Immunovirological and environmental screening reveals actionable risk factors for fatal COVID-19 during post-vaccination nursing home outbreaks

Abstract

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.

Emergence of the B.1.214.2 SARS-CoV-2 lineage with an Omicron-like spike insertion and a unique upper airway immune signature

“…Conversely, we observed a reduction in innate Natural Killer (NK) cells and Th17 differentiation, alongside a decrease in complement system genes, without affecting MHC class I antigen presentation. This pattern diverges from previous ndings in other nursing home COVID-19 outbreaks 11 and broader cohorts [44][45][46] .…”

“…Finally, taking advantage of our nationwide surveillance of SARS-CoV-2 nursing home outbreaks, we unveil a moderately severe clinical phenotype in high-risk elderly with an 8.7% case fatality ratio, which is lower than the 20-35% case fatality ratio we observed in other post-vaccine nursing home outbreaks with Gamma, Delta and Mu variants 11 . This clinical phenotype might be explained by systemic broad cross-neutralizing antibodies combined with a novel and distinct upper respiratory tract immune signature in B.1.214.2-infected nursing home residents, as compared to other high-fatality (> 10%) postvaccine outbreaks with Delta, Gamma and Mu variants.…”

“…This clinical phenotype might be explained by systemic broad cross-neutralizing antibodies combined with a novel and distinct upper respiratory tract immune signature in B.1.214.2-infected nursing home residents, as compared to other high-fatality (> 10%) postvaccine outbreaks with Delta, Gamma and Mu variants. Noteworthy limitations of this study include the absence of SARS-CoV-2 aerosol detection during the outbreak, which we recently demonstrated as a useful marker of long-lasting exposure in other nursing home outbreaks 11 . However, the high attack rate (53.5%), the long duration of the outbreak (> 4 weeks), and the detection of PCR-positive residents on all three oors of the nursing home strongly suggest high exposure in all residents, including the PCRnegatives.…”

“…7A) between residents infected after the rst or second vaccination dose. Leveraging our nationwide surveillance effort, neutralizing antibody levels in this outbreak were compared to those in a similar-sized outbreak caused by the Mu variant 11 , showing no signi cant differences in immune response, despite the presence of cross-neutralizing antibodies (Figs. 7A and 7B).…”

“…Despite Delta replacing all other circulating strains of SARS-CoV-2 in early summer 2021, our group recently demonstrated that co-circulating non-dominant variants of concern (Gamma) and even variants of interest (Mu) were able to cause high-fatality outbreaks in high-risk elderly, even when fully vaccinated 11 . In addition, Delta, Gamma, and Mu nursing home outbreaks revealed a fatal immune signature, characterized by an increase in Th17 activation and high IFNB1 transcript levels but no difference in type I IFN signalization 11 accounted for over 50% of the sequenced cases 8 . Therefore, a thorough investigation of the phylogeographic origin and immune characteristics of this variant was warranted.…”