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Figure.  Naturally Acquired Serum IgG Antibodies to SARS-CoV-2 Over Time in Previously PCR Positive HWs
Naturally Acquired Serum IgG Antibodies to SARS-CoV-2 Over Time in Previously PCR Positive HWs

Naturally acquired serum immunoglobin (Ig) G antibodies to the S1 domain of the spike protein of SARS-CoV-2 over time in hospital workers (HWs) who previously received positive polymerase chain reaction (PCR) results for SARS-CoV-2. The line represents mean IgG as a function of days from positive PCR test, based on a natural cubic spline (2 df). The 95% CI was constructed via 10 000 bootstrap samples of HWs. IgG antibody measurements were determined based on optical density ratios with an upper threshold of 11 based on assay saturation.

Table.  Study Cohort Characteristics
Study Cohort Characteristics
1.
Chen  X, Chen  Z, Azman  AS,  et al.  Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis.   Lancet Glob Health. 2021;9(5):e598-e609. doi:10.1016/S2214-109X(21)00026-7PubMedGoogle ScholarCrossref
2.
Rodda  LB, Netland  J, Shehata  L,  et al.  Functional SARS-CoV-2–specific immune memory persists after mild COVID-19.   Cell. 2021;184(1):169-183.e17. doi:10.1016/j.cell.2020.11.029PubMedGoogle ScholarCrossref
3.
Caturegli  G, Materi  J, Howard  BM, Caturegli  P.  Clinical validity of serum antibodies to SARS-CoV-2 : a case-control study.   Ann Intern Med. 2020;173(8):614-622. doi:10.7326/M20-2889PubMedGoogle ScholarCrossref
4.
Manisty  C, Treibel  TA, Jensen  M,  et al.  Time series analysis and mechanistic modelling of heterogeneity and sero-reversion in antibody responses to mild SARS-CoV-2 infection.   EBioMedicine. 2021;65:103259. doi:10.1016/j.ebiom.2021.103259PubMedGoogle Scholar
5.
Van Elslande  J, Gruwier  L, Godderis  L, Vermeersch  P.  Estimated half-life of SARS-CoV-2 anti-spike antibodies more than double the half-life of anti-nucleocapsid antibodies in healthcare workers.   Clin Infect Dis. 2021;ciab219. doi:10.1093/cid/ciab219PubMedGoogle Scholar
6.
Institute of Medicine.  Priorities for the National Vaccine Plan. National Academies Press; 2010.
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    Research Letter
    Infectious Diseases
    August 30, 2021

    Durability of Spike Immunoglobin G Antibodies to SARS-CoV-2 Among Health Care Workers With Prior Infection

    Author Affiliations
    • 1Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 2Johns Hopkins School of Public Health, Baltimore, Maryland
    JAMA Netw Open. 2021;4(8):e2123256. doi:10.1001/jamanetworkopen.2021.23256
    Introduction

    Herd immunity is needed to reduce deaths, prevent transmission, and minimize the emergence of SARS-CoV-2 variants. The durability of serum antibodies against the spike protein of this virus provides insights into immunologic memory following natural infection.1 Recent literature supports that the levels of spike antibodies induced by natural infection correlate with neutralization and protect against subsequent infection.2 We evaluated the durability of naturally acquired spike immunoglobin (Ig) G antibodies to SARS-CoV-2 among a cohort of health care workers.

    Methods

    Beginning in June 2020, 3015 hospital workers (HWs) at 5 regional hospitals in the Johns Hopkins Health System consented to participate and were enrolled in a prospective cohort study to determine the seroprevalence of spike antibodies to SARS-CoV-2. This study was approved by the Johns Hopkins University institutional review board. Cohort results followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline. Data were analyzed March 2021.

    Participants provided serum samples and completed surveys (including providing demographic data and exposures) every 3 to 4 months after enrollment. SARS-CoV-2 polymerase chain reaction (PCR)–testing and immunization data were collected from electronic health records. A convenience sample of HWs who tested positive for SARS-CoV-2 and then had at least 1 positive anti–SARS-CoV-2 IgG measurement prior to vaccination were included in this analysis. Serum specimens were tested using an enzyme-linked immunosorbent assay (Euroimmun) that targets the S1 subunit of the SARS-CoV-2 spike protein and measures optical density ratios. We applied an internally derived IgG cutoff ratio (>1.23) for greater sensitivity and specificity with an upper threshold of 11 based on assay saturation.3,4

    Median serum IgG ratios as a function of time (ie, days from positive PCR test) were visualized using a natural cubic spline (with 2 df) with 95% bootstrap CIs to account for multiple serum samples within HWs. A linear mixed model with random intercept for each HW quantified the relative change in serum IgG ratio per day from a positive PCR test. A sensitivity analysis, including only HWs with multiple serum samples, estimated the within-participant relative change in IgG by separating the cross-sectional and longitudinal effect of time. Analysis was conducted using R version 4.0.2 (R Project for Statistical Computing). The threshold for statistical significance was α < .05 in 2-sided tests.

    Results

    Among the cohort of 3015 HWs (2359 [78.3%] women; median [interquartile range {IQR}] age, 38.4 [31.6-50.0] years), 170 (5.6%) HWs had positive PCR results for SARS-CoV-2, of which only 94 (3.1%) were tested for spike antibodies after infection but before vaccination (57 HWs received 1 antibody test after PCR positive, 36 received 2 tests, and 1 received 3 tests). Of the 94 HWs, 90 (96%) were non-Hispanic/Latino and 70 (74%) were White; the median (IQR) age of HWs tested after PCR-positive results was 37.5 (31.1-46.7) years (Table).

    The median spike IgG antibody ratios as a function of days from positive PCR test are shown in the Figure. Fifty-two of 59 (88%), 30 of 40 (75%), and 25 of 33 (76%) HWs who tested less than 100, 100 to 200, and more than 200 days post-PCR were IgG positive, respectively. IgG antibodies were positive in 72% (8 of 11) of those tested more than 250 days postinfection. The estimated rate of IgG decay was 7% per month (95% CI, 3%-10%). In participants with multiple tests postinfection, the within-participant rate of decay was 7% (95% CI, 3%-11%) per month.

    Discussion

    Our results demonstrated the durability of spike antibodies to SARS-CoV-2 up to 10 months after natural infection. The Centers for Disease Control and Prevention acknowledges that prior SARS-CoV-2 infection reduces the risk of reinfection for a minimum 90-day period. Our data demonstrate durability of IgG titers well beyond this period and extend recently published intervals of 6 to 8 months.2,5

    This study was limited by its use of a convenience sample nested within a longitudinal cohort of hospital workers, which means results may not be generalizable. Additional studies are also needed to determine whether antibody levels represent lasting immunity to the evolving SARS-CoV-2.

    As vaccine supply remains limited globally, those with naturally derived antibodies may contribute to herd immunity. Therefore, some countries may consider prioritizing vaccination for those without measurable antibodies, a strategy used in prior vaccination campaigns when shortages exist.6 However, more research is needed to understand protection against emerging variants based on natural vs vaccine-derived immunity.

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    Article Information

    Accepted for Publication: June 27, 2021.

    Published: August 30, 2021. doi:10.1001/jamanetworkopen.2021.23256

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Egbert ER et al. JAMA Network Open.

    Corresponding Author: Amanda K. Debes, PhD, MS, Department of International Health, 615 N Wolfe St, E5036, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205 (adebes1@jhu.edu).

    Author Contributions: Dr Milstone had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Egbert, Milstone, Debes.

    Acquisition, analysis, or interpretation of data: All authors.

    Drafting of the manuscript: Egbert, Colantuoni, Debes.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Xiao, Colantuoni, Debes.

    Obtained funding: Milstone.

    Administrative, technical, or material support: Egbert, Caturegli, Gadala, Debes.

    Supervision: Milstone.

    Conflict of Interest Disclosures: None reported.

    Funding/Support: This study was supported through the generosity of the collective community of donors to the Johns Hopkins University School of Medicine and the Johns Hopkins Health System for COVID research. Research reported in this publication was also supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number K24AI141580 (Dr Milstone).

    Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    Additional Contributions: The authors would like to thank members of the Johns Hopkins Hospital Clinical Immunology Laboratory, Danielle Koontz, MA, MS, and Annie Voskertchian, MPH, of the Johns Hopkins Division of Pediatric Infectious Diseases. Contributors received no additional compensation.

    References
    1.
    Chen  X, Chen  Z, Azman  AS,  et al.  Serological evidence of human infection with SARS-CoV-2: a systematic review and meta-analysis.   Lancet Glob Health. 2021;9(5):e598-e609. doi:10.1016/S2214-109X(21)00026-7PubMedGoogle ScholarCrossref
    2.
    Rodda  LB, Netland  J, Shehata  L,  et al.  Functional SARS-CoV-2–specific immune memory persists after mild COVID-19.   Cell. 2021;184(1):169-183.e17. doi:10.1016/j.cell.2020.11.029PubMedGoogle ScholarCrossref
    3.
    Caturegli  G, Materi  J, Howard  BM, Caturegli  P.  Clinical validity of serum antibodies to SARS-CoV-2 : a case-control study.   Ann Intern Med. 2020;173(8):614-622. doi:10.7326/M20-2889PubMedGoogle ScholarCrossref
    4.
    Manisty  C, Treibel  TA, Jensen  M,  et al.  Time series analysis and mechanistic modelling of heterogeneity and sero-reversion in antibody responses to mild SARS-CoV-2 infection.   EBioMedicine. 2021;65:103259. doi:10.1016/j.ebiom.2021.103259PubMedGoogle Scholar
    5.
    Van Elslande  J, Gruwier  L, Godderis  L, Vermeersch  P.  Estimated half-life of SARS-CoV-2 anti-spike antibodies more than double the half-life of anti-nucleocapsid antibodies in healthcare workers.   Clin Infect Dis. 2021;ciab219. doi:10.1093/cid/ciab219PubMedGoogle Scholar
    6.
    Institute of Medicine.  Priorities for the National Vaccine Plan. National Academies Press; 2010.
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