Yearlong COVID-19 Infection Reveals Within-Host Evolution of SARS-CoV-2 in a Patient With B-Cell Depletion

Nussenblatt, Véronique; Roder, Allison; Das, Sanchita; Wit, Emmie de; Youn, Jung-Ho; Banakis, Stephanie; Mushegian, Alexandra; Mederos, Christopher; Wang, Wei; Chung, Matthew; Pérez-Pérez, Lizzette; Palmore, Tara N.; Brudno, Jennifer N.; Kochenderfer, James N.; Ghedin, Elodie

doi:10.1093/infdis/jiab622

Cited by 73 publications

(57 citation statements)

References 27 publications

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“…Moreover, a strong selection on SARS-CoV-2 has been reported after convalescent plasma therapy in immunosuppressed individuals, leading to the emergence of viral variants with reduced susceptibility to neutralizing antibodies [12,21,22,32]. Interestingly, the presence of mutations was more frequently observed in samples of days 143 and 207 compared to the earliest available one, and it led to the identification of multiple intra-host microevolution pathways considering the 7-month period of infection.…”

Section: Discussionmentioning

confidence: 99%

Long-term SARS-CoV-2 Asymptomatic Carriage in an Immunocompromised Host: Clinical, Immunological, and Virological Implications

et al. 2022

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Purpose SARS-CoV-2 infection in immunocompromised hosts is challenging, and prolonged viral shedding can be a common complication in these patients. We describe the clinical, immunological, and virological course of a patient with eosinophilic granulomatosis with polyangiitis, who developed the status of long-term asymptomatic SARS-CoV-2 carrier for more than 7 months. Methods Over the study period, the patient underwent 20 RT-PCR tests for SARS-CoV-2 detection on nasopharyngeal swabs. In addition, viral cultures and genetic investigation of SARS-CoV-2 were performed. As for immunological assessment, serological and specific T-cell testing was provided at different time points. Results Despite the patient showing a deep drug-induced B and T adaptive immunity impairment, he did not experience COVID-19 progression to severe complications, and the infection remained asymptomatic during the follow-up period, but he was not able to achieve viral clearance for more than 7 months. The infection was finally cleared by SARS-CoV-2-specific monoclonal antibody treatment, after that remdesivir and convalescent plasma failed in this scope. The genetic investigations evidenced that the infection was sustained by multiple viral subpopulations that had apparently evolved intra-host during the infection. Conclusion Our case suggests that people with highly impaired B- and T-cell adaptive immunity can prevent COVID-19 progression to severe complications, but they may not be able to clear SARS-CoV-2 infection. Immunocompromised hosts with a long-term infection may play a role in the emergence of viral variants.

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Section: Discussionmentioning

confidence: 99%

Long-term SARS-CoV-2 Asymptomatic Carriage in an Immunocompromised Host: Clinical, Immunological, and Virological Implications

et al. 2022

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“…This appears to differ from the observations of Al Khatib et al who reported increased numbers of biallelic subconsensus variants (indicating AAF:RAF mixtures) in individuals classified as severe cases compared to individuals with mild cases [30] with comorbidities similar to the IM- patients studied here. It is also important to acknowledge that we were not able to study single patients over extended time series known to have extended for up to one year by other investigators [46]. Therefore, we did not have the opportunity to compare potential evolution of SARS-CoV-2 variants within individual IM+ and IM- patients over time.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, given reports that have suggested evolution of complexed populations of SARS-CoV-2 in immunocompromised people [44][45][46][47], we were interested to compare infections between IM+ and IM-individuals. While normalizing for overall complexity by comparing infections that occurred within time-similar cohorts, we did not observe increased numbers of iSNVs in IMpatients.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, given published reports of extensive SARS-CoV-2 sequence diversity in association with infected immunocompromised (IM-) individuals [44][45][46][47], we have evaluated the complexity of SARS-CoV-2 sequence in the context of the immunological conditions of the infected individuals in our study. Because the infections studied included asymptomatic individuals and those who receive primary care outside the VA Northeast Ohio Healthcare System, it was not possible to conduct a complete association study on this focus.…”

Section: Association Between Immunological Competence and Sars-cov-2 ...mentioning

confidence: 99%

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COVID-19 Infection and Transmission Includes Complex Sequence Diversity

Chan

Jones

Linger

et al. 2022

Preprint

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SARS-CoV-2 whole genome sequencing has played an important role in documenting the emergence of polymorphisms in the viral genome and its continuing evolution during the COVID-19 pandemic. Here we present data from over 360 patients to characterize the complex sequence diversity of individual infections identified during multiple variant surges (e.g., Alpha and Delta; requiring ≥ 80% genome coverage and ≥100X read depth). Across our survey, we observed significantly increasing SARS-CoV-2 sequence diversity during the pandemic and frequent occurrence of multiple biallelic sequence polymorphisms in all infections. This sequence polymorphism shows that SARS-CoV-2 infections are heterogeneous mixtures. Convention for reporting microbial pathogens guides investigators to report a majority consensus sequence. In our study, we found that this approach would under-report at least 79% of the observed sequence variation. As we find that this sequence heterogeneity is efficiently transmitted from donors to recipients, our findings illustrate that infection complexity must be monitored and reported more completely to understand SARS-CoV-2 infection and transmission dynamics involving both immunocompetent and immunocompromised patients. Many of the nucleotide changes that would not be reported in a majority consensus sequence have now been observed as lineage defining SNPs in Omicron BA.1 and/or BA.2 variants. This suggests that minority alleles in earlier SARS-CoV-2 infections may play an important role in the continuing evolution of new variants of concern.AUTHOR SUMMARYEvolution of the virus causing COVID-19 (SARS-CoV-2) has been associated with significant transmission surges. With evolution of SARS-CoV-2, evidence has accumulated regarding increased transmissibility of lineages, varying severity of illness, evasion of vaccines and diagnostic tests. Continuous tracking of SARS-CoV-2 lineage evolution distills very large and complex viral sequence data sets down to consensus sequences that report the majority nucleotide at each of over 29,000 positions in the SARS-CoV-2 genome. We observe that this eliminates considerable sequence variation and leads to a significant underestimation of SARS-CoV-2 infection diversity and transmission complexity. Additionally, concentration on the majority consensus sequence diverts attention from genetic variation that may contribute significantly to the continuing evolution of the COVID-19 pandemic.

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“…Major deletions and loss of function mutations in accessory proteins are not uncommon 29 . Such mutations have been documented in immunocompromised patients and are generally associated with milder symptoms 30 . The accessory protein mutations emerging in this case are specific to residues of functional domains, implying a more nuanced effect, rather than more general loss of function mutations.…”

Section: Mutations In Immunomodulatory Viral Proteins and Their Predi...mentioning

confidence: 99%

SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient

Shapira

Weiner

Sorek-Abramovich

et al. 2022

Preprint

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Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in immunocompromised patients may lead to accelerated viral mutation rate, immune evasion and persistent viral shedding over many months. Here we report the case of a severely immunocompromised cancer patient infected with the Delta variant of SARS-CoV-2 for over 8 months. Genome sequencing of samples taken after repeated monoclonal antibody treatments reveal the emergence and accumulation of mutations enabling escape from neutralization by antibodies. Mutations emerging in accessory and non-structural viral proteins target specific residues of immunomodulatory domains, potentially leading to loss of some functions, while preserving others. The mutated virus managed to completely overcome neutralization by monoclonal antibodies while remaining viable and infective. Our results suggest that the loss of specific immunomodulatory viral functions might confer a selective advantage in immunocompromised hosts. We also compare between mutations emerging in the presence and absence of neutralizing antibodies.

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Yearlong COVID-19 Infection Reveals Within-Host Evolution of SARS-CoV-2 in a Patient With B-Cell Depletion

Cited by 73 publications

References 27 publications

Long-term SARS-CoV-2 Asymptomatic Carriage in an Immunocompromised Host: Clinical, Immunological, and Virological Implications

Long-term SARS-CoV-2 Asymptomatic Carriage in an Immunocompromised Host: Clinical, Immunological, and Virological Implications

COVID-19 Infection and Transmission Includes Complex Sequence Diversity

SARS-CoV-2 evolution and evasion from multiple antibody treatments in a cancer patient

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