Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection | Infectious Diseases | JN Learning | AMA Ed Hub [Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 18.204.227.34. Please contact the publisher to request reinstatement.
[Skip to Content Landing]

Association of SARS-CoV-2 Seropositive Antibody Test With Risk of Future Infection

Educational Objective: To evaluate evidence of SARS-CoV-2 infection based on diagnostic nucleic acid amplification test (NAAT) among patients with positive vs negative test results for antibodies.
Key Points

Question  Can observational clinical data from commercial laboratories be used to evaluate the comparative risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection for individuals who are antibody positive vs those who are antibody negative?

Finding  In this cohort study of more than 3.2 million US patients with a SARS-CoV-2 antibody test, 0.3% of those indexed with positive test results had evidence of a positive nucleic acid amplification test beyond 90 days after index, compared with 3.0% indexed with negative antibody test results.

Meaning  Individuals who are seropositive for SARS-CoV-2 based on commercial assays may be at decreased future risk of SARS-CoV-2 infection.

Abstract

Importance  Understanding the effect of serum antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on susceptibility to infection is important for identifying at-risk populations and could have implications for vaccine deployment.

Objective  The study purpose was to evaluate evidence of SARS-CoV-2 infection based on diagnostic nucleic acid amplification test (NAAT) among patients with positive vs negative test results for antibodies in an observational descriptive cohort study of clinical laboratory and linked claims data.

Design, Setting, and Participants  The study created cohorts from a deidentified data set composed of commercial laboratory tests, medical and pharmacy claims, electronic health records, and hospital chargemaster data. Patients were categorized as antibody-positive or antibody-negative according to their first SARS-CoV-2 antibody test in the database.

Main Outcomes and Measures  Primary end points were post-index diagnostic NAAT results, with infection defined as a positive diagnostic test post-index, measured in 30-day intervals (0-30, 31-60, 61-90, >90 days). Additional measures included demographic, geographic, and clinical characteristics at the time of the index antibody test, including recorded signs and symptoms or prior evidence of coronavirus 2019 (COVID) diagnoses or positive NAAT results and recorded comorbidities.

Results  The cohort included 3 257 478 unique patients with an index antibody test; 56% were female with a median (SD) age of 48 (20) years. Of these, 2 876 773 (88.3%) had a negative index antibody result, and 378 606 (11.6%) had a positive index antibody result. Patients with a negative antibody test result were older than those with a positive result (mean age 48 vs 44 years). Of index-positive patients, 18.4% converted to seronegative over the follow-up period. During the follow-up periods, the ratio (95% CI) of positive NAAT results among individuals who had a positive antibody test at index vs those with a negative antibody test at index was 2.85 (95% CI, 2.73-2.97) at 0 to 30 days, 0.67 (95% CI, 0.6-0.74) at 31 to 60 days, 0.29 (95% CI, 0.24-0.35) at 61 to 90 days, and 0.10 (95% CI, 0.05-0.19) at more than 90 days.

Conclusions and Relevance  In this cohort study, patients with positive antibody test results were initially more likely to have positive NAAT results, consistent with prolonged RNA shedding, but became markedly less likely to have positive NAAT results over time, suggesting that seropositivity is associated with protection from infection. The duration of protection is unknown, and protection may wane over time.

Sign in to take quiz and track your certificates

Buy This Activity

JN Learning™ is the home for CME and MOC from the JAMA Network. Search by specialty or US state and earn AMA PRA Category 1 CME Credit™ from articles, audio, Clinical Challenges and more. Learn more about CME/MOC

Article Information

Accepted for Publication: January 28, 2021.

Published Online: February 24, 2021. doi:10.1001/jamainternmed.2021.0366

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Harvey RA et al. JAMA Internal Medicine.

Corresponding Author: Lynne T. Penberthy, MD, MPH, National Cancer Institute, National Institutes of Health, 9609 Medical Center Dr, Rockville, MD 20850 (lynne.penberthy@nih.gov).

Author Contributions: Mr Harvey and Dr Rassen had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Harvey, Rassen, Turenne, Leonard, Klesh, Kaufman, Cohen, Petkov, Cronin, Van Dyke, Lowy, Sharpless, Penberthy.

Acquisition, analysis, or interpretation of data: Harvey, Rassen, Kabelac, Turenne, Leonard, Klesh, Meyer, Kaufman, Anderson, Cohen, Petkov, Lowy, Sharpless, Penberthy.

Drafting of the manuscript: Harvey, Rassen, Kabelac, Kaufman, Anderson, Sharpless, Penberthy.

Critical revision of the manuscript for important intellectual content: Harvey, Rassen, Turenne, Leonard, Klesh, Meyer, Kaufman, Anderson, Cohen, Petkov, Cronin, Van Dyke, Lowy, Sharpless, Penberthy.

Statistical analysis: Harvey, Rassen, Kabelac, Turenne.

Obtained funding: Harvey, Leonard, Klesh, Cohen.

Administrative, technical, or material support: Harvey, Rassen, Kabelac, Turenne, Leonard, Klesh, Meyer, Kaufman, Cohen, Petkov, Sharpless.

Supervision: Harvey, Rassen, Turenne, Leonard, Klesh, Petkov, Cronin, Van Dyke, Sharpless, Penberthy.

Other - engagement of laboratory collaboration partners: Leonard, Klesh.

Conflict of Interest Disclosures: Mr Harvey is an employee of Aetion, Inc, which received payment for services for the submitted work. Dr Rassen reported other from the National Institutes of Health during the conduct of the study, and is an employee of and has an ownership stake in Aetion, Inc. Ms Kabelac is an employee of Aetion, which received payment for services for the submitted work during the conduct of the study. Ms Turenne is an employee of Aetion, which received payment for services for the submitted work. Ms Leonard reported other from the National Cancer Institute, payment made to HealthVerity for data license and analytics during the conduct of the study; request for proposal from National Cancer Institute; and nonfinancial support from the US Food and Drug Administration outside the submitted work. Ms Klesh reported other from the National Cancer Institute, payment made to HealthVerity for data license and analytics during the conduct of the study; request for proposal from National Cancer Institute and nonfinancial support from the US Food and Drug Administration outside the submitted work. Dr Kaufman is an employee of and owns stock in Quest Diagnostics. Dr Anderson was senior vice president of LabCorp during the conduct of the study, and is on advisory boards for OmniSeq, GeneCentric, Emulate, Kiatech, and Johnson & Johnson. Dr Cohen is an employee and shareholder of Covance (LabCorp) during the conduct of the study. No other disclosures were reported.

Funding/Support: This work was funded by the National Cancer Institute, Office of the Director.

Role of the Funder/Sponsor: The National Cancer Institute 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 would like to thank Tony Fauci, MD, and Cliff Lane, MD, for comments on the manuscript; both are associated with the National Institute of Allergy and Infectious Diseases of the National Institutes of Health and neither received any compensation for their assistance with this article.

References
1.
Stadlbauer  D , Tan  J , Jiang  K ,  et al.  Repeated cross-sectional sero-monitoring of SARS-CoV-2 in New York City.   Nature. 2020. Published online November 3, 2020. doi:10.1038/s41586-020-2912-6PubMedGoogle Scholar
2.
Wajnberg  A , Amanat  F , Firpo  A ,  et al.  Robust neutralizing antibodies to SARS-CoV-2 infection persist for months.   Science. 2020;370(6521):1227-1230. Published online October 28, 2020. doi:10.1126/science.abd7728PubMedGoogle ScholarCrossref
3.
Gudbjartsson  DF , Norddahl  GL , Melsted  P ,  et al.  Humoral immune response to SARS-CoV-2 in Iceland.   N Engl J Med. 2020;383(18):1724-1734. doi:10.1056/NEJMoa2026116PubMedGoogle ScholarCrossref
4.
Long  Q-X , Tang  X-J , Shi  Q-L ,  et al.  Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.   Nat Med. 2020;26(8):1200-1204. doi:10.1038/s41591-020-0965-6PubMedGoogle ScholarCrossref
5.
Ward  H , Atchison  CJ , Whitaker  M ,  et al  Antibody prevalence for SARS-CoV-2 in England following first peak of the pandemic: REACT2 study in 100,000 adults.   medRxiv. Published online August 21, 2020. doi:10.1101/2020.08.12.20173690Google Scholar
6.
Zuo  J , Dowell  A , Pearce  H ,  et al  Robust SARS-CoV-2-specific T-cell immunity is maintained at 6 months following primary infection.   bioRxiv. Published online January 1, 2020. doi:10.1101/2020.11.01.362319Google Scholar
7.
Ibarrondo  FJ , Fulcher  JA , Goodman-Meza  D ,  et al.  Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19.   N Engl J Med. 2020;383(11):1085-1087. doi:10.1056/NEJMc2025179PubMedGoogle ScholarCrossref
8.
Pray  IW .  COVID-19 outbreak at an overnight summer school retreat—Wisconsin, July–August 2020.   MMWR Morb Mortal Wkly Rep. 2020;69(43);1600–1604. doi:10.15585/mmwr.mm6943a4Google Scholar
9.
Addetia  A , Crawford  KH , Dingens  A ,  et al  Neutralizing antibodies correlate with protection from SARS-CoV-2 in humans during a fishery vessel outbreak with high attack rate.   Journ Clin Microbiol. 2020;58(11):e02107-20. doi:10.1128/JCM.02107-20Google Scholar
10.
Jeremias  S .  First case of COVID-19 reinfection detected in the US.  American Journal of Managed Care. October 12, 2020. Accessed November 11, 2020. https://www.ajmc.com/view/first-case-of-covid-19-reinfection-detected-in-the-us
11.
Boomerang  JVL . Albany County resident reinfected with COVID-19 months after recovery. Casper Star-Tribune Online. October 29, 2020. Accessed November 11, 2020. https://trib.com/news/state-and-regional/health/albany-county-resident-reinfected-with-covid-19-months-after-recovery/article_b88aeff7-091e-5afb-9ee3-1b5715e9e219.html
12.
Tillett  RL , Sevinsky  JR , Hartley  PD ,  et al.  Genomic evidence for reinfection with SARS-CoV-2: a case study.   Lancet Infect Dis. 2021;21(1):52-58. doi:10.1016/S1473-3099(20)30764-7PubMedGoogle ScholarCrossref
13.
Iwasaki  A .  What reinfections mean for COVID-19.   Lancet Infect Dis. 2021;21(1):3-5. doi:10.1016/S1473-3099(20)30783-0PubMedGoogle ScholarCrossref
14.
Hoang  VT , Dao  TL , Gautret  P .  Recurrence of positive SARS-CoV-2 in patients recovered from COVID-19.   J Med Virol. 2020;92(11):2366-2367. doi:10.1002/jmv.26056PubMedGoogle ScholarCrossref
15.
Li  N , Wang  X , Lv  T .  Prolonged SARS-CoV-2 RNA shedding: not a rare phenomenon.   J Med Virol. 2020;92(11):2286-2287. doi:10.1002/jmv.25952PubMedGoogle ScholarCrossref
16.
AlJishi  JM , Al-Tawfiq  JA .  Intermittent viral shedding in respiratory samples of patients with SARS-CoV-2: observational analysis with infection control implications.   J Hosp Infect. 2021;107:98-100. doi:10.1016/j.jhin.2020.09.011PubMedGoogle ScholarCrossref
17.
Lee  PH , Tay  WC , Sutjipto  S ,  et al.  Associations of viral ribonucleic acid (RNA) shedding patterns with clinical illness and immune responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.   Clin Transl Immunology. 2020;9(7):e1160. doi:10.1002/cti2.1160PubMedGoogle Scholar
18.
Li  TZ , Cao  ZH , Chen  Y ,  et al.  Duration of SARS-CoV-2 RNA shedding and factors associated with prolonged viral shedding in patients with COVID-19.   J Med Virol. Published online July 9, 2020.PubMedGoogle Scholar
19.
Morone  G , Palomba  A , Iosa  M ,  et al.  Incidence and persistence of viral shedding in COVID-19 post-acute patients with negativized pharyngeal swab: a systematic review.   Front Med (Lausanne). 2020;7:562. doi:10.3389/fmed.2020.00562PubMedGoogle ScholarCrossref
20.
Surkova  E , Nikolayevskyy  V , Drobniewski  F .  False-positive COVID-19 results: hidden problems and costs.   Lancet Respir Med. 2020;8(12):1167-1168. doi:10.1016/S2213-2600(20)30453-7PubMedGoogle ScholarCrossref
21.
Agarwal  V , Venkatakrishnan  AJ , Puranik  A ,  et al.  Long-term SARS-CoV-2 RNA shedding and its temporal association to IgG seropositivity.   Cell Death Discov. 2020;6(1):138. doi:10.1038/s41420-020-00375-yPubMedGoogle ScholarCrossref
22.
Meschi  S , Colavita  F , Bordi  L ,  et al; INMICovid-19 laboratory team.  Performance evaluation of Abbott ARCHITECT SARS-CoV-2 IgG immunoassay in comparison with indirect immunofluorescence and virus microneutralization test.   J Clin Virol. 2020;129:104539. doi:10.1016/j.jcv.2020.104539PubMedGoogle Scholar
23.
US Food and Drug Administration. EUA authorized serology test performance. December 7, 2020. Accessed December 7, 2020. https://www.fda.gov/medical-devices/coronavirus-disease-2019-covid-19-emergency-use-authorizations-medical-devices/eua-authorized-serology-test-performance
24.
US Food and Drug Administration. Real-world evidence. November 24, 2020. Accessed December 28, 2020. https://www.fda.gov/science-research/science-and-research-special-topics/real-world-evidence
25.
Sherman  RE , Anderson  SA , Dal Pan  GJ ,  et al.  Real-world evidence—what is it and what can it tell us?   N Engl J Med. 2016;375(23):2293-2297. doi:10.1056/NEJMsb1609216PubMedGoogle ScholarCrossref
26.
von Elm  E , Altman  DG , Egger  M , Pocock  SJ , Gøtzsche  PC , Vandenbroucke  JP ; STROBE Initiative.  The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.   Ann Intern Med. 2007;147(8):573-577. doi:10.7326/0003-4819-147-8-200710160-00010PubMedGoogle ScholarCrossref
27.
Sethuraman  N , Jeremiah  SS , Ryo  A .  Interpreting diagnostic tests for SARS-CoV-2.   JAMA. 2020;323(22):2249-2251. doi:10.1001/jama.2020.8259 PubMedGoogle ScholarCrossref
28.
Ainsworth  M , Andersson  M , Auckland  K ,  et al; National SARS-CoV-2 Serology Assay Evaluation Group.  Performance characteristics of five immunoassays for SARS-CoV-2: a head-to-head benchmark comparison.   Lancet Infect Dis. 2020;20(12):1390-1400. doi:10.1016/S1473-3099(20)30634-4PubMedGoogle ScholarCrossref
29.
Theel  ES , Harring  J , Hilgart  H , Granger  D .  Performance characteristics of four high-throughput immunoassays for detection of IgG antibodies against SARS-CoV-2.   J Clin Microbiol. 2020;58(8):e01243-20. doi:10.1128/JCM.01243-20 PubMedGoogle Scholar
30.
Hopkins  JS . Pfizer’s Covid-19 vaccine proves 90% effective in latest trials. Wall Street Journal. November 9, 2020. Accessed November 9, 2020. https://www.wsj.com/articles/covid-19-vaccine-from-pfizer-and-biontech-works-better-than-expected-11604922300
31.
National Institutes of Health. Promising interim results from clinical trial of NIH-Moderna COVID-19 vaccine. November 15, 2020. Accessed December 11, 2020. https://www.nih.gov/news-events/news-releases/promising-interim-results-clinical-trial-nih-moderna-covid-19-vaccine
32.
Polack  FP , Thomas  SJ , Kitchin  N ,  et al; C4591001 Clinical Trial Group.  Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine.   N Engl J Med. 2020;383(27):2603-2615. doi:10.1056/NEJMoa2034577PubMedGoogle ScholarCrossref
33.
Lumley  SF , O’Donnell  D , Stoesser  NE ,  et al; Oxford University Hospitals Staff Testing Group.  Antibody status and incidence of SARS-CoV-2 infection in health care workers.   N Engl J Med. 2020. doi:10.1056/NEJMoa2034545PubMedGoogle Scholar
34.
Pottegård  A , Kurz  X , Moore  N , Christiansen  CF , Klungel  O .  Considerations for pharmacoepidemiological analyses in the SARS-CoV-2 pandemic.   Pharmacoepidemiol Drug Saf. 2020;29(8):825-831. doi:10.1002/pds.5029PubMedGoogle ScholarCrossref
35.
Camm  AJ , Fox  KAA .  Strengths and weaknesses of “real-world” studies involving non-vitamin K antagonist oral anticoagulants.   Open Heart. 2018;5(1):e000788. doi:10.1136/openhrt-2018-000788PubMedGoogle Scholar
36.
Makady  A , de Boer  A , Hillege  H , Klungel  O , Goettsch  W ; (on behalf of GetReal Work Package 1).  What is real-world data? a review of definitions based on literature and stakeholder interviews.   Value Health. 2017;20(7):858-865. doi:10.1016/j.jval.2017.03.008PubMedGoogle ScholarCrossref
37.
Miksad  RA , Abernethy  AP .  Harnessing the power of real-world evidence (RWE): a checklist to ensure regulatory-grade data quality.   Clin Pharmacol Ther. 2018;103(2):202-205. doi:10.1002/cpt.946PubMedGoogle ScholarCrossref
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
If you are not a JN Learning subscriber, you can either:
Subscribe to JN Learning for one year
Buy this activity
jn-learning_Modal_Multimedia_LoginSubscribe_Purchase
Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close

Name Your Search

Save Search
Close
With a personal account, you can:
  • Track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
jn-learning_Modal_SaveSearch_NoAccess_Purchase
Close

Lookup An Activity

or

Close

My Saved Searches

You currently have no searches saved.

Close
With a personal account, you can:
  • Access free activities and track your credits
  • Personalize content alerts
  • Customize your interests
  • Fully personalize your learning experience
Education Center Collection Sign In Modal Right
Close