SARS-CoV-2 shedding and evolution in immunocompromised hosts during the Omicron period: a multicenter prospective analysis

Raglow, Zoe; Surie, Diya; Chappell, James D.; Zhu, Yuwei; Martin, Emily T.; Kwon, Jennie H.; Frosch, Anne E.; Mohamed, Amira; Gilbert, Julie; Bendall, Emily E.; Bahr, Auden; Halasa, Natasha; Talbot, H. Keipp; Grijalva, Carlos G.; Baughman, Adrienne; Womack, Kelsey N.; Johnson, Cassandra; Swan, Sydney A.; Koumans, Emilia; McMorrow, Meredith L.; Harcourt, Jennifer L.; Atherton, Lydia J.; Burroughs, Ashley; Thornburg, Natalie J.; Self, Wesley H.; Lauring, Adam S.

doi:10.1101/2023.08.22.23294416

Cited by 7 publications

(9 citation statements)

References 76 publications

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“…7d , p-value = 0.043 Mann Whitney U), indicating that purifying selection is occurring in the CD4+/CD8+ tandem depleted mice. Further, the rates observed in our mouse isolates fall into similar ranges observed in immunocompromised individuals with prolonged infections (≥21 days) 46 . Over 76% of the iSNVs were C-to-T transitions ( Fig.…”

Section: Resultssupporting

confidence: 79%

CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment

Kar,

Johnson,

Vanderheiden

et al. 2024

Preprint

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SARS-CoV-2 is the causative agent of COVID-19 and continues to pose a significant public health threat throughout the world. Following SARS-CoV-2 infection, virus-specific CD4+ and CD8+ T cells are rapidly generated to form effector and memory cells and persist in the blood for several months. However, the contribution of T cells in controlling SARS-CoV-2 infection within the respiratory tract are not well understood. Using C57BL/6 mice infected with a naturally occurring SARS-CoV-2 variant (B.1.351), we evaluated the role of T cells in the upper and lower respiratory tract. Following infection, SARS-CoV-2-specific CD4+ and CD8+ T cells are recruited to the respiratory tract and a vast proportion secrete the cytotoxic molecule Granzyme B. Using antibodies to deplete T cells prior to infection, we found that CD4+ and CD8+ T cells play distinct roles in the upper and lower respiratory tract. In the lungs, T cells play a minimal role in viral control with viral clearance occurring in the absence of both CD4+ and CD8+ T cells through 28 days post-infection. In the nasal compartment, depletion of both CD4+ and CD8+ T cells, but not individually, results in persistent and culturable virus replicating in the nasal compartment through 28 days post-infection. Using in situ hybridization, we found that SARS-CoV-2 infection persisted in the nasal epithelial layer of tandem CD4+ and CD8+ T cell-depleted mice. Sequence analysis of virus isolates from persistently infected mice revealed mutations spanning across the genome, including a deletion in ORF6. Overall, our findings highlight the importance of T cells in controlling virus replication within the respiratory tract during SARS-CoV-2 infection.

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Section: Resultssupporting

confidence: 79%

CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment

Kar,

Johnson,

Vanderheiden

et al. 2024

Preprint

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“…A meta-analysis study of SARS-CoV-2 persistent infection individuals showed that SARS-CoV-2 evolution was significantly faster in these persistent infected immunocompromised patients than that in the general human population 26 . A recent cohort study also reported that although prolonged replication-competent Omicron SARS-CoV-2 infections were uncommon, the within-host evolution reported an increased nonsynonymous mutation rate in persistent patients compared to short infections, where the persistently infected individuals accumulated globally distinct Spike mutations 27 . Animal spillover and human-to-animal SARS-CoV-2 spillback have been frequently reported 28 .…”

Section: Discussion/conclusionmentioning

confidence: 98%

Bayesian phylogenetics on globally emerging SARS-CoV-2 variant BA.2.86 suggest global distribution and rapid evolution

Rothstein,

Qiu,

Robison

et al. 2023

Preprint

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Using bioinformatic pipelines and Bayseian phylogenetic analyses, we characterized a SARS-CoV-2 variant designated by the World Health Organization as a variant under monitoring in August 2023. Here we analyze the genomes of this SARS-CoV-2 variant, BA.2.86, deposited into GISAID within the two weeks of its emergence (2023-08-14 first submission to 2023-08-31), including the first BA.2.86 genome reported from a traveler originating from Japan. We present bioinformatics methods using publicly available tools to help analysts identify the lineage-defining 12 nucleotide insertion (S:Ins16MPLF), which is often masked by most bioinformatics pipelines. We also applied maximum-likelihood and Bayesian phylogenetics to demonstrate the high mutational rate of the tree branch leading to the emergence of BA.2.86, hinting at possible origins, and predict that BA.2.86 emerged around May 2023 and spread globally rapidly. Taken together, these results provide a framework for more rigorous bioinformatics approaches for teams performing genomic surveillance on viral respiratory pathogens.

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“…A number of these mutations (K356, V445, G446, N450, L452, and P621) were also observed in omicron sub-lineages within immunocompromised patients. This may indicate that reduced immune functions within some individuals may be a source of highly mutated SARS-CoV2 lineages (31, 32). BA.2.86 has also evolved several descendants including JN.1 which harbors three mutations in non S-proteins and a hallmark S455L mutation in the spike protein (2).…”

Section: Discussionmentioning

confidence: 99%

Reverse mutational scanning of spike BA.2.86 identifies the epitopes contributing to immune escape from polyclonal sera

Bdeir,

Lüddecke,

Maaß

et al. 2024

Preprint

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SUMMARYThe recently detected Omicron BA.2.86 lineage contains more than 30 amino acid mutations relative to BA.2. Here, we identify the epitopes driving immune escape of BA.2.86 and its derivative JN.1 (BA.2.86 + S455L) lineage. We investigated the cross-reactive humoral immunity within a cohort of health care workers against Omicron BA.2.86 and JN.1 by employing pseudo-viral mutants. We demonstrate that BA.2.86 and especially JN.1 evaded neutralization by serum antibodies of fully vaccinated individuals. To discern the contribution of individual epitope mutations to immune escape, we constructed a library of 33 BA.2.86 mutants, each of which harbored a single revertant mutation going back to BA.2. This library was used in a reverse mutational scanning approach to define serum neutralization titers against each epitope separately. The mutations within the receptor binding domain (RBD) at position K356T and to a lesser extent the mutations N460K, V483Δ, A484K, and F486P enhanced the immune escape. More surprisingly, the mutation 16insMPLF within the spike N-terminal domain (NTD) and the mutation P621S in S1/S2 significantly contributed to antibody escape of BA.2.86. Upon XBB.1.5 booster vaccination, neutralization titers against JN.1 and BA.2.86 improved relative to all ancestral strains, and the residual immune escape was driven by mutations at positions 16insMPLF, Δ144Y, E544K, P621S, and A484K.

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SARS-CoV-2 shedding and evolution in immunocompromised hosts during the Omicron period: a multicenter prospective analysis

Cited by 7 publications

References 76 publications

CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment

CD4+ and CD8+ T cells are required to prevent SARS-CoV-2 persistence in the nasal compartment

Bayesian phylogenetics on globally emerging SARS-CoV-2 variant BA.2.86 suggest global distribution and rapid evolution

Reverse mutational scanning of spike BA.2.86 identifies the epitopes contributing to immune escape from polyclonal sera

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