A comprehensive, longitudinal analysis of humoral responses specific to four recombinant antigens of SARS-CoV-2 in severe and non-severe COVID-19 patients

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Abstract

There is an urgent need for effective treatment and preventive vaccine to contain this devastating global pandemic, which requires a comprehensive understanding of humoral responses specific to SARS-CoV-2 during the disease progression and convalescent phase of COVID-19 patients. We continuously monitored the serum IgM and IgG responses specific to four SARS-CoV-2 related antigens, including the nucleoprotein (NP), receptor binding domain (RBD), S1 protein, and ectodomain (ECD) of the spike protein among non-severe and severe COVID-19 patients for seven weeks since disease onset. Most patients generated humoral responses against NP and spike protein-related antigens but with their distinct kinetics profiles. Combined detection of NP and ECD antigens as detecting antigen synergistically improved the sensitivity of the serological assay, compared to that of using NP or RBD as detection antigen. 80.7% of convalescent sera from COVID-19 patients revealed that the varying extents of neutralization activities against SARS-CoV-2. S1-specific and ECD-specific IgA responses were strongly correlated with the neutralization activities in non-severe patients, but not in severe patients. Moreover, the neutralizing activities of the convalescent sera were shown to significantly decline during the period between 21 days to 28 days after hospital discharge, accompanied by a substantial drop in RBD-specific IgA response. Our data provide evidence that are crucial for serological testing, antibody-based intervention, and vaccine design of COVID-19.

Author summary

The world is facing an unprecedented challenge with communities and economies affected by the growing pandemic of coronavirus disease 2019 (COVID-19). Currently, there is no vaccine or effective drugs have been approved to treat or prevent COVID-19. The development of antibody response to SARS-CoV-2, the virus that causes COVID-19, started to be reported but remained largely elusive. Understanding the adaptive responses where the body makes antibodies that specifically bind to the SARS-CoV-2 among COVID-19 patients provides fundamental information for developing effective treatment and preventive vaccine. In this study, we not only successively analyzed the specificity and magnitude of antibody responses using four SARS-CoV-2 related antigens, but also monitored the neutralization potency of the convalescent sera from COVID-19 patients at the time point of hospital discharge and follow-up visit. Our results indicated that most patients generated humoral responses against nucleoprotein and three spike protein-related antigens with their distinct kinetics profiles. Additionally, most convalescent sera had the varying extents of neutralization activities against SARS-CoV-2. Of note, we identified that IgA antibody responses specific to S1 and ECD were strongly correlated with neutralization activities in non-severe patients, but not in severe patients. Furthermore, we identified a significant reduction of neutralizing activities of the convalescent sera within one month. Our data provide a collective basis of serological testing, antibody-based intervention, and vaccine design of 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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Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Kelvin Kai-Wang To, Owen Tsang, Wai-Shing Leung … (2020)

Summary Background Coronavirus disease 2019 (COVID-19) causes severe community and nosocomial outbreaks. Comprehensive data for serial respiratory viral load and serum antibody responses from patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not yet available. Nasopharyngeal and throat swabs are usually obtained for serial viral load monitoring of respiratory infections but gathering these specimens can cause discomfort for patients and put health-care workers at risk. We aimed to ascertain the serial respiratory viral load of SARS-CoV-2 in posterior oropharyngeal (deep throat) saliva samples from patients with COVID-19, and serum antibody responses. Methods We did a cohort study at two hospitals in Hong Kong. We included patients with laboratory-confirmed COVID-19. We obtained samples of blood, urine, posterior oropharyngeal saliva, and rectal swabs. Serial viral load was ascertained by reverse transcriptase quantitative PCR (RT-qPCR). Antibody levels against the SARS-CoV-2 internal nucleoprotein (NP) and surface spike protein receptor binding domain (RBD) were measured using EIA. Whole-genome sequencing was done to identify possible mutations arising during infection. Findings Between Jan 22, 2020, and Feb 12, 2020, 30 patients were screened for inclusion, of whom 23 were included (median age 62 years [range 37–75]). The median viral load in posterior oropharyngeal saliva or other respiratory specimens at presentation was 5·2 log10 copies per mL (IQR 4·1–7·0). Salivary viral load was highest during the first week after symptom onset and subsequently declined with time (slope −0·15, 95% CI −0·19 to −0·11; R 2=0·71). In one patient, viral RNA was detected 25 days after symptom onset. Older age was correlated with higher viral load (Spearman's ρ=0·48, 95% CI 0·074–0·75; p=0·020). For 16 patients with serum samples available 14 days or longer after symptom onset, rates of seropositivity were 94% for anti-NP IgG (n=15), 88% for anti-NP IgM (n=14), 100% for anti-RBD IgG (n=16), and 94% for anti-RBD IgM (n=15). Anti-SARS-CoV-2-NP or anti-SARS-CoV-2-RBD IgG levels correlated with virus neutralisation titre (R 2>0·9). No genome mutations were detected on serial samples. Interpretation Posterior oropharyngeal saliva samples are a non-invasive specimen more acceptable to patients and health-care workers. Unlike severe acute respiratory syndrome, patients with COVID-19 had the highest viral load near presentation, which could account for the fast-spreading nature of this epidemic. This finding emphasises the importance of stringent infection control and early use of potent antiviral agents, alone or in combination, for high-risk individuals. Serological assay can complement RT-qPCR for diagnosis. Funding Richard and Carol Yu, May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, and Sanming Project of Medicine.

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Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

Quan-Xin Long, Xiao-Jun Tang, Qiu-Lin Shi … (2020)

The clinical features and immune responses of asymptomatic individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have not been well described. We studied 37 asymptomatic individuals in the Wanzhou District who were diagnosed with RT-PCR-confirmed SARS-CoV-2 infections but without any relevant clinical symptoms in the preceding 14 d and during hospitalization. Asymptomatic individuals were admitted to the government-designated Wanzhou People's Hospital for centralized isolation in accordance with policy1. The median duration of viral shedding in the asymptomatic group was 19 d (interquartile range (IQR), 15-26 d). The asymptomatic group had a significantly longer duration of viral shedding than the symptomatic group (log-rank P = 0.028). The virus-specific IgG levels in the asymptomatic group (median S/CO, 3.4; IQR, 1.6-10.7) were significantly lower (P = 0.005) relative to the symptomatic group (median S/CO, 20.5; IQR, 5.8-38.2) in the acute phase. Of asymptomatic individuals, 93.3% (28/30) and 81.1% (30/37) had reduction in IgG and neutralizing antibody levels, respectively, during the early convalescent phase, as compared to 96.8% (30/31) and 62.2% (23/37) of symptomatic patients. Forty percent of asymptomatic individuals became seronegative and 12.9% of the symptomatic group became negative for IgG in the early convalescent phase. In addition, asymptomatic individuals exhibited lower levels of 18 pro- and anti-inflammatory cytokines. These data suggest that asymptomatic individuals had a weaker immune response to SARS-CoV-2 infection. The reduction in IgG and neutralizing antibody levels in the early convalescent phase might have implications for immunity strategy and serological surveys.

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Author and article information

Contributors

Yuxin Chen: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing

Xin Tong: Role: MethodologyRole: Project administration

Yang Li: Role: Validation

Bin Gu: Role: Resources

Jiawei Yan: Role: Resources

Yong Liu: Role: SoftwareRole: SupervisionRole: Validation

Han Shen: Role: Resources

Rui Huang:

ORCID: http://orcid.org/0000-0002-3189-7960

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: VisualizationRole: Writing – original draft

Chao Wu:

ORCID: http://orcid.org/0000-0002-1657-010X

Role: ConceptualizationRole: Funding acquisitionRole: ResourcesRole: SupervisionRole: Writing – review & editing

Ron A. M. Fouchier: Role: Editor

Journal

Journal ID (nlm-ta): PLoS Pathog

Journal ID (iso-abbrev): PLoS Pathog

Journal ID (publisher-id): plos

Journal ID (pmc): plospath

Title: PLoS Pathogens

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Print): 1553-7366

ISSN (Electronic): 1553-7374

Publication date (Electronic): 10 September 2020

Publication date Collection: September 2020

Volume: 16

Issue: 9

Electronic Location Identifier: e1008796

Affiliations

[1 ] Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China

[2 ] Department of Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China

[3 ] Medical Technology School of Xuzhou Medical University, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou, Jiangsu, China

[4 ] Department of Laboratory Medicine, the Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China

[5 ] Department of Laboratory Medicine, Xuzhou Infectious Disease Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China

[6 ] Department of Experimental Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China

Erasmus Medical Center, NETHERLANDS

Author notes

The authors have declared that no competing interests exist.

* E-mail: dr.wu@ 123456nju.edu.cn (CW); doctor_hr@ 123456126.com (RH)

Author information

Rui Huang http://orcid.org/0000-0002-3189-7960

Chao Wu http://orcid.org/0000-0002-1657-010X

Article

Publisher ID: PPATHOGENS-D-20-00962

DOI: 10.1371/journal.ppat.1008796

PMC ID: 7482996

PubMed ID: 32913364

SO-VID: fab165df-7c13-46b1-b4e0-31574c3eddd4

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 8 May 2020

Date accepted : 9 July 2020

Page count

Figures: 6, Tables: 2, Pages: 16

Funding

Funded by: Fundamental Research Funds for Central Universities of the Central South University (CN)

Award ID: 14380459

Award Recipient :

ORCID: http://orcid.org/0000-0002-1657-010X

Chao Wu

This study was supported by the Fundamental Research Funds for the Central Universities (No. 14380459 to CW). the Medical Science and technology Development Foundation, Nanjing Department of Health (YKK19056 to YC), Nanjing Medical Science and Technique Development Foundation (QRX17141 to YC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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ScienceOpen disciplines: Infectious disease & Microbiology

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A comprehensive, longitudinal analysis of humoral responses specific to four recombinant antigens of SARS-CoV-2 in severe and non-severe COVID-19 patients

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Most cited references 23

Clinical Characteristics of Coronavirus Disease 2019 in China

Temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by SARS-CoV-2: an observational cohort study

Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections

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