Background:The impact of the emergence of SARS-CoV-2 variants on the severity and
clinical outcomes of COVID-19 is controversial. Preliminary studies estimated that the
probability of death associated with variant of concern (VOC) B.1.1.7, the UK variant, is
55% higher than that associated with pre-existing variants. However, no difference has
been found in another study. In Brazil, infection with VOC P1 has been suggested to be
associated with an increased case fatality rate in young adults. The effect of other
"variants of concern" (Beta, B.1.351; Delta, B.1.617.2, or the most recent Omicron
variants) or "variants of interest" (A27, B.1.525, etc.) on the severity of the disease
and the prognosis of severe forms is unknown. More generally, whether virological
characteristics including the mutational patterns of the different viral proteins (e.g.,
Spike, NSP proteins, ORF6) could be associated with a different immune response and
subsequent severity of the disease is unknown. ln the next coming months, new variants
carrying the same or new mutational patterns will continue to emerge in different
geographic areas, as a result of the collective immune pressure induced by natural
infection and vaccination. Monitoring their dynamics over time and their impact on
disease severity is required for refining national and international disease control
policies.

In this project, a large prospective multicenter observational cohort promoted by the
Assistance Publique-Hôpitaux de Paris (AP-HP) will be conducted, to understand the effect
of SARS-CoV-2 genetic variability on the outcome of COVID-19 disease in patients with
severe illness. The study will include critically ill patients hospitalized for acute
respiratory failure/acute respiratory distress syndrome (ARDS) associated with COVID-19.
The objective of the work will be to characterize the SARS-CoV-2 variants found in this
population over time, and to identify and phenotypically characterize specific
mutations/mutational patterns associated with the different clinical outcomes (primary
clinical endpoint defined as mortality at day-28). The impact of the mutations on viral
infectivity, sensitivity to neutralizing antibodies and ability to induced cytokine
production will be assessed in vitro and ex-vivo respectively, in appropriate models
available in the laboratory. Further to full-length viral genome sequencing, our in-house
shotgun metagenomics method will be used to characterize the effect of SARS-CoV-2
variations on respiratory transcriptomic expression profiles and the relationship with
the clinical evolutionary profiles.

Design of the study Prospective multicentre observational cohort study

Main objective: To unravel the relationships between specific viral mutations/mutational
patterns and the clinical outcomes of COVID-19 in patients hospitalized in intensive care
units (ICUs) for acute respiratory failure following severe SARS-CoV-2 infection.

Schedule for the study: Inclusion period: 24 months; Participation period: 28 days ;
Total duration : 24 months + 28 days;