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

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Abstract

COVID-19 patients show varying severity of the disease ranging from asymptomatic to requiring intensive care. Although a number of SARS-CoV-2 specific monoclonal antibodies 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 bulk and plasma B-cells collected over multiple time points during infection to characterize signatures of B-cell response to SARS-CoV-2 in 19 patients. Using principled statistical approaches, we determined differential features of BCRs associated with different disease severity. We identified 38 significantly expanded clonal lineages shared among patients as candidates for specific responses to SARS-CoV-2. Using single-cell sequencing, we verified reactivity of BCRs shared among individuals to SARS-CoV-2 epitopes. Moreover, we identified natural emergence of a BCR with cross-reactivity to SARS-CoV-1 and SARS-CoV-2 in a number of patients. Our results provide important insights for development of rational therapies and vaccines against COVID-19.

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Clinical Characteristics of Coronavirus Disease 2019 in China

Wei-jie Guan, Zheng-yi Ni, Yu Hu … (2020)

Abstract Background Since December 2019, when coronavirus disease 2019 (Covid-19) emerged in Wuhan city and rapidly spread throughout China, data have been needed on the clinical characteristics of the affected patients. Methods We extracted data regarding 1099 patients with laboratory-confirmed Covid-19 from 552 hospitals in 30 provinces, autonomous regions, and municipalities in mainland China through January 29, 2020. The primary composite end point was admission to an intensive care unit (ICU), the use of mechanical ventilation, or death. Results The median age of the patients was 47 years; 41.9% of the patients were female. The primary composite end point occurred in 67 patients (6.1%), including 5.0% who were admitted to the ICU, 2.3% who underwent invasive mechanical ventilation, and 1.4% who died. Only 1.9% of the patients had a history of direct contact with wildlife. Among nonresidents of Wuhan, 72.3% had contact with residents of Wuhan, including 31.3% who had visited the city. The most common symptoms were fever (43.8% on admission and 88.7% during hospitalization) and cough (67.8%). Diarrhea was uncommon (3.8%). The median incubation period was 4 days (interquartile range, 2 to 7). On admission, ground-glass opacity was the most common radiologic finding on chest computed tomography (CT) (56.4%). No radiographic or CT abnormality was found in 157 of 877 patients (17.9%) with nonsevere disease and in 5 of 173 patients (2.9%) with severe disease. Lymphocytopenia was present in 83.2% of the patients on admission. Conclusions During the first 2 months of the current outbreak, Covid-19 spread rapidly throughout China and caused varying degrees of illness. Patients often presented without fever, and many did not have abnormal radiologic findings. (Funded by the National Health Commission of China and others.)

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Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals

Davide Robbiani, Christian Gaebler, Frauke Muecksch … (2020)

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2 1–5 . Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titers: less than 1:50 in 33% and below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

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Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

Dora Pinto, Young-Jun Park, Martina Beltramello … (2020)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a newly emerged coronavirus that is responsible for the current pandemic of coronavirus disease 2019 (COVID-19), which has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 20201,2. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe several monoclonal antibodies that target the S glycoprotein of SARS-CoV-2, which we identified from memory B cells of an individual who was infected with severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003. One antibody (named S309) potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2, by engaging the receptor-binding domain of the S glycoprotein. Using cryo-electron microscopy and binding assays, we show that S309 recognizes an epitope containing a glycan that is conserved within the Sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails that include S309 in combination with other antibodies that we identified further enhanced SARS-CoV-2 neutralization, and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309 and antibody cocktails containing S309 for prophylaxis in individuals at a high risk of exposure or as a post-exposure therapy to limit or treat severe disease.

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Journal

Journal ID (nlm-ta): medRxiv

Journal ID (publisher-id): MEDRXIV

Title: medRxiv

Publisher: Cold Spring Harbor Laboratory

Publication date (Electronic): 05 April 2021

Electronic Location Identifier: 2020.07.13.20153114

Affiliations

[1. ]Department of Physics, University of Washington, 3910 15th Ave Northeast, Seattle, WA 98195, USA

[2. ]HKU-Pasteur Research Pole, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.

[3. ]Max Planck Institute for Dynamics and Self-organization, Am Faßberg 17, 37077 Göttingen, Germany

[4. ]Department of Genome Sciences, University of Washington, 3720 15th Ave NE, Seattle, WA 98195, USA

[5. ]Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, WA 98109, USA

[6. ]Laboratoire de physique de l’ecole normale supérieure (PSL University), CNRS, Sorbonne Université, and Université de Paris, 75005 Paris, France

[7. ]Infectious Diseases Centre, Princess Margaret Hospital, Hospital Authority of Hong Kong

[8. ]Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA

[9. ]The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA

[10. ]Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA

[11. ]Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA

[12. ]Center for Biophysics and Quantitative Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.

Author notes

[†]

current address: Dyno Therapeutics, 1 Kendall Square, Building 1400E, Suite 202, Cambridge, MA 02139

Author Contributions

Z.M., H.Lv, J. O, I.A.W., J.S.M.P. N.C.W., A.N., and C.K.P.M. conceived and designed the study. O.T.-Y.T. organized patient recruitment, data collection, and sampling. H.Lv, G.K.Y., W.W.N., and C.K.P.M. prepared the next-generation sequencing libraries and performed the ELISA experiments. M.Y., H.Liu, and N.C.W. and expressed and purified the proteins. Z.M., J.O., W.S.D., G.I., and A.N. analyzed the data and performed the modelling work and statistical inference. Z.M., H.Lv, N.C.W., A.N., and C.K.P.M. wrote the paper. All authors reviewed and edited the paper.

[*]

equal contribution

[# ]equal contribution and corresponding authors: Armita Nourmohammad: armita@ 123456uw.edu , Nicholas C. Wu: nicwu@ 123456illinois.edu , and Chris Ka Pun Mok: ch02mkp@ 123456hku.hk

Article

DOI: 10.1101/2020.07.13.20153114

PMC ID: 7373151

PubMed ID: 32699862

SO-VID: ff12e489-3827-4319-b723-45a98b0f5eb7

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

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Novel Coronavirus Disease COVID-19

Most cited references 70

Clinical Characteristics of Coronavirus Disease 2019 in China

Convergent Antibody Responses to SARS-CoV-2 in Convalescent Individuals

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody

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