Durability of Antibody Levels After Vaccination With mRNA SARS-CoV-2 Vaccine in Individuals With or Without Prior Infection | Infectious Diseases | JAMA | JAMA Network
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Figure.  Waning IgG Antibodies to SARS-CoV-2 After Vaccination in Health Care Workers With or Without Prior SARS-CoV-2 Infection
Waning IgG Antibodies to SARS-CoV-2 After Vaccination in Health Care Workers With or Without Prior SARS-CoV-2 Infection

Prior SARS-CoV-2 infection was defined as positive SARS-CoV-2 polymerase chain reaction (PCR) test results prior to receipt of the first dose of the mRNA vaccine. The dotted lines represent the positive IgG threshold, at an antibody measurement of 1.23, the lines represent the unadjusted median antibody measurements as a function of days following mRNA vaccination, based on natural cubic splines (2 degrees of freedom) for each group, and shaded areas represent 95% CIs for the unadjusted median antibody measurements.

Table.  Adjusted Antibody Measurements Over Time After 2 Doses of mRNA SARS-CoV-2 Vaccine in Health Care Workers With or Without Prior SARS-CoV-2 Infection
Adjusted Antibody Measurements Over Time After 2 Doses of mRNA SARS-CoV-2 Vaccine in Health Care Workers With or Without Prior SARS-CoV-2 Infection
1.
Khoury  DS, Cromer  D, Reynaldi  A,  et al.  Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.   Nat Med. 2021;27(7):1205-1211. doi:10.1038/s41591-021-01377-8PubMedGoogle ScholarCrossref
2.
Bergwerk  M, Gonen  T, Lustig  Y,  et al.  Covid-19 breakthrough infections in vaccinated health care workers.   N Engl J Med. 2021;385(16):1474-1484. doi:10.1056/NEJMoa2109072PubMedGoogle ScholarCrossref
3.
Schmidt  F, Weisblum  Y, Rutkowska  M,  et al.  High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape.   Nature. 2021. doi:10.1038/s41586-021-04005-0PubMedGoogle Scholar
4.
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
5.
Debes  AK, Xiao  S, Colantuoni  E,  et al.  Association of vaccine type and prior SARS-CoV-2 infection with symptoms and antibody measurements following vaccination among health care workers.   JAMA Intern Med. 2021. doi:10.1001/jamainternmed.2021.4580PubMedGoogle Scholar
6.
Parry  H, Bruton  R, Stephens  C,  et al.  Extended interval BNT162b2 vaccination enhances peak antibody generation in older people.  MedRxiv. Preprint posted May 17, 2021. doi:10.1101/2021.05.15.21257017
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    Research Letter
    November 1, 2021

    Durability of Antibody Levels After Vaccination With mRNA SARS-CoV-2 Vaccine in Individuals With or Without Prior Infection

    Author Affiliations
    • 1Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 2Johns Hopkins School of Public Health, Baltimore, Maryland
    JAMA. Published online November 1, 2021. doi:10.1001/jama.2021.19996

    Waning serum antibodies against SARS-CoV-2 have raised questions about long-term immunity. Lower antibody levels to SARS-CoV-2 spike protein are associated with breakthrough infections after vaccination, prompting consideration of booster doses.1,2 Prior infection may enhance protection from vaccination, stimulating inquiry about hybrid immunity.3 Our objective was to examine SARS-CoV-2 spike IgG antibodies in a longitudinal cohort, comparing antibody durability in individuals who received an mRNA SARS-CoV-2 vaccine with or without prior SARS-CoV-2 infection.

    Methods

    A convenience sample of 3500 health care workers from the Johns Hopkins Health System were enrolled starting June 2020 and followed up through September 3, 2021. Participants provided serum samples longitudinally, separated by at least 90 days. SARS-CoV-2 polymerase chain reaction (PCR) test results and vaccination dates (inside and outside the health system) were collected from electronic health records. Included participants had a serum sample collected at least 14 days after receiving the second dose of an mRNA SARS-CoV-2 vaccine. Previous SARS-CoV-2 infection was defined by the date of positive SARS-CoV-2 PCR test results prior to first vaccine dose. IgG antibody measurements were obtained using an enzyme-linked immunosorbent assay (Euroimmun), estimating optical density ratios with a lower threshold of 1.23 and upper threshold of 11.00 based on assay saturation.4,5 Linear regression models for log-transformed postvaccination antibody measurements were used to compare absolute and relative differences in median antibody measurements among health care workers with or without prior SARS-CoV-2 infection at 1, 3, and 6 months and health care workers with PCR-confirmed prior SARS-CoV-2 infection less than or equal to 90 days and greater than 90 days before receipt of the vaccine at 1 and 3 months, after adjusting for vaccine type, age, and sex. Statistical significance was defined as a 95% CI that did not include 1.00 for the relative adjusted median and a 95% CI that did not include 0 for the absolute difference in adjusted median. Analyses were performed in R software, version 4.0.2 (R Foundation).

    Ethical approval was obtained from the institutional review board at Johns Hopkins University with verbal consent.

    Results

    Of the 1960 health care workers who provided serum samples at least 14 days after receipt of the second vaccine dose, 73 (3.7%) had evidence of previous infection (41 with positive PCR results ≤90 days before vaccination and 32 with positive PCR results >90 days before vaccination). Of these 1960 participants, 80% were women, 95% were Non-Hispanic/Latino, and 80% were White. The median (IQR) age of participants was 40.4 (32.6-52.1) years.

    Among participants without previous SARS-CoV-2 infection, the adjusted median antibody measurements were 8.69 (95% CI, 8.56-8.80) at 1 month, 7.28 (95% CI, 7.15-7.40) at 3 months, and 4.55 (95% CI, 4.16-4.91) at 6 months after vaccination (Figure, A and Table). Compared with participants without previous SARS-CoV-2 infection, those with prior infection maintained higher postvaccination adjusted median antibody measurements by an absolute difference of 1.25 (95% CI, 0.86-1.62) (relative difference, 14% [95% CI, 10%-19%]) at 1 month, 1.42 (95% CI, 0.98-1.86) (relative difference, 19% [95% CI, 13%-26%]) at 3 months, and 2.56 (95% CI, 1.66-4.08) (relative difference, 56% [95% CI, 35%-94%]) at 6 months. Individuals with PCR-confirmed infection more than 90 days before vaccination had higher postvaccination adjusted antibody measurements, compared with those with PCR-confirmed infection less than or equal to 90 days before vaccination, of 10.52 (95% CI, 10.13-11.00) (absolute difference, 0.86 [95% CI, 0.28-1.48]; relative difference, 9% (95% CI, 3%-16%]) at 1 month and 9.31 (95% CI, 8.47-9.98) (absolute difference, 1.09 [95% CI, 0.17-1.92]; relative difference, 13% [95% CI, 2%-24%]) at 3 months (Figure, B and Table).

    Discussion

    Health care workers with prior SARS-CoV-2 infection followed by 2 doses of mRNA vaccine (3 independent exposures to spike antigen) developed higher spike antibody measurements than individuals with vaccination alone. Consistent with work comparing extended vaccine dosing intervals, the study showed that a longer interval between infection and first vaccine dose may enhance the antibody response.6

    Limitations of the study included defining SARS-CoV-2 infection as positive PCR test results (potentially misclassifying participants with unconfirmed prior infection), the use of convenience sampling, and a small proportion of included participants with infection prior to vaccination. The study also did not examine neutralization titers or reinfection. Generalizability may be limited by a majority female, White, middle-aged population.

    Further investigation is warranted to determine whether increased postvaccination antibody durability in previously infected individuals is attributable to number of exposures, interval between exposures, or the interplay between natural and vaccine-derived immunity. Studies are needed to elucidate how serological testing can inform optimal vaccine timing and need for booster doses.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Associate Editor.
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    Article Information

    Corresponding Author: Diana Zhong, MD, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E Monument St, Baltimore, MD 21205 (dzhong5@jhmi.edu).

    Accepted for Publication: October 21, 2021.

    Published Online: November 1, 2021. doi:10.1001/jama.2021.19996

    Author Contributions: Dr Milstone had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Zhong and Xiao contributed equally as co–first authors.

    Concept and design: Zhong, Debes, Egbert, Milstone.
    Acquisition, analysis, or interpretation of data: All authors.
    Drafting of the manuscript: Zhong, Xiao, Debes, Colantuoni.
    Critical revision of the manuscript for important intellectual content: All authors.
    Statistical analysis: Xiao, Debes, Colantuoni.
    Obtained funding: Milstone.
    Administrative, technical, or material support: Zhong, Debes, Egbert.
    Supervision: Debes, Colantuoni, Milstone.

    Conflict of Interest Disclosures: Dr Milstone reported receiving grant support from Merck outside the submitted work. No other disclosures were reported.

    Funding/Support: Research reported in this publication was supported in part by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under awards T32AI007291 (Dr Zhong) and K24AI141580 (Dr Milstone) and the generosity of the collective community of donors to the Johns Hopkins University School of Medicine and the Johns Hopkins Health System for COVID-19 research.

    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.

    Additional Contributions: We thank members of the Johns Hopkins Hospital Clinical Immunology Laboratory, Danielle Koontz, MAS, and Ani Voskertchian, MPH (Johns Hopkins University School of Medicine), for study coordination; Shaun Truelove, PhD (Johns Hopkins University Bloomberg School of Public Health), for intellectual contribution; Avinash Gadala, PhD (Johns Hopkins Health System), for data management; and Benjamin Mark Landrum, MD; Morgan Katz, MD; S. Sonia Qasba, MD, MPH; and Pooja Gupta, MD (Johns Hopkins University School of Medicine), for help with study recruitment. Lastly, we thank Kirsten Vannice, PhD, MHS (Bill and Melinda Gates Foundation), for providing contribution to the analysis. None of the contributors above received compensation for their roles.

    References
    1.
    Khoury  DS, Cromer  D, Reynaldi  A,  et al.  Neutralizing antibody levels are highly predictive of immune protection from symptomatic SARS-CoV-2 infection.   Nat Med. 2021;27(7):1205-1211. doi:10.1038/s41591-021-01377-8PubMedGoogle ScholarCrossref
    2.
    Bergwerk  M, Gonen  T, Lustig  Y,  et al.  Covid-19 breakthrough infections in vaccinated health care workers.   N Engl J Med. 2021;385(16):1474-1484. doi:10.1056/NEJMoa2109072PubMedGoogle ScholarCrossref
    3.
    Schmidt  F, Weisblum  Y, Rutkowska  M,  et al.  High genetic barrier to SARS-CoV-2 polyclonal neutralizing antibody escape.   Nature. 2021. doi:10.1038/s41586-021-04005-0PubMedGoogle Scholar
    4.
    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
    5.
    Debes  AK, Xiao  S, Colantuoni  E,  et al.  Association of vaccine type and prior SARS-CoV-2 infection with symptoms and antibody measurements following vaccination among health care workers.   JAMA Intern Med. 2021. doi:10.1001/jamainternmed.2021.4580PubMedGoogle Scholar
    6.
    Parry  H, Bruton  R, Stephens  C,  et al.  Extended interval BNT162b2 vaccination enhances peak antibody generation in older people.  MedRxiv. Preprint posted May 17, 2021. doi:10.1101/2021.05.15.21257017
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