Next-Generation Sequencing of T and B Cell Receptor Repertoires from COVID-19 Patients Showed Signatures Associated with Severity of Disease

Schultheiß, Christoph; Paschold, Lisa; Simnica, Donjetë; Mohme, Malte; Willscher, Edith; Wenserski, Lisa von; Scholz, Rebekka; Wieters, Imke; Dahlke, Christine; Tolosa, Eva; Sedding, Daniel; Ciesek, Sandra; Addo, Marylyn M.; Binder, Mascha

doi:10.1016/j.immuni.2020.06.024

Cited by 296 publications

(422 citation statements)

References 62 publications

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“…Consistent with the notion of SARS-CoV-2 infection activating a recall of cross-reactive HCoV S specific Abs, the COVID sera Abs exhibited significantly slower off-rates with HCoV-HKU1 and HCoV-NL63 S-proteins compared to pre-pandemic sera Abs ( Fig. 2A-B [20][21][22][23][24][25][26] . Compared to the crossreactive mAbs, the nucleotide SHM levels in SARS-CoV-2 specific mAbs were much lower (VH, 0-17% (median = 0.7%) VL, 0-3.5% (median = 1.8%)) ( appear to bind a proximal epitope at the base of the trimer.…”

Section: Resultssupporting

confidence: 81%

Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Song

Callaghan

et al. 2020

Preprint

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Pre-existing immune responses to seasonal endemic coronaviruses could have profound consequences for antibody responses to SARS-CoV-2, either induced in natural infection or through vaccination. Such consequences are well established in the influenza and flavivirus fields. A first step to establish whether pre-existing responses can impact SARS-CoV-2 infection is to understand the nature and extent of cross-reactivity in humans to coronaviruses. We compared serum antibody and memory B cell responses to coronavirus spike (S) proteins from pre-pandemic and SARS-CoV-2 convalescent donors using a series of binding and functional assays. We found weak evidence of pre-existing SARS-CoV-2 cross-reactive serum antibodies in pre-pandemic donors. However, we found stronger evidence of pre-existing cross-reactive memory B cells that were activated on SARS-CoV-2 infection. Monoclonal antibodies (mAbs) isolated from the donors showed varying degrees of cross-reactivity with betacoronaviruses, including SARS and endemic coronaviruses. None of the cross-reactive mAbs were neutralizing except for one that targeted the S2 subunit of the S protein. The results suggest that pre-existing immunity to endemic coronaviruses should be considered in evaluating antibody responses to SARS-CoV-2.

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Section: Resultssupporting

confidence: 81%

Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Song

Callaghan

et al. 2020

Preprint

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“…These results, particularly the presence of individuals with low neutralizing antibodies are interesting as each individual in our cohort has recovered from SARS-CoV-2 infection. This observation suggests that either we missed the period of robust neutralizing antibody production in certain individuals or other mechanisms, such as potent SARS-CoV-2 specific T-cell responses 35,36,[37][38][39][40][41] , provided effective viral clearance and immunity. Future studies coupling assessment of antibody and T-cell responses with key clinical information (age, sex, severity of symptoms) will be essential to fully understand this complex immune response.…”

Section: Discussionmentioning

confidence: 99%

High titers of multiple antibody isotypes against the SARS-CoV-2 spike receptor-binding domain and nucleoprotein associate with better neutralization

Noval

Rodriguez-Rodriguez

Louie

et al. 2020

Preprint

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Understanding antibody responses to SARS-CoV-2 is indispensable for the development of containment measures to overcome the current COVID-19 pandemic. Here, we determine the ability of sera from 101 recovered healthcare workers to neutralize both authentic SARS-CoV-2 and SARS-CoV-2 pseudotyped virus and address their antibody titers against SARS-CoV-2 nucleoprotein and spike receptor-binding domain. Interestingly, the majority of individuals have low neutralization capacity and only 6% of the healthcare workers showed high neutralizing titers against both authentic SARS-CoV-2 virus and the pseudotyped virus. We found the antibody response to SARS-CoV-2 infection generates antigen-specific isotypes as well as a diverse combination of antibody isotypes, with high titers of IgG, IgM and IgA against both antigens correlating with neutralization capacity. Importantly, we found that neutralization correlated with antibody titers as quantified by ELISA. This suggests that an ELISA assay can be used to determine seroneutralization potential. Altogether, our work provides a snapshot of the SARS-CoV-2 neutralizing antibody response in recovered healthcare workers and provides evidence that possessing multiple antibody isotypes may play an important role in SARS-CoV-2 neutralization.

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“…S7). Previous work has also identified sharing of BCRs among COVID-19 patients, which was interpreted by the authors as evidence for large-scale convergence of immune responses (Galson et al, 2020;Nielsen et al, 2020;Schultheiß et al, 2020). Although BCR sharing can be due to convergent response to common antigens, it can also arise from convergent recombination leading to the same receptor sequence (Elhanati et al, 2018;Pogorelyy et al, 2018a) or simply from experimental biases.…”

Section: Sharing Of Bcrs Among Individualsmentioning

confidence: 87%

Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

Montague

Otwinowski

et al. 2020

Preprint

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COVID-19 patients show varying severity of the disease ranging from asymptomatic to requiring intensive care. Although a number of monoclonal antibodies against SARS-CoV-2 have been identified, we still lack an understanding of the overall landscape of B-cell receptor (BCR) repertoires in COVID-19 patients. Here, we used high-throughput sequencing of BCR repertoires collected over multiple time points during an infection to characterize statistical and dynamical signatures of the B-cell response to SARS-CoV-2 in 19 patients with different disease severities. Based on principled statistical approaches, we determined differential sequence features of BCRs associated with different disease severity. We identified 34 significantly expanded rare clonal lineages shared among patients as candidates for a specific response to SARS-CoV-2. Moreover, we identified natural emergence of a BCR with cross-reactivity to SARS-CoV and SARS-CoV-2 in a number of patients. Overall, our results provide important insights for development of rational therapies and vaccines against COVID-19.

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Next-Generation Sequencing of T and B Cell Receptor Repertoires from COVID-19 Patients Showed Signatures Associated with Severity of Disease

Cited by 296 publications

References 62 publications

Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

Cross-reactive serum and memory B cell responses to spike protein in SARS-CoV-2 and endemic coronavirus infection

High titers of multiple antibody isotypes against the SARS-CoV-2 spike receptor-binding domain and nucleoprotein associate with better neutralization

Dynamics of B-cell repertoires and emergence of cross-reactive responses in COVID-19 patients with different disease severity

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