Lemmens Ann , Van den Poel Bea , De Bock Sonja , Laffut Wim , Van Even Ellen , Van Acker Jos , Verfaillie Charlotte , Vanlaere Elke , De Rauw Klara , Waumans Luc , Van Meensel Britt , Cartuyvels Reinoud , Raymaekers Marijke , Verhasselt Bruno , Hellemans Jorn , Vanhee Merijn , Reynders Marijke , Boulouffe Caroline , Djiena Achille , Broucke Caroline , Catry Boudewijn , Lagrou Katrien , Van Ranst Marc , Neyts Johan , Baele Guy , Maes Piet , André Emmanuel , Dellicour Simon , Van Weyenbergh Johan 
Published: May 2023

Coronavirus Disease 2019 (COVID-19) vaccination has resulted in excellent protection against fatal disease, including in older adults. However, risk factors for post-vaccination fatal COVID-19 are largely unknown. We comprehensively studied three large nursing home outbreaks (20–35% fatal cases among residents) by combining severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) aerosol monitoring, whole-genome phylogenetic analysis and immunovirological profiling of nasal mucosa by digital nCounter transcriptomics. Phylogenetic investigations indicated that each outbreak stemmed from a single introduction event, although with different variants (Delta, Gamma and Mu). SARS-CoV-2 was detected in aerosol samples up to 52 d after the initial infection. Combining demographic, immune and viral parameters, the best predictive models for mortality comprised IFNB1 or age, viral ORF7a and ACE2 receptor transcripts. Comparison with published pre-vaccine fatal COVID-19 transcriptomic and genomic signatures uncovered a unique IRF3 low/IRF7 high immune signature in post-vaccine fatal COVID-19 outbreaks. A multi-layered strategy, including environmental sampling, immunomonitoring and early antiviral therapy, should be considered to prevent post-vaccination COVID-19 mortality in nursing homes.