Chronic SARS-CoV-2 infection and viral evolution in a hypogammaglobulinaemic individual

Abstract

There is widespread interest in the capacity for SARS-CoV-2 evolution in the face of selective pressures from host immunity, either naturally acquired post-exposure or from vaccine acquired immunity. Allied to this is the potential for long perm persistent infections within immune compromised individuals to allow a broader range of viral evolution in the face of sub-optimal immune driven selective pressure. Here we report on an immunocompromised individual who is hypogammaglobulinaemic and was persistently infected with SARS-CoV-2 for over 290 days, the longest persistent infection recorded in the literature to date. During this time, nine samples of viral nucleic acid were obtained and analysed by next-generation sequencing. Initially only a single mutation (L179I) was detected in the spike protein relative to the prototypic SARS-CoV-2 Wuhan-Hu-1 isolate, with no further changes identified at day 58. However, by day 155 the spike protein had acquired a further four amino acid changes, namely S255F, S477N, H655Y and D1620A and a two amino acid deletion (ΔH69/ΔV70). Infectious virus was cultured from a nasopharyngeal sample taken on day 155 and next-generation sequencing confirmed that the mutations in the virus mirrored those identified by sequencing of the corresponding swab sample. The isolated virus was susceptible to remdesivir in vitro, however a 17-day course of remdesivir started on day 213 had no effect on the viral RT-PCR cycle threshold (Ct) value. On day 265 the patient was treated with the combination of casirivimab and imdevimab. The patient experienced progressive resolution of all symptoms over the next 8 weeks and by day 311 the virus was no longer detectable by RT-PCR. The ΔH69/ΔV70 deletion in the N-terminus of the spike protein which arose in our patient is also present in the B.1.1.7 variant of concern and has been associated with viral escape mutagenesis after treatment of another immunocompromised patient with convalescent plasma. Our data confirms the significance of this deletion in immunocompromised patients but illustrates it can arise independently of passive antibody transfer, suggesting the deletion may be an enabling mutation that compensates for distant changes in the spike protein that arise under selective pressure.

COVID-19 and X-linked agammaglobulinemia (XLA) – insights from a monogenic antibody deficiency

“…Recent analysis of a second immunocompromised adult with hypogammaglobulinaemia and SARS-CoV-2 infection for over 290 days has subsequently demonstrated similar viral escape mutations can also arise independently of CPT [41 ▪▪ ]. In this instance, following failure of remdesivir, treatment with the combination of casirivimab and imdevimab at day 265 achieved progressive resolution of all symptoms over the next 8 weeks, and clearance by RT-PCR was achieved by day 311 [41 ▪▪ ].…”

“…Performing phylogenetic analysis on ultra-deep whole-genome sequential sequencing on samples from a chronically infected immunosuppressed individual with SARS-CoV-2, they showed CPT was accompanied by viral evolution and reduced sensitivity to neutralizing antibodies [40 ▪▪ ]. Recent analysis of a second immunocompromised adult with hypogammaglobulinaemia and SARS-CoV-2 infection for over 290 days has subsequently demonstrated similar viral escape mutations can also arise independently of CPT [41 ▪▪ ]. In this instance, following failure of remdesivir, treatment with the combination of casirivimab and imdevimab at day 265 achieved progressive resolution of all symptoms over the next 8 weeks, and clearance by RT-PCR was achieved by day 311 [41 ▪▪ ].…”

The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK

“…There are a number of studies on chronically or persistently infected individuals which contain longitudinal sampling of the viruses present (Avanzato et al 2020;Choi et al 2020;Clark et al 2021;Karim et al 2021;Kemp et al 2021;Ramírez et al 2021;Stanevich et al 2021;Voloch et al 2020;Weigang et al 2021;Williamson et al 2021). Across these studies, there were an average of 4.0 (95% confidence interval: 0.63 to 9.76) evolutionary events (i.e.…”

“…Start of infection was taken to be the start of symptoms or the date of the first positive PCR test depending on what was available for each study. End of infection was the date of the final negative PCR test in the study (Avanzato et al 2020;Karim et al 2021;Stanevich et al 2021;Voloch et al 2020;Weigang et al 2021;Williamson et al 2021), death (Choi et al 2020) or when the individual was lost to follow up (Ramírez et al 2021).…”

The network of SARS-CoV-2—cancer molecular interactions and pathways

“…Nonetheless, well-known oncogenic viruses like HPV typically establish long-term infections, but there is no evidence of long-term viral latency of SARS-CoV-2 [6]. Exceptions to this are immunodeficient individuals, such as some cancer patients, who are at risk of rapid viral evolution and prolonged infection [23,24]. Long-term infections in these patients represent a source of variation for the virus that aids intra -host and inter -host transmission [25], and requires additional mitigation strategies such as self-isolation, immunization, combination monoclonal antibodies and antiviral agents.…”