SARS-CoV-2 genomic evolution during a severe and long-lasting omicron infection under antiviral therapy

Prolonged SARS-CoV-2 infection observed in immunocompromised individuals even in the presence of antiviral treatment provides opportunities for viruses to evolve in immune escape and drug-resistant variants.

A 72-year-old male with IgG4-related disease was admitted to the Emergency Department of a city Hospital in Milan and then transferred to Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico in December 2023, due to respiratory distress due to SARS-CoV-2 infection diagnosed in November 2023. After 117 days since the onset of the infection, and two cycles of sotrovimab/remdesivir combined therapy, the clinical improvement allowed the hospital discharge, notwithstanding the persistent SARS-CoV-2 positivity. Fifteen days later, the patient was re-admitted to the hospital due to worsening clinical conditions. After a third cycle of sotrovimab/remdesivir combined therapy prolonged with nirmatrelvir/ritonavir, nasopharyngeal load dropped and clinical conditions improved, ending with a successful discharge. SARS-CoV-2 whole genome sequences, obtained at six time-points of infection, showed an FL.1.5.1 recombinant form infection and a genetic distance of median (IQR) 0.00052 (0.00041-0.00066) similar to the genetic distance observed among the 43 contemporaneous FL.1.5.1 recombinant forms (p = 0.098). De novo SNPs were observed at all time points, with a peak (n = 70) at day 133 of infection, corresponding to the time of the second hospitalization. Six non-synonymous mutations (three in the RdRp and three in the spike protein, four of them known to be associated with drug resistance) appeared transiently, after the third and fourth course of sotrovimab 500 mg/remdesivir combination. Five de novo SNPs, three of them in the spike protein, were fixed over the long-lasting infection. The spike N856K, associated with reduced fusogenicity and infectivity in Omicron BA.1, was completely replaced by constitutive N at day 136.

This clinical case confirms the intra-host evolution dynamics of SARS-CoV-2 in an immunocompromised, prolonged-infected individual, involving positions associated with drug resistance and fusogenic traits of SARS-CoV-2. These results underscore the importance of the early detection of SARS-CoV-2 infection in immunocompromised individuals, and its rapid containment using highly effective treatment, to limit serious complications and the risk of new and potentially concerning viral variants emergence.