SARS-CoV-2: Chronic Infection and Variants of Concern

Updated August 11, 2023

3 DEC 2020: Persistence and Evolution of SARS-CoV-2 in an Immunocompromised Host (NEJM)
“Phylogenetic analysis was consistent with persistent infection and accelerated viral evolution. Amino acid changes were predominantly in the spike gene and the receptor-binding domain, which make up 13% and 2%” 

5 FEB 2021: SARS-CoV-2 evolution during treatment of chronic infection (Nature)
“These data reveal strong selection on SARS-CoV-2 during convalescent plasma therapy, which is associated with the emergence of viral variants that show evidence of reduced susceptibility to neutralizing antibodies in immunosuppressed individuals.”

5 MAY 2021: Researchers Tie Severe Immunosuppression to Chronic COVID-19 and Virus Variants (JAMA)

27 JUN 2021: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Sequence Characteristics of Coronavirus Disease 2019 (COVID-19) Persistence and Reinfection (Clinical Infectious Diseases)
”Patients with persistent coronavirus disease 2019 (COVID-19) demonstrated more rapid accumulation of sequence changes than seen with community-driven evolution with continued evolution during convalescent plasma or monoclonal antibody treatment.”

26 AUG 2021: The continuous evolution of SARS-CoV-2 in South Africa: a new lineage with rapid accumulation of mutations of concern and global detection (medRxiv preprint)
“Like several other VOCs, C.1.2 has accumulated a number of substitutions beyond what would be expected from the background SARS-CoV-2 evolutionary rate. This suggests the likelihood that these mutations arose during a period of accelerated evolution in a single individual with prolonged viral infection through virus-host co-evolution.” 

19 OCT 2021: A cancer survivor had the longest documented COVID-19 infection. Here’s what scientists learned (Science)
PREPRINT: Year-long COVID-19 infection reveals within-host evolution of SARS-CoV-2 in a patient with B cell depletion (medRxiv)
“The unique viral mutations found in this study highlight the importance of analyzing viral evolution in protracted SARS-CoV-2 infection, especially in immunosuppressed hosts, and the implication of these mutations in the emergence of viral variants.” 

7 DEC 2021: Emergence of SARS-CoV-2 resistance mutations in a patient who received anti-SARS-COV2 spike protein monoclonal antibodies: a case report (BMC Infectious Diseases)
“We here report the case of an immunosuppressed patient infected with a B.1.1.7 variant, who received a combination of monoclonal antibodies, and subsequently selected mutations K417N, E484K and Q493R on Spike protein of SARS-CoV-2.”

7 DEC 2021: De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: A case report (medRxiv preprint)
”In summary, we identified the de novo emergence of a RDV-resistance mutation, E802D, following initiation of RDV in an immunocompromised patient with persistent SARS-CoV-2 infection. While the finding is limited to a single case and requires confirmation of its generalizability in larger patient populations, it suggests that RDV may impart a selective pressure in vivo to drive evolution of the virus.”

7 DEC 2021: SARS-CoV-2 evolved during advanced HIV disease immunosuppression has Beta-like escape of vaccine and Delta infection elicited immunity (medRxiv preprint)
“What surprised us in the participant with prolonged infection was that, over the 6-month period where SARS-CoV-2 titer was high, infection was for the most part asymptomatic. One explanation is that the virus evolved attenuated pathogenicity or had low pathogenicity to begin with. Another may that high pathogen levels over time are tolerated because immunosuppression reduces the inflammatory response.”

28 JAN 2022: Persistent SARS-CoV-2 Infection with Accumulation of Mutations in a Patient with Poorly Controlled HIV Infection (SSRN)
“A 22-year-old female with uncontrolled advanced HIV infection was persistently infected with SARS-CoV-2 beta variant for 9 months, the virus accumulating >20 additional mutations.”

3 MAR 2022: Emergence of Progressive Mutations in SARS-CoV-2 From a Hematologic Patient With Prolonged Viral Replication (frontiers in Microbiology)
”We documented a hematologic patient with prolonged SARS-CoV-2 viral replication in whom emergence of viral mutations was documented after the consecutive use of antivirals and convalescent plasma.The virus detected in the last of 12 clinical samples (day 237) had accumulated 22 changes in amino acids and 29 in nucleotides. Some of these changes, such as the E484Q, were mutations of concern as defined by WHO. This finding represents an enormous epidemiological threat and poses a major clinical challenge.”

9 MAR 2022: Resistance Mutations in SARS-CoV-2 Delta Variant after Sotrovimab Use (NEJM Letter to Editor)
“These data show the persistence of viable SARS-CoV-2 in patients after sotrovimab infusions and the rapid development of spike gene mutations associated with high-level sotrovimab resistance in vitro. These findings underscore the importance of stewardship of monoclonal antibodies, particularly because sotrovimab is one of the few monoclonal antibodies with retained activity against the B.1.1.529 (omicron) variant”

17 MAR 2022: De novo emergence of a remdesivir resistance mutation during treatment of persistent SARS-CoV-2 infection in an immunocompromised patient: a case report (Nature Communications)
“We present a case of an immunocompromised patient with acquired B-cell deficiency who developed an indolent, protracted course of SARS-CoV-2 infection. Remdesivir therapy alleviated symptoms and produced a transient virologic response, but her course was complicated by recrudescence of high-grade viral shedding.” 

6 APR 2022: High incidence of sotrovimab resistance and viral persistence after treatment of immunocompromised patients infected with the SARS-CoV-2 Omicron variant (medRxiv preprint)
“Viral evolution towards resistance against sotrovimab can explain treatment failure in most immunocompromised patients and these patients can remain infectious after treatment. Therefore, documenting viral clearance after treatment is recommended to avoid that these patients unintentionally become a source of new, sotrovimab resistant, variants.”  

20 JUN 2022: Drivers of adaptive evolution during chronic SARS-CoV-2 infections (Nature)
We found evidence for dynamic polymorphic viral populations in most patients, suggesting that a compromised immune system selects for antibody evasion in particular niches in a patient’s body. We suggest that a tradeoff exists between antibody evasion and transmissibility and that extensive monitoring of chronic infections is necessary to further understanding of VOC emergence.”
Article from GenEngNews:

25 NOV 2022: SARS-CoV-2 evolution, post-Omicron (
“we hypothesise that these ‘complex’ recombinants, like the saltation variants, have emerged from chronic infections. In the case of XAY, XBA, XBC, and XAW, these likely arose from chronic infections where the individual was initially infected by Delta and subsequently superinfected with BA.2.”
Author Explains:

30 NOV 2022: SARS-CoV-2 evolves increased infection elicited cell death and fusion in an immunosuppressed individual (medRxiv preprint)
“We assayed a virus isolated from early in the course of infection at day 6 post-diagnosis, at day 190 post-diagnosis, as well as at the intermediate timepoints. The day 6 isolate already evolved a considerable number of mutations, or alternatively, the infecting virus was mutated. Between day 6 and day 190 post-diagnosis, the infection evolved immune escape from neutralizing antibodies, consistent with what is observed in long-term SARS-CoV-2 infections in individuals with immunosuppression24. However, the ability of the virus to induce cell fusion and cell death upon infection also changed through the course of evolution. While the early viral isolate induced lower cell fusion and death compared to ancestral virus, induction of fusion and cell death increased with evolution”

28 JUN 2023: Identification of a molnupiravir-associated mutational signature in SARS-CoV-2 sequencing databases (medRxiv preprint)
“if some patients treated with molnupiravir do not fully clear SARS-CoV-2 infections, there could be the potential for onward transmission of molnupiravir-mutated viruses.”