[en] 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.
Disciplines :
Microbiology
Author, co-author :
Cuypers, Lize; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
Keyaerts, Els; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
Hong, Samuel Leandro ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Gorissen, Sarah; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
Menezes, Soraya Maria; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Starick, Marick; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Van Elslande, Jan; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium
Weemaes, Matthias; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium
Wawina-Bokalanga, Tony; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Marti-Carreras, Joan; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Vanmechelen, Bert; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Van Holm, Bram ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Bloemen, Mandy ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Dogne, Jean-Michel; Department of Pharmacy, Namur Research Institute for Life Sciences, University of Namur, Namur, Belgium
Dufrasne, François ; Laboratory of Proteomics and Microbiology, University of Mons, Mons, Belgium ; Department of Infectious Diseases, Laboratory of Viral Diseases, National Institute for Public Health (Sciensano), Brussels, Belgium
Durkin, Keith ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Laboratory of Human Genetics, GIGA Research Institute, Liège, Belgium
Ruelle, Jean; Medical Microbiology Unit (MBLG), Institute of Experimental and Clinical Research (IREC), Université Catholique de Louvain, Brussels, Belgium
De Mendonca, Ricardo; Université Libre de Bruxelles (ULB), Brussels, Belgium
Wollants, Elke; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Vermeersch, Pieter; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium
COVID-19 Genomics Belgium Consortium
Boulouffe, Caroline; Infectious Disease Surveillance Unit, Agence pour une vie de qualité (AVIQ), Wallonia, Belgium
Djiena, Achille; Infectious Disease Surveillance Unit, Agence pour une vie de qualité (AVIQ), Wallonia, Belgium
Catry, Boudewijn; Unit Healthcare-Associated Infections and Antimicrobial Resistance, Sciensano, Brussels, Belgium
Lagrou, Katrien; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
Van Ranst, Marc; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Neyts, Johan; Department of Microbiology, Immunology and Transplantation, Laboratory Virology and Chemotherapy, Rega Institute, KU Leuven, Leuven, Belgium
Baele, Guy; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
Maes, Piet; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium
André, Emmanuel; Department of Laboratory Medicine, National Reference Centre for Respiratory Pathogens, University Hospitals Leuven, Leuven, Belgium ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Microbiology, KU Leuven, Leuven, Belgium
Dellicour, Simon; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium ; Spatial Epidemiology Lab (SpELL), Université Libre de Bruxelles, Bruxelles, Belgium
Van Weyenbergh, Johan ; Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical and Epidemiological Virology, Rega Institute, KU Leuven, Leuven, Belgium. johan.vanweyenbergh@kuleuven.be
FWO - Fonds Wetenschappelijk Onderzoek Vlaanderen KU Leuven - Catholic University of Leuven F.R.S.-FNRS - Fonds de la Recherche Scientifique
Funding text :
We would like to acknowledge the numerous diagnostics laboratories involved in performing the consecutive screenings in the three nursing homes and for sharing detailed RT–qPCR results. Special thanks go to the representatives of the three nursing homes for providing additional and detailed information to make this collaboration fruitful: the (nursing) staff of Nos Tayons in Nivelles (with specific support of P. Gilbert), of Les Cytises nursing home in Braives and of Ter Burg in Zaventem (with special thanks to N. Deblaere, R. Verschueren and K. Boydens). UZ Leuven, as national reference center for respiratory pathogens, is supported by Sciensano, which is gratefully acknowledged. J.M.C. was supported by the HONOURs Marie-Sklodowska-Curie training network (grant 721367). This work is also supported by ‘Interne Fondsen KU Leuven/Internal Funds KU Leuven’ project 3M170314 and C3/20/105 awarded to P.M. The sequencing capacity of this work was supported, in part, by a COVID-19 research grant of ‘Fonds Wetenschappelijk Onderzoek’/Research Foundation Flanders (grant G0H4420N) awarded to P.M., G.B. and E.A. S.D. is supported by the ‘Fonds National de la Recherche Scientifique’ (FNRS, Belgium) and by the European Union Horizon 2020 project MOOD (grant agreement no. 874850). G.B. acknowledges support from the Internal Funds KU Leuven (grant C14/18/094) and from the Research Foundation–Flanders (‘Fonds voor Wetenschappelijk Onderzoek–Vlaanderen’, G0E1420N and G098321N), the latter grant also for S.D. J.V.W. is supported by the Research Foundation–Flanders (G0A0621N and G065421N). P.V. is a senior clinical investigator of the Research Foundation–Flanders. K.K.A. is supported by Research Foundation–Flanders (FWO G0G4220N). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Hardy, J. O. et al. A world apart: levels and determinants of excess mortality due to COVID-19 in care homes: the case of the Belgian region of Wallonia during the spring 2020 wave. Demogr. Res. 45, 1011–1040 (2021). DOI: 10.4054/DemRes.2021.45.33
Dellicour, S. et al. Investigating the drivers of the spatio-temporal heterogeneity in COVID-19 hospital incidence—Belgium as a study case. Int. J. Health Geogr. 20, 29 (2021). DOI: 10.1186/s12942-021-00281-1
Gillain, S., Belche, J.-L. & Moreau, J.-F. COVID-19 epidemic in the nursing homes in Belgium. J. Nursing Home Res. 6, 40–42 (2020).
Suñer, C. et al. A retrospective cohort study of risk factors for mortality among nursing homes exposed to COVID-19 in Spain. Nat. Aging 1, 579–584 (2021). DOI: 10.1038/s43587-021-00079-7
Collier, D. A. et al. Age-related immune response heterogeneity to SARS-CoV-2 vaccine BNT162b2. Nature 596, 417–422 (2021). DOI: 10.1038/s41586-021-03739-1
Grange, Z. et al. Characteristics and risk of COVID-19-related death in fully vaccinated people in Scotland. Lancet 398, 1799–1800 (2021). DOI: 10.1016/S0140-6736(21)02316-3
Juthani, P. V. et al. Hospitalisation among vaccine breakthrough COVID-19 infections. Lancet Infect. Dis. 21, 1485–1486 (2021). DOI: 10.1016/S1473-3099(21)00558-2
Thompson, D.-C. et al. The impact of COVID-19 pandemic on long-term care facilities worldwide: an overview on international issues. Biomed. Res. Int. 4, 8870249 (2020).
Thomas, S. J. et al. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine through 6 months. N. Engl. J. Med. 385, 1761–1773 (2021). DOI: 10.1056/NEJMoa2110345
Haas, E. J. et al. Impact and effectiveness of mRNA BNT162b2 vaccine against SARS-CoV-2 infections and COVID-19 cases, hospitalizations, and deaths following a nationwide vaccination campaign in Israel: an observational study using national surveillance data. Lancet 397, 1819–1829 (2021). DOI: 10.1016/S0140-6736(21)00947-8
Cabezas, C. et al. Associations of BNT162b2 vaccination with SARS-CoV-2 infection and hospital admission and death with covid-19 in nursing homes and healthcare workers in Catalonia: prospective cohort study. BMJ 374, n1868 (2021). DOI: 10.1136/bmj.n1868
Suetens, C. et al. Increasing risk of breakthrough COVID-19 in outbreaks with high attack rates in European long-term care facilities, July to October 2021. Euro Surveill. 26, 2101070 (2021). DOI: 10.2807/1560-7917.ES.2021.26.49.2101070
Rivasi, G. et al. Course and lethality of SARS-CoV-2 epidemic in nursing homes after vaccination in Florence, Italy. Vaccines (Basel) 9, 1174 (2021). DOI: 10.3390/vaccines9101174
Faggiano, F. et al. An outbreak of COVID-19 among mRNA-vaccinated nursing home residents. Vaccines (Basel) 9, 859 (2021). DOI: 10.3390/vaccines9080859
McMichael, T. et al. Epidemiology of COVID-19 in a long-term care facility in King County, Washington. N. Engl. J. Med. 382, 2005–2011 (2020). DOI: 10.1056/NEJMoa2005412
World Health Organization. WHO criteria for COVID-19-related death. https://www.who.int/news-room/commentaries/detail/estimating-mortality-from-covid-19 (2020).
Aalto, U. L. et al. COVID-19 pandemic and mortality in nursing homes across USA and Europe up to October 2021. Eur. Geriatr. Med. 13, 705–709 (2022). DOI: 10.1007/s41999-022-00637-1
Mbalayen, F. et al. The COVID-19 pandemic and responses in nursing homes: a cross-sectional study in four European countries. Int. J. Environ. Res. Public Health 19, 15290 (2022). DOI: 10.3390/ijerph192215290
Menezes, S. M., Braz, M., Llorens-Rico, V., Wauters, J. & Van Weyenbergh, J. Endogenous IFNβ expression predicts outcome in critical patients with COVID-19. Lancet Microbe 2, e235–e236 (2021). DOI: 10.1016/S2666-5247(21)00063-X
Llorens-Rico, V. et al. Clinical practices underlie COVID-19 patient respiratory microbiome composition and its interactions with the host. Nat. Commun. 12, 6243 (2021). DOI: 10.1038/s41467-021-26500-8
Fukutani, K. F. et al. In situ immune signatures and microbial load at the nasopharyngeal interface in children with acute respiratory infection. Front. Microbiol. 9, 2475 (2018). DOI: 10.3389/fmicb.2018.02475
Lee, G. C. et al. Immunologic resilience and COVID-19 survival advantage. J. Allergy Clin. Immunol. 148, 1176–1191 (2021).
Chua, R. L. et al. COVID-19 severity correlates with airway epithelium–immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 38, 970–979 (2020). DOI: 10.1038/s41587-020-0602-4
Unterman, A. et al. Single-cell multi-omics reveals dyssynchrony of the innate and adaptive immune system in progressive COVID-19. Nat. Commun. 13, 440 (2022). DOI: 10.1038/s41467-021-27716-4
Yoo, J. S. et al. SARS-CoV-2 inhibits induction of the MHC class I pathway by targeting the STAT1-IRF1-NLRC5 axis. Nat. Commun. 12, 6602 (2021). DOI: 10.1038/s41467-021-26910-8
Vigón, L. et al. Impaired cytotoxic response in PBMCs from patients with COVID-19 admitted to the ICU: biomarkers to predict disease severity. Front. Immunol. 12, 665329 (2021). DOI: 10.3389/fimmu.2021.665329
Castro de Moura, M. et al. Epigenome-wide association study of COVID-19 severity with respiratory failure. EBioMedicine 66, 103339 (2021). DOI: 10.1016/j.ebiom.2021.103339
Zhang, Q. et al. Inborn errors of type I IFN immunity in patients with life-threatening COVID-19. Science 370, eabd4570 (2020). DOI: 10.1126/science.abd4570
Boudewijns, R. et al. STAT2 signaling restricts viral dissemination but drives severe pneumonia in SARS-CoV-2 infected hamsters. Nat. Commun. 11, 5838 (2020). DOI: 10.1038/s41467-020-19684-y
Goncalves, D. et al. Antibodies against type I interferon: detection and association with severe clinical outcome in COVID-19 patients. Clin. Transl. Immunol. 10, e1327 (2021). DOI: 10.1002/cti2.1327
Bastard, P. et al. Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1. J. Exp. Med. 218, e20210554 (2021). DOI: 10.1084/jem.20210554
Bastard, P. et al. Autoantibodies against type I IFNs in patients with life-threatening COVID-19. Science 370, eabd4585 (2020). DOI: 10.1126/science.abd4585
van der Wijst, M. G. P. et al. Type I interferon autoantibodies are associated with systemic immune alterations in patients with COVID-19. Sci. Transl. Med. 13, eabh2624 (2021). DOI: 10.1126/scitranslmed.abh2624
Zhang, Q., Bastard, P., COVID Human Genetic Effort, Cobat, A. & Casanova, J.-L.Human genetic and immunological determinants of critical COVID-19. Nature 603, 587–598 (2022). DOI: 10.1038/s41586-022-04447-0
Monk, P. D., Marsden, R. J. & Tear, V. J. Safety and efficacy of inhaled nebulised interferon beta-1a (SNG001) for treatment of SARS-CoV-2 infection: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir. Med. 9, 196–206 (2021). DOI: 10.1016/S2213-2600(20)30511-7
Alavi Darazam, I. et al. Role of interferon therapy in severe COVID-19: the COVIFERON randomized controlled trial. Sci. Rep. 11, 8059 (2021). DOI: 10.1038/s41598-021-86859-y
Kalil, A. C. et al. Efficacy of interferon beta-1a plus remdesivir compared with remdesivir alone in hospitalised adults with COVID-19: a double-bind, randomised, placebo-controlled, phase 3 trial. Lancet Respir. Med. 9, 1365–1376 (2021). DOI: 10.1016/S2213-2600(21)00384-2
Ader, F. et al. An open-label randomized controlled trial of the effect of lopinavir/ritonavir, lopinavir/ritonavir plus IFN-β-1a and hydroxychloroquine in hospitalized patients with COVID-19. Clin. Microbiol. Infect. 27, 1826–1837 (2021). DOI: 10.1016/j.cmi.2021.05.020
Vinh, D. C. et al. Harnessing type I IFN immunity against SARS-CoV-2 with early administration of IFN-β. J. Clin. Immunol. 41, 1425–1442 (2021). DOI: 10.1007/s10875-021-01068-6
Park, A. & Iwasaki, A. Type I and type III interferons—induction, signaling, evasion, and application to combat COVID-19. Cell Host Microbe 27, 870–878 (2020). DOI: 10.1016/j.chom.2020.05.008
Lopez, J. et al. Early nasal type I IFN immunity against SARS-CoV-2 is compromised in patients with autoantibodies against type I IFNs. J. Exp. Med. 218, e20211211 (2021). DOI: 10.1084/jem.20211211
Hu, H. et al. Increased circulating cytokines have a role in COVID-19 severity and death with a more pronounced effect in males: a systematic review and meta-analysis. Front. Pharmacol. 13, 802228 (2022). DOI: 10.3389/fphar.2022.802228
Van Weyenbergh, J., Wietzerbin, J., Rouillard, D., Barral-Netto, M. & Liblau, R. Treatment of multiple sclerosis patients with interferon-beta primes monocyte-derived macrophages for apoptotic cell death. J. Leukoc. Biol. 70, 745–748 (2001). DOI: 10.1189/jlb.70.5.745
Sancéau, J., Hiscott, J., Delattre, O. & Wietzerbin, J. IFN-β induces serine phosphorylation of Stat-1 in Ewing’s sarcoma cells and mediates apoptosis via induction of IRF-1 and activation of caspase-7. Oncogene 19, 3372–3383 (2000). DOI: 10.1038/sj.onc.1203670
Dierckx, T. et al. IFN-β induces greater antiproliferative and proapoptotic effects and increased p53 signaling compared with IFN-α in PBMCs of adult T-cell leukemia/lymphoma patients. Blood Cancer J. 7, e519 (2017). DOI: 10.1038/bcj.2016.126
Mavrikaki, M. et al. Severe COVID-19 is associated with molecular signatures of aging in the human brain. Nat. Aging 2, 1130–1137 (2022). DOI: 10.1038/s43587-022-00321-w
Leal, F. E. et al. Comprehensive antiretroviral restriction factor profiling reveals the evolutionary imprint of the ex vivo and in vivo IFN-β response in HTLV-1-associated neuroinflammation. Front. Microbiol. 9, 985 (2018). DOI: 10.3389/fmicb.2018.00985
Menezes, S. M. et al. CD80+ and CD86+ B cells as biomarkers and possible therapeutic targets in HTLV-1 associated myelopathy/tropical spastic paraparesis and multiple sclerosis. J. Neuroinflammation 11, 18 (2014). DOI: 10.1186/1742-2094-11-18
Bastard, P., Zhang, Q., Zhang, S. Y., Jouanguy, E. & Casanova, J. L. Type I interferons and SARS-CoV-2: from cells to organisms. Curr. Opin. Immunol. 74, 172–182 (2022). DOI: 10.1016/j.coi.2022.01.003
Hadjadj, J. et al. Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients. Science 369, 718–724 (2020). DOI: 10.1126/science.abc6027
Gómez-Carballa, A. et al. A multi-tissue study of immune gene expression profiling highlights the key role of the nasal epithelium in COVID-19 severity. Environ. Res. 210, 112890 (2022). DOI: 10.1016/j.envres.2022.112890
Pescarmona, R. et al. Comparison of RT–qPCR and NanoString in the measurement of blood interferon response for the diagnosis of type I interferonopathies. Cytokine 113, 446–452 (2019). DOI: 10.1016/j.cyto.2018.10.023
Khoo, S. H. et al. Optimal dose and safety of molnupiravir in patients with early SARS-CoV-2: a phase I, open-label, dose-escalating, randomized controlled study. J. Antimicrob. Chemother. 76, 3286–3295 (2021). DOI: 10.1093/jac/dkab318
Fischer, W. A. 2nd et al. A phase 2a clinical trial of molnupiravir in patients with COVID-19 shows accelerated SARS-CoV-2 RNA clearance and elimination of infectious virus. Sci. Transl. Med. 14, eabl7430 (2022). DOI: 10.1126/scitranslmed.abl7430
Abdelnabi, R. et al. Molnupiravir inhibits replication of the emerging SARS-CoV-2 variants of concern in a hamster infection model. J. Infect. Dis. 224, 749–753 (2021). DOI: 10.1093/infdis/jiab361
Sun, F., Lin, Y., Wang, X., Gao, Y. & Ye, S. Paxlovid in patients who are immunocompromised and hospitalised with SARS-CoV-2 infection. Lancet Infect. Dis. 22, 1279 (2022). DOI: 10.1016/S1473-3099(22)00430-3
Najjar-Debbiny, R. et al. Effectiveness of paxlovid in reducing severe COVID-19 and mortality in high risk patients. Clin. Infect. Dis. 76, e342–e349 (2023).
Saravolatz, L. D., Depcinski, S. & Sharma, M. Molnupiravir and nirmatrelvir–ritonavir: oral COVID antiviral drugs. Clin. Infect. Dis. 76, 165–171 (2023).
Our World in Data. Coronavirus (COVID-19) Vaccinations. https://ourworldindata.org/covid-vaccinations
Smith, D. J. et al. COVID-19 mortality and vaccine coverage—Hong Kong Special Administrative Region, China, January 6, 2022–March 21, 2022. MMWR Morb. Mortal. Wkly Rep. 71, 545–548 (2022). DOI: 10.15585/mmwr.mm7115e1
Freed, N. E., Vlkova, M., Faisal, M. B. & Silander, O. K. Rapid and inexpensive whole-genome sequencing of SARS-CoV-2 using 1200 bp tiled amplicons and Oxford Nanopore Rapid Barcoding. Biol. Methods Protoc/ 5, bpaa014 (2020). DOI: 10.1093/biomethods/bpaa014
Minh, B. Q. et al. IQ-TREE 2: new models and efficient methods for phylogenetic inference in the genomic era. Mol. Biol. Evol. 37, 1530–1534 (2020). DOI: 10.1093/molbev/msaa015
Tavaré, S. Some probabilistic and statistical problems in the analysis of DNA sequences. Lectures Math. Life Sci. 17, 57–86 (1986).
Sagulenko, P., Puller, V. & Neher, R. A. TreeTime: maximum-likelihood phylodynamic analysis. Virus Evol. 4, vex042 (2018). DOI: 10.1093/ve/vex042
