Humoral Response Dynamics Following Infection with SARS-CoV-2
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
Introduction
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) specific antibodies have been shown to neutralize the virus in-vitro. Understanding antibody dynamics following SARS-CoV-2 infection is therefore crucial. Sensitive measurement of SARS-CoV-2 antibodies is also vital for large seroprevalence surveys which inform government policies and public health interventions. However, rapidly waning antibodies following SARS-CoV-2 infection could jeopardize the sensitivity of serological testing on which these surveys depend.
Methods
This prospective cohort study of SARS-CoV-2 humoral dynamics in a central London hospital analyzed 137 serial samples collected from 67 participants seropositive to SARS-CoV-2 by the Meso-Scale Discovery assay. Antibody titers were quantified to the SARS-CoV-2 nucleoprotein (N), spike (S-)protein and the receptor-binding-domain (RBD) of the S-protein. Titers were log-transformed and a multivariate log-linear model with time-since-infection and clinical variables was fitted by Bayesian methods.
Results
The mean estimated half-life of the N-antibody was 52 days (95% CI 42-65). The S- and RBD-antibody had significantly longer mean half-lives of 81 days (95% CI 61-111) and 83 days (95% CI 55-137) respectively. An ACE-2-receptor competition assay demonstrated significant correlation between the S and RBD-antibody titers and ACE2-receptor blocking in-vitro. The time-to-a-negative N-antibody test for 50% of the seropositive population was predicted to be 195 days (95% CI 163-236).
Discussion
After SARS-CoV-2 infection, the predicted half-life of N-antibody was 52 days with 50% of seropositive participants becoming seronegative to this antibody at 195 days. Widely used serological tests that depend on the N-antibody will therefore significantly underestimate the prevalence of infection following the majority of infections.
Significance statement
We believe that our study has significant and urgent public health and translational impact. Firstly, our findings demonstrate that the half-life of the SARS-CoV-2 nucleoprotein antibody is only 52 days. This has immediate and important implications for large-scale seroprevalence surveys, government policy and mathematical modelling predictions which rely on serological tests that target this antibody. Secondly, the slower decay of the SARS-CoV-2 spike protein antibody identified in this study makes assays to the spike protein a more reliable target for serological assays in the longer term. We demonstrate a strong positive linear correlation between spike/RBD antibody and ACE-2 receptor binding in vitro. Our findings are therefore likely to reflect the time to loss of a functional antibody response in SARS-CoV-2.
Funding
GOSH charity, Wellcome Trust (201470/Z/16/Z and 220565/Z/20/Z). GOSH NIHR Funded Biomedical Research Centre.
Trial registration number
NCT04380896.
Article activity feed
-
SciScore for 10.1101/2020.07.16.20155663: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources Measurement of SARS-CoV-2 serum antibody and viral RNA by PCR: All serological samples were analysed by the Meso Scale Discovery (MSD) Chemiluminescent binding assay that detects and quantifies anti-SARS-CoV-2 IgG specific for trimeric S-protein, RBD and N-protein. anti-SARS-CoV-2 IgGsuggested: NoneN-proteinsuggested: NoneThe 21-day starting point for antibody decay was chosen a-priori based on existing data of antibody responses to SARS-CoV-2.(25) Plotting the rate of decay against time supported our hypothesis that the rate of the negative exponential decay would remain constant over time … SciScore for 10.1101/2020.07.16.20155663: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources Measurement of SARS-CoV-2 serum antibody and viral RNA by PCR: All serological samples were analysed by the Meso Scale Discovery (MSD) Chemiluminescent binding assay that detects and quantifies anti-SARS-CoV-2 IgG specific for trimeric S-protein, RBD and N-protein. anti-SARS-CoV-2 IgGsuggested: NoneN-proteinsuggested: NoneThe 21-day starting point for antibody decay was chosen a-priori based on existing data of antibody responses to SARS-CoV-2.(25) Plotting the rate of decay against time supported our hypothesis that the rate of the negative exponential decay would remain constant over time (Supplementary Figure 2). SARS-CoV-2.suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Viral neutralization assays remain the gold-standard in vitro correlate of protection and the lack of formal neutralization tests is a limitation of the study. ACE-2 receptor competition assays such as the MSD competitive binding assay have been shown to correlate well with formal viral neutralization assays(33). The ACE-2 competition assay used in this study had a strong positive linear correlation with both S-antibody titers (R2=0.72) and RBD-antibody titres (R2=0.77). Therefore, our observed decline in S-antibody titers is likely to be proportional to declines in functional receptor blocking activity. Our negative exponential model of antibody decay assumed a constant rate of decay over time. Negative exponential models of antibody decay are frequently used to model antibody decay,(34, 35) and this assumption was supported by plotting the rate of decay over time (Supplementary Materials Fig.2). Nevertheless, increased serial antibody measurements will enable us to test this hypothesis further and refine our half-life predictions accordingly. Whilst the severity of infection among our study participants is likely to be representative of community infection, our findings may be biased to healthcare workers. Moreover, a population of paediatric healthcare workers are more likely to be repeatedly exposed to seasonal CoV infection. We do not know to what extent this influences our measurements of the SARS-CoV-2 humoral response or our estimates of antibody decay. Recent studies...
Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04380896 Recruiting COVID-19 Staff Testing of Antibody Responses Study (Co-Stars… Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
-
-
SciScore for 10.1101/2020.07.16.20155663: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Informed consent was obtained from all participants. Randomization not detected. Blinding not detected. Power Analysis The Study Protocol and Supplementary Materials submitted with this paper include detailed methods, power calculations and the data analysis approach. Sex as a biological variable Fifty-three participants (79%) of the cohort were women and 25% were from Black, Asian, Minority Ethnic (BAME) backgrounds (17/67). Table 2: Resources
Antibodies Sentences Resources Dhimple Patel Philippa Wiltshire Annie Susay Anna Ryan Luke Lancaster Kavita Thind Kate Speller Rachel Sterling Connor Tugulu Sandhya Ghurburrun Steffi Gray Joy Mugas Moe Kishma … SciScore for 10.1101/2020.07.16.20155663: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement Informed consent was obtained from all participants. Randomization not detected. Blinding not detected. Power Analysis The Study Protocol and Supplementary Materials submitted with this paper include detailed methods, power calculations and the data analysis approach. Sex as a biological variable Fifty-three participants (79%) of the cohort were women and 25% were from Black, Asian, Minority Ethnic (BAME) backgrounds (17/67). Table 2: Resources
Antibodies Sentences Resources Dhimple Patel Philippa Wiltshire Annie Susay Anna Ryan Luke Lancaster Kavita Thind Kate Speller Rachel Sterling Connor Tugulu Sandhya Ghurburrun Steffi Gray Joy Mugas Moe Kishma Kathleen Akpokomua Sophie White Eleana Pieri Sabina Shamsad Demi Alexandrou Odera Aguele Anamika Jain Subishma Gautam Oliver Simms Corresponding author contact details: Dr Louis Grandjean Department of Infection, Inflammation and Immunity, Institute of Child Health, 30 Guilford Street, London, WC1N l.grandjean@ucl.ac.uk Trial registration number: Key words: immunity, NCT04380896. serology, antibody, COVID-19, virus, nucleoprotein, spike protein ELISA, kinetics, neutralisation, SARS-CoV-2, Abstract Objectives Design Setting To understand humoral dynamics following SARS-CoV-2 infection Prospective Cohort Study Great Ormond Street Hospital (Central London Paediatric Hospital) Participants 67 healthcare workers aged >18 years who provided monthly serial serological samples from 29th April 2020 until 30 Main outcome measures The th June 2020. NCT04380896suggested: None<div style="margin-bottom:8px"> <div><b>COVID-19, virus, nucleoprotein, spike protein ELISA</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">change in monthly serial antibody titers to SARS-CoV-2 nucleoprotein (N), spike protein and the receptor binding domain of the spike protein.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>SARS-CoV-2 nucleoprotein (N)</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">The spike and RBD antibody had significantly longer mean half-lives of 81 days (95% CI 61-111) and 83 days (95% CI 55-137) respectively.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>RBD</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">An ACE-2 receptor competition assay demonstrated significant correlation between the spike and RBD antibody titers and ACE2 receptor blocking in-vitro.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>ACE2</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">[3] trimeric spike syndrome coronavirus-2 (SARS-CoV-2), Specific immunoglobulin (IgG) antibody (S) protein, nucleoprotein (N) protein an responses and the enveloped to the RNA β- SARS-CoV-2 receptor-binding domain (RBD) develop between 6-15 days following disease-onset.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>SARS-CoV-2), Specific immunoglobulin (IgG</b></div> <div>suggested: None</div> </div> <div style="margin-bottom:8px"> <div><b>antibody (S) protein, nucleoprotein (N</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">[7] The dynamics and duration of the antibody response to S-protein, N-protein and the RBD following infection or exposure with SARS-CoV-2 remain poorly understood.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>S-protein, N-protein</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">The half-life of the N-antibody was significantly shorter than that of the trimeric S- and RBD- antibodies with a mean of 81 and 84 days, respectively.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>RBD-</b></div> <div>suggested: (Imported from the IEDB Cat# RBD-23D3, <a href="https://scicrunch.org/resources/Any/search?q=AB_2848096">AB_2848096</a>)</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Recent studies have hypothesized that previous exposure to CoVs may confer some protection against SARS-CoV-2[36] and may need to be accounted for when modelling transmission or longevity dynamics. [37] Results are conflicting, however, and it remains unclear if any cross- reactivity is T-cell or antibody mediated.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>SARS-CoV-2</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">Recent findings from animal studies support the role of neutralizing antibodies as a correlate of immunity. [11,16,17] Similarly, a controlled human infection model of seasonal CoV 229E demonstrated waning of IgG-specific antibodies within 1 year, with subsequent reinfection of 6/9 individuals upon homologous viral challenge, albeit without clinical symptoms. [44] If reinfection does occur, severity of disease may therefore be attenuated, unless antibody-dependent disease enhancement by sub-neutralising antibody titers occurs. [42] Furthermore, robust memory T-cell responses to specific SARS-CoV-2 peptides are elicited following infection; this also includes seronegative and/or pauci-symptomatic individuals. [15,40,41] As such, anamnestic cell-mediated immune responses may prevent clinically significant re-infection, in keeping with other viral pathogens such as measles and hepatitis A.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>antibody-dependent disease enhancement by sub-neutralising</b></div> <div>suggested: None</div> </div> </td></tr><tr><td style="min-width:100px;text-align:center; padding-top:4px;" colspan="2"><b>Software and Algorithms</b></td></tr><tr><td style="min-width:100px;text=align:center"><i>Sentences</i></td><td style="min-width:100px;text-align:center"><i>Resources</i></td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">This is important, given that only 1% of 20-30 year olds and 18% of >80 year olds diagnosed COVID-19 cases are hospitalized, making our study population representative of the majority of community SARS-CoV-2 infections. [31] Severe disease has been associated with higher antibody titers and a longer duration of antibody response following both SARS and MERS. [9,20,21,32] When long-term follow-up studies of hospitalized SARS-CoV-2 patients are published, we therefore expect the half-life estimates to increase due to the increased severity of initial disease.</td><td style="min-width:100px;border-bottom:1px solid lightgray"> <div style="margin-bottom:8px"> <div><b>MERS.</b></div> <div>suggested: None</div> </div> </td></tr></table>Data from additional tools added to each annotation on a weekly basis.
About SciScore
SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.
-