An In-Depth Characterization of SARS-CoV-2 Omicron Lineages and Clinical Presentation in Adult Population Distinguished by Immune Status

This retrospective study analyzed SARS-CoV-2 Omicron variability since its emergence, focusing on immunocompromised (IPs) and non-immunocompromised adult people (NIPs). Phylogenetic analysis identified at least five major Omicron lineage groups circulating in Central Italy, from December 2021 to December 2023: (a) BA.1 (34.0%), (b) BA.2 + BA.4 (25.8%), (c) BA.5 + BF (10.8%), (d) BQ + BE + EF (9.2%), and (e) Recombinants (20.2%). The BA.2 + BA.4 lineages were more common in IPs compared to NIPs (30.9% vs. 17.8%, respectively; <i>p</i> = 0.011); conversely, Recombinants were less prevalent in IPs than in NIPs (16.0% vs. 27.1%, respectively; <i>p</i> = 0.018). High-abundant single nucleotide polymorphisms (SNPs; prevalence ≥ 40%) and non-synonymous SNPs (prevalence ≥ 20%) increased during the emergence of new variants, rising from BA.1 to Recombinants (54 to 92, and 43 to 70, respectively, both <i>p</i> < 0.001). Evaluating the genetic variability, 109 SNPs were identified as being involved in significant positive or negative associations in pairs (phi > 0.70, <i>p</i> < 0.001), with 19 SNPs associated in 3 distinct clusters (bootstrap > 0.96). Multivariate regression analysis showed that hospitalization was positively associated with one specific cluster, including S686R and A694S in Spike and L221F in Nucleocapsid (AOR: 2.74 [95% CI: 1.13-6.64, <i>p</i> = 0.025]), and with increased age (AOR:1.03 [95% CI: 1.00-1.06], <i>p</i> = 0.028). Conversely, negative associations with hospitalization were observed for female gender and previous vaccination status (AORs: 0.34 [95% CI: 0.14-0.83], <i>p</i> = 0.017 and 0.19 (95% CI: 0.06-0.63, <i>p</i> = 0.006, respectively). Interestingly, the S686R SNP located in a furin cleavage site suggests its potential pathogenetic role. The results show how Omicron genetic diversification significantly influences disease severity and hospitalization, together with age, sex, and vaccination status as key factors.