Long-Term Persistence of Spike Antibody and Predictive Modeling of Antibody Dynamics Following Infection with SARS-CoV-2
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Abstract
Background
Antibodies to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) have been shown to neutralize the virus in-vitro . Similarly, animal challenge models suggest that neutralizing antibodies isolated from SARS-CoV-2 infected individuals prevent against disease upon re-exposure to the virus. Understanding the nature and duration of the antibody response following SARS-CoV-2 infection is therefore critically important.
Methods
Between April and October 2020 we undertook a prospective cohort study of 3555 healthcare workers in order to elucidate the duration and dynamics of antibody responses following infection with SARS-CoV-2. After a formal performance evaluation against 169 PCR confirmed cases and negative controls, the Meso-Scale Discovery assay was used to quantify in parallel, antibody titers to the SARS-CoV-2 nucleoprotein (N), spike (S) protein and the receptor-binding-domain (RBD) of the S-protein. All seropositive participants were followed up monthly for a maximum of 7 months; those participants that were symptomatic, with known dates of symptom-onset, seropositive by the MSD assay and who provided 2 or more monthly samples were included in the analysis. Survival analysis was used to determine the proportion of sero-reversion (switching from positive to negative) from the raw data. In order to predict long-term antibody dynamics, two hierarchical longitudinal Gamma models were implemented to provide predictions for the lower bound (continuous antibody decay to zero, “Gamma-decay”) and upper bound (decay-to-plateau due to long lived plasma cells, “Gamma-plateau”) long-term antibody titers.
Results
A total of 1163 samples were provided from 349 of 3555 recruited participants who were symptomatic, seropositive by the MSD assay, and were followed up with 2 or more monthly samples. At 200 days post symptom onset, 99% of participants had detectable S-antibody whereas only 75% of participants had detectable N-antibody. Even under our most pessimistic assumption of persistent negative exponential decay, the S-antibody was predicted to remain detectable in 95% of participants until 465 days [95% CI 370-575] after symptom onset. Under the Gamma-plateau model, the entire posterior distribution of S-antibody titers at plateau remained above the threshold for detection indefinitely. Surrogate neutralization assays demonstrated a strong positive correlation between antibody titers to the S-protein and blocking of the ACE-2 receptor in-vitro [R 2 =0.72, p<0.001]. By contrast, the N-antibody waned rapidly with a half-life of 60 days [95% CI 52-68].
Discussion
This study has demonstrated persistence of the spike antibody in 99% of participants at 200 days following SARS-CoV-2 symptoms and rapid decay of the nucleoprotein antibody. Diagnostic tests or studies that rely on the N-antibody as a measure of seroprevalence must be interpreted with caution. Our lowest bound prediction for duration of the spike antibody was 465 days and our upper bound predicted spike antibody to remain indefinitely in line with the long-term seropositivity reported for SARS-CoV infection. The long-term persistence of the S-antibody, together with the strong positive correlation between the S-antibody and viral surrogate neutralization in-vitro , has important implications for the duration of functional immunity following SARS-CoV-2 infection.
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SciScore for 10.1101/2020.11.20.20235697: (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: Serum antibodies titers were measured by the Meso Scale Discovery (MSD) Chemiluminescent binding assay that simultaneously detects and quantifies anti-SARS-CoV-2 IgG specific for trimeric S-protein, RBD and N-protein. anti-SARS-CoV-2 IgGsuggested: NoneN-proteinsuggested: 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 …SciScore for 10.1101/2020.11.20.20235697: (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: Serum antibodies titers were measured by the Meso Scale Discovery (MSD) Chemiluminescent binding assay that simultaneously detects and quantifies anti-SARS-CoV-2 IgG specific for trimeric S-protein, RBD and N-protein. anti-SARS-CoV-2 IgGsuggested: NoneN-proteinsuggested: 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:One potential limitation of this study is the fact that only 38% of participants had an available confirmatory positive PCR result. In order to mitigate this concern, prior to the study taking place, a formal performance evaluation of the MSD assay was undertaken among 169 confirmed PCR positive SARS-CoV-2 participants that demonstrated a 97.9% sensitivity and 97.4% specificity at 21 days post infection57. This makes the proportion of false positive serological tests likely to be small and therefore have little impact on our findings. Viral neutralization assays remain the gold-standard in vitro correlate of protection; as such, the lack of formal ‘authentic’ neutralization tests is another limitation of the study. However, ACE-2 receptor competition assays, such as the MSD competitive binding assay, have been shown to correlate well with formal viral neutralization assays, enabling their use as a suitable surrogate functional test58. 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. Recent studies have hypothesized that previous exposure to seasonal CoVs - to which healthcare workers may be disproportionately exposed - may confer some protection against SARS-CoV-212,19,53–56,58 and may need to be accounted for when modeling transmission or longevity dynamics59. Our estimates of the time-to-negativity are also dependent on the negative thresholds and lower limi...
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.
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