Antibody response using six different serological assays in a completely PCR-tested community after a COVID-19 outbreak - The CoNAN study

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Abstract

Objectives

Due to a substantial proportion of asymptomatic and mild courses, many SARS-CoV-2 infections remain unreported. Therefore, assessment of seroprevalence may detect the real burden of disease. We aimed at determining and characterizing the rate of SARS-CoV-2 infections and the resulting seroprevalence in a defined population. The primary objective of the study was to assess SARS-CoV-2 antibody seroprevalence using six different IgG detecting immunoassays. Secondary objectives of the study were: i.) to determine potential risk factors for symptomatic vs. asymptomatic Covid19 courses; ii.) to investigate the rate of virus RNA-persistence.

Methods

CoNAN is a population-based cohort study performed in the community Neustadt am Rennsteig, Germany that was quarantined from March 22 ^nd to April 5 ^th after six SARS-CoV-2 cases were detected in the villages’ population. The SARS-CoV-2 outbreak compromised 51 cases and 3 deaths. The CoNAN study was performed from May 13th to May 22nd 2020 six weeks after a SARS-CoV-2 outbreak.

Results

We enrolled a total of 626 participants (71% of the community population) for PCR- and antibody testing in the study. All actual SARS-CoV-2 PCR tests were negative. Fifty-two out of 620 (8.4%) participants had antibodies against SARS-CoV-2 in at least two different assays. There were 38 participants with previously PCR-confirmed SARS-CoV-2 infection. Of those, only 19 (50%) displayed anti-SARS-CoV-2 antibodies. We also show that antibody positive participants with symptoms compatible with a respiratory tract infection had significantly higher antibody levels then asymptomatic participants (EU-assay: Median 2.9 vs. 7.2 IgG-index, p=0.002; DS-assay: Median 45.2 vs. 143 AU/mL, p=0.002). Persisting viral replication was not detected.

Conclusions

Our data question the relevance and reliability of IgG antibody testing to detect past SARS-CoV-2 infections six weeks after an outbreak. We conclude that assessing immunity for SARS-CoV-2 infection should not only rely on antibody tests.

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Most cited references 20

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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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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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Author and article information

Journal

Journal ID (nlm-ta): Clin Microbiol Infect

Journal ID (iso-abbrev): Clin Microbiol Infect

Title: Clinical Microbiology and Infection

Publisher: The Author(s). Published by Elsevier Ltd on behalf of European Society of Clinical Microbiology and Infectious Diseases.

ISSN (Print): 1198-743X

ISSN (Electronic): 1469-0691

Publication date PMC-release: 20 November 2020

Publication date (Electronic): 20 November 2020

Affiliations

[18 ]Technische Universität Ilmenau, Ilmenau, Germany

[11 ]Technische Universität Ilmenau, Ilmenau, Germany

[12 ]Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena (IBBJ), Jena University Hospital – Friedrich Schiller University, Jena, Germany

[13 ]Children’s Hospital, Jena University Hospital – Friedrich Schiller University, Jena, Germany

[14 ]Department of Anesthesiology and Intensive Care Medicine Jena University Hospital – Friedrich Schiller University, Jena, Germany

[15 ]Institute for Infectious Disease and Infection Control, Jena University Hospital – Friedrich Schiller University, Jena, Germany

[16 ]Institute of Immunology, Jena University Hospital – Friedrich Schiller University, Jena, Germany

[17 ]Institute of Medical Microbiology, Jena University Hospital – Friedrich Schiller University, Jena, Germany

[1 ]Institute for Infectious Diseases and Infection Control, Jena University Hospital- Friedrich Schiller University, Jena, Germany

[2 ]Center for Sepsis Control and Care (CSCC), Jena University Hospital- Friedrich Schiller University, Jena, Germany

[3 ]Department of Anesthesiology and Intensive Care, Jena University Hospital- Friedrich Schiller University, Jena, Germany

[4 ]Institute of Medical Statistics, Computer and Data Sciences, Jena University Hospital- Friedrich Schiller University, Jena, Germany

[5 ]Institute of Medical Microbiology, Jena University Hospital- Friedrich Schiller University, Jena, Germany

[6 ]Institute of Clinical Chemistry and Laboratory Diagnostics and Integrated Biobank Jena (IBBJ), Jena University Hospital- Friedrich Schiller University, Jena, Germany

[7 ]Institute of Immunology, Jena University Hospital- Friedrich Schiller University, Jena, Germany

[8 ]Department of Medicine I, Division of Infectious Diseases and Tropical Medicine, Medical University of Vienna, Vienna, Austria

[9 ]Children’s Hospital, Jena University Hospital- Friedrich Schiller University, Jena, Germany

[10 ]Thuringian State Office for Consumer Protection, Bad Langensalza, Germany

Author notes

[∗ ]Corresponding Author: Institute for Infectious Diseases and Infection Control, Jena University Hospital – Friedrich Schiller University Am Klinikum 1 07747 Jena, Germany Tel.: +49 3641.9-324794; fax: +49 3641.9-324652

Article

Publisher Item ID: S1198-743X(20)30705-9

DOI: 10.1016/j.cmi.2020.11.009

PMC ID: 7677041

PubMed ID: 33221432

SO-VID: 34d5a3f8-3fd4-4bae-9e76-ce30720a287c

License:

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

History

Date received : 1 September 2020

Date revision received : 9 November 2020

Date accepted : 11 November 2020

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Antibody response using six different serological assays in a completely PCR-tested community after a COVID-19 outbreak - The CoNAN study

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Abstract

Objectives

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Conclusions

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Most cited references 20

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

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

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