Identification of driver genes for severe forms of COVID-19 in a deeply phenotyped young patient cohort (preprint)

The etiopathogenesis of severe COVID-19 remains unknown. Indeed given major confounding factors (age and co-morbidities), true drivers of this condition have remained elusive. Here, we employ an unprecedented multi-omics analysis, combined with artificial intelligence, in a young patient cohort where major co-morbidities have been excluded at the onset. Here, we established a three-tier cohort of individuals younger than 50 years without major comorbidities. These included 47 "critical" (in the ICU under mechanical ventilation) and 25 "non-critical" (in a noncritical care ward) COVID-19 patients as well as 22 healthy individuals. The analyses included whole-genome sequencing, whole-blood RNA sequencing, plasma and blood mononuclear cells proteomics, cytokine profiling and high-throughput immunophenotyping. An ensemble of machine learning, deep learning, quantum annealing and structural causal modeling led to key findings. Critical patients were characterized by exacerbated inflammation, perturbed lymphoid/myeloid compartments, coagulation and viral cell biology. Within a unique gene signature that differentiated critical from noncritical patients, several driver genes promoted severe COVID-19 among which the upregulated metalloprotease ADAM9 was key. This gene signature was replicated in an independent cohort of 81 critical and 73 recovered COVID-19 patients, as were ADAM9 transcripts, soluble form and proteolytic activity. Ex vivo ADAM9 inhibition affected SARS-CoV-2 uptake and replication in human lung epithelial cells. In conclusion, within a young, otherwise healthy, COVID-19 cohort, we provide the landscape of biological perturbations in vivo where a unique gene signature differentiated critical from non-critical patients. The key driver, ADAM9, interfered with SARS-CoV-2 biology. A repositioning strategy for anti-ADAM9 therapeutic is feasible. One sentence summaryEtiopathogenesis of severe COVID19 in a young patient population devoid of comorbidities.

Evolution of human antibody responses up to one year after SARS-CoV-2 infection (preprint)

Assessment of the kinetics of SARS-CoV-2 antibodies is essential to predict protection against reinfection and durability of vaccine protection. Here, we longitudinally measured Spike (S) and Nucleocapsid (N)-specific antibodies in 1,309 healthcare workers (HCW) including 393 convalescent COVID-19 and 916 COVID-19 negative HCW up to 405 days. From M1 to M7-9 after infection, SARS-CoV-2 antibodies decreased moderately in convalescent HCW in a biphasic model, with men showing a slower decay of anti-N (p=0.02), and a faster decay of anti-S (p=0.0008) than women. At M11-13, anti-N antibodies dramatically decreased (half-life: 210 days) while anti-S stabilized (half-life: 630 days) at a median of 2.41 log Arbitrary Units (AU)/mL (Interquartile Range (IQR): 2.11 -2.75). One case of reinfection was recorded in convalescent HCW (0.47 per 100 person-years) versus 50 in COVID-19 negative HCW (10.11 per 100 person-years). Correlation with live-virus neutralization assay revealed that variants D614G and B.1.1.7, but not B.1.351, were sensitive to anti-S antibodies at 2.3 log AU/mL, while IgG [≥] 3 log AU/mL neutralized all three variants. After SARS-CoV-2 vaccination, anti-S levels reached 4 logs regardless of pre-vaccination IgG levels, type of vaccine, and number of doses. Our study demonstrates a long-term persistence of anti-S IgG antibodies that may protect against reinfection. By significantly increasing cross-neutralizing antibody titers, a single-dose vaccination strengthens protection against escape mutants.

Sex differences in the decline of neutralizing antibodies to SARS-CoV-2 (preprint)

The evolution of SARS-CoV-2 humoral response in infected individuals remains poorly characterized. Here, we performed a longitudinal study of sera from 308 RT-qPCR+ individuals with mild disease, collected at two time-points, up to 6 months post-onset of symptoms (POS). We performed two anti-S and one anti-N serology assays and quantified neutralizing antibodies (NAbs). At month 1 (M1), males, individuals > 50 years of age or with a body mass index (BMI) > 25 exhibited higher levels of antibodies. Antibody levels decreased over time. At M3-6, anti-S antibodies persisted in 99% of individuals while anti-N IgG were measurable in only 59% of individuals. The decline in anti-S and NAbs was faster in males than in females, independently of age and BMI. Our results show that some serology tests are less reliable overtime and suggest that the duration of protection after SARS-CoV-2 infection or vaccination will be different in women and men.