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SARS-CoV-2 Serology (COVID-19) Antibody (IgG), Qualitative (39504); SARS-CoV-2 Antibody (IgG), Nucleocapsid, Qualitative (39749); SARS-CoV-2 Serology (COVID-19) Antibodies (IgG, IgM), Qualitative (31672); SARS-CoV-2 Antibody (IgG), Spike, Semiquantitative

Test code(s) 39504, 39749, 31672, 34499

The FAQ information attached by the previously provided link has been retired. The link continues to be available for your historic reference. Current FAQs can be viewed at QuestDiagnostics.com/FAQs.

Question 1. What kind of immunoassay does Quest Diagnostics utilize for SARS-CoV-2 (COVID-19) antibody testing?  

Quest utilizes only SARS-CoV-2 antibody tests that have received emergency use authorization (EUA) from the US Food and Drug Administration (FDA). At present, EUA SARS-CoV-2 antibody tests fall into 2 main groups: 

  1. Laboratory-based immunoassays: Several types of immunoassays are available in this category, such as enzyme-linked immunosorbent assays (ELISAs), chemiluminescent microparticle immunoassays (CMIAs), and immunometric assays.1,2 Within this laboratory-based test group, assays can be qualitative, semiquantitative, or quantitative and are generally performed using serum.2 These immunoassays use a solid phase coated with viral antigen to bind SARS-CoV-2 antibodies, but different tests may use different solid phases. For example, ELISAs use a plate and CMIAs use paramagnetic microparticles.1 Quest currently offers high-complexity laboratory-based qualitative immunoassays for SARS-CoV-2. One is for immunoglobulin G (IgG) and the other is a duplex assay for SARS-CoV-2 IgG/Immunoglobulin M (IgM). Our IgG and combination IgG/IgM tests are amenable to high-throughput methodologies commensurate with national pandemic testing needs.

  2. Rapid diagnostic tests (RDTs): These are typically lateral flow assays that can be used for point-of-care (POC) testing. RDTs most frequently test for SARS-CoV-2 IgG, IgM.1 These tests usually use blood specimens from a finger stick, and some can use saliva or other specimen types.1,2

At this time, our SARS-CoV-2 antibody tests are laboratory-based, qualitative, and semiquantitative immunoassays; we do not offer RDTs at this time. See question 3 for more information regarding test names, test codes, and performance characteristics. 

Question 2. What is the FDA policy for commercial manufacturers and laboratory development/use of serology tests for SARS-CoV-2?

The FDA’s first guidance in early spring of 2020 to the developers of SARS-CoV-2 antibody tests was more flexible than for molecular tests. On May 4, 2020, the FDA revised this policy to require antibody test developers to submit EUA requests, with their validation data, within 10 business days from the date they notified the FDA of their validation testing OR from the date of this policy, whichever is later.2 The FDA provided specific performance threshold recommendations for specificity and sensitivity.2

SARS-CoV-2 IgG and IgM antibody assays offered by Quest have been authorized through an EUA process.3-9 The FDA has created a website to summarize the performance of the serology tests that have been granted EUA.4 On April 17, 2020, the FDA also issued a letter for healthcare providers recommending continued use of serologic tests, as appropriate, with awareness of their limitations.8

Question 3. What are the performance characteristics of Quest’s SARS-CoV-2 antibody immunoassays? 

Before patient specimen testing, Quest verifies the performance characteristics of the FDA EUA-designated assays by completing CLIA/CAP-specified in-laboratory verification using stringent acceptability criteria for precision, reproducibility, accuracy, method comparison, cross-reactivity, and clinical performance. Highlights of the manufacturers’ clinical performance of the SARS-CoV-2 IgG and IgM kits used at Quest are as follows:  

  1. SARS-CoV-2 Serology (COVID-19) Antibody (IgG), Qualitative (39504): a qualitative test for SARS-CoV-2 IgG antibodies to spike proteina

    1. Estimated assay sensitivity is approximately 90.0%3 for specimens collected at least 15 days post-symptom onset,3 based on positive percent agreement (PPA)4 of SARS-CoV-2 IgG serology results for specimens from patients positive for SARS-CoV-2 RNA.3

    2. Estimated assay specificity is >99.9%,3 based on negative percent agreement (NPA)4 assessed by performing cross-reactivity studies utilizing serum samples positive for antibodies to other respiratory viruses pre– and post–COVID-19 time periods.3

  2. SARS-CoV-2 Antibody (IgG), Nucleocapsid, Qualitative (test code 39749; also a component of the IgM/IgG panel [test code 39749])

    1. Estimated assay sensitivity is >99.6%5 for specimens collected at least 15 days post-symptom onset,5 based on PPA4 of SARS-CoV-2 IgG serology results among SARS-CoV-2 RNA−positive patients.5

    2. Estimated assay specificity is >99.9%,5 based on NPA4 assessed by performing cross-reactivity studies utilizing serum specimens positive for antibodies to other respiratory viruses pre- and post-COVID-19 time periods.5

  3. SARS-CoV-2 Serology (COVID-19) Antibodies, IgM Qualitative (a component of the IgM/IgG panel [test code 31672])

    1. Estimated assay sensitivity is 95%6 for specimens collected at least 15 days post-symptom onset,6 based on PPA4of SARS-CoV-2 IgM serology results among SARS-CoV-2RNA positive patients.6

    2. Estimated specificity is >99%6 based on NPA4  assessed by performing SARS-CoV-2 IgM tests on serum specimens positive for antibodies to other respiratory viruses pre– and post–COVID-19 time periods.6

  4. SARS-CoV-2 Antibody (IgG), Spike, Semiquantitative (test code 34499)

    1. Estimated assay sensitivity is >99.9%7 for specimens collected at least 15 days post-symptom onset,7 based on PPA4 of SARS-CoV-2 IgG serology results among SARS-CoV-2 RNA−positive patients.7

    2. Estimated assay specificity is approximately 99.9%,7 based on NPA4 assessed by performing cross-reactivity studies utilizing serum specimens positive for antibodies to other respiratory viruses pre– and post–COVID-19 time periods.7

aRequisitions for test code 39504 received at Quest labs in Atlanta, Miami, and Tampa will continue to report detection of IgG to spike or nucleocapsid proteins, unspecified. Customers of these performing labs who would like to specifically request SARS-CoV-2 spike IgG or SARS-CoV-2 nucleocapsid IgG should contact their local sales representative or call 1.866.697.8378. 

Question 4. How soon do IgM and IgG antibodies to SARS-CoV-2 appear in a patient who has been infected with SARS-CoV-2?

The antibody response to SARS-CoV-2 usually starts with IgM and/or IgA being detectable first, followed by the longer-lasting and more specific IgG. Data suggest that IgM antibodies can be detected within a few days post-infection6 and IgG antibodies will be detectable from some individuals by 10 days after COVID-19 symptom onset.3-5,7 However, some people do not generate detectable IgG antibodies after infection, because of an underlying immune disorder, immunosuppression, or other, as yet unidentified, reasons.9,10 Additionally, an individual’s immune response can vary in the speed and strength of IgM and IgG production upon exposure to SARS-CoV-2, based on infective dose, viral burden, or host factors.9,10 In a review of current advances in SARS-CoV-2 serology testing, the combined use of IgM and IgG detection resulted in a higher sensitivity than that observed when detecting either antibody isotype alone.9,10

Question 5. Should antibody tests be used to diagnose current SARS-CoV-2 infection?

No. At present, no antibody tests have an FDA EUA specified intended use that includes definitive diagnosis of, or ruling out of, current SARS-CoV-2 infection.2-7 Serologic IgM and IgG assays provide information about whether a person has developed an immune response to a COVID-19 spike vaccine or recent/prior infection with SARS-CoV-2.2-7 A molecular diagnostic RNA assay should be considered to confirm the diagnosis of current infection.2 Although the FDA has not specified the intended use of antibody tests to diagnose SARS-CoV-2 infection, serologic assays may be used to support clinical assessment of

  • Persons who present to clinicians late in their illnesses (9-14 days after symptom onset), when used in conjunction with viral detection tests11; and

  • Persons suspected to have a post-infectious syndrome caused by SARS-CoV-2 infection (eg, multisystem inflammatory syndrome in children [MIS-C]).11

Question 6. How do I interpret SARS-CoV-2 Serology (COVID-19) Antibody (IgG), Qualitative results?

Results from a qualitative (spike) test for SARS-CoV-2 IgG can be positive (reactive), negative (non-reactive), or, occasionally, equivocal (borderline).12,13

A positive result indicates detection of SARS-CoV-2 IgG, which indicates an immune response to a COVID-19 spike vaccine or recent/prior infection with SARS-CoV-2.  It usually takes at least 10 days after symptom onset for IgG to reach detectable levels. Although the relationship between IgG positivity and immunity to SARS-CoV-2 has not yet been established, detection of IgG may suggest an immune response to SARS-CoV-2 after resolution of infection or in response to vaccination. It is currently not known for how long IgG remains detectable after vaccination or exposure to SARS-CoV-2.12,13

A negative (non-reactive) result indicates that SARS-CoV-2 IgG is not present at a level that is detectable by the SARS-CoV-2 Serology (COVID-19) Antibody (IgG), Immunoassay.12,13 Negative results suggest that a person has not been infected with SARS-CoV-2 or has been very recently infected (antibodies have not yet been produced).12,13 Such a patient is at risk of infection, however, the rate of IgG development varies between individuals. A detectable IgG response usually takes at least 10 days after vaccination or exposure but may take up to 3 weeks or longer to develop in some patients, and some people may not develop antibodies at all. The IgG response is usually slower in people who are either taking immunosuppressive therapies or are immunocompromised because of a health condition.12,13 Given the variability in timing of an IgG response, a repeat serology IgG test should be considered after an additional 2- to -3-week period for patients who are initially antibody negative and are thought to have clinically recovered from a SARS-CoV-2 infection.12,13

An equivocal (borderline) result indicates that IgG was detected at a level close to the threshold of the limit of detection for the test.12,13 Equivocal results may occur for unidentified reasons or may represent an early infection, detection of an IgG generated from a past infection (refer to Question 9 for cross-reactivity with non-SARS-CoV-2 coronavirus strains), or, in some cases, an underlying immune disorder, immunosuppression, or other conditions.12,13

In populations with a high prevalence of infection with non-SARS-CoV-2 coronavirus strains, a positive result could also be due to past or present infection with 1 of these strains (refer to Question 12).

Question 7. How do I interpret SARS-CoV-2 (COVID-19) Serology Antibody (IgM) (a component of the IgG/IgM, qualitative, panel) results?

Quest only offers SARS-CoV-2 IgM in a panel that includes a separate IgG determination. The results from this qualitative test for SARS-CoV-2 IgM can be positive (reactive) or negative (non-reactive).14

A positive (reactive) result indicates that antibodies to SARS-CoV-2 were detected and the individual has potentially been infected with SARS-CoV-2.14 SARS-CoV-2 IgM is generally detectable in blood several days after initial infection. Detection of IgM may indicate a recent infection.14 It is unknown how long SARS-CoV-2 IgM remains detectable post-infection.11,14

Whether SARS-CoV-2 antibodies confer immunity to infection also remains unknown.11,14 Incorrect assumptions of immunity may lead to premature discontinuation of physical distancing requirements and could increase the risk of infection for individuals, their household members, and the public.14

A negative test result means that SARS-CoV-2 IgM was not present in the specimen at levels above the limit of detection.6 However, patients tested early after infection may not have detectable antibodies despite active infection. A negative result should not be used to rule out infection. Testing of patient specimens for the presence of virus material (eg, RNA or antigen) should be performed if acute infection is suspected.14

A recent publication supports the use of simultaneous IgG/IgM measurements (regardless of method) to significantly improve assay sensitivity.9 Regardless of the test result, individuals should continue to follow CDC guidelines to reduce the risk of infection, including social distancing and wearing masks.14

Question 8. How do I interpret a positive result on a qualitative SARS-CoV-2 spike or nucleocapsid IgG antibody test?

The first 2 COVID-19 vaccines launched in the United States comprise messenger RNA (mRNA) that carries instructions for making SARS-CoV-2 spike protein. The spike protein is on the outside of the virus and is used for attachment and entry into the human host cell.15 A positive SARS-CoV-2 spike IgG antibody result may indicate an immune response to either a COVID-19 vaccine and/or a recent/prior naturally acquired infection with SARS-CoV-2.3,7,8 However, use of antibody testing with pre- and post-vaccine administration is currently not recommended by either the FDA or CDC.

A positive/reactive nucleocapsid antibody test result indicates recent or prior infection with the virus and an immune response to SARS-CoV-2 (COVID-19).4,5

Question 9. How do I interpret a positive/reactive result on a semiquantitative SARS-CoV-2 spike IgG immunoassay?    

A SARS-CoV-2 semi-quantitative IgG test result is reported as positive at an index15 of ≥1.00. This positive result means that an individual has developed an immune response to SARS-CoV-2 infection or a SARS-CoV-2 spike mRNA vaccine within the limit of detection of the assay.15 However, a positive result may also suggest an immune response to the SARS-CoV-2 spike mRNA vaccine. Since much is still not known about the body’s immune response to this virus, this test result cannot be used to indicate a level of immunity or rule out the chance for reinfection.15 This test should not be used to diagnose current SARS-CoV-2 infection. If a current infection is suspected, direct molecular or antigen testing for SARS-CoV-2 is necessary.7,15

Conversely, a negative result is reported at an index7 of <1.00. A negative semiquantitative antibody result means that the patient serum specimen had no SARS-CoV-2 spike IgG antibodies, or that the relative level of antibodies in the patient specimen was below the index cutoff.7,15

Note: this index value should not be interpreted as a measurement of durable immunity or protection from SARS-CoV-2 infection or reinfection. Durability and duration of immunity to SARS-CoV-2 is still not clearly defined and continues to be an area of national and global scientific and public health research.18 Results obtained with this assay may not be used interchangeably with values obtained with different manufacturers' test methods.

Question 10. Does a positive result for IgG and/or IgM antibody to SARS-CoV-2 mean that the patient is immune to reinfection? 

The presence of IgG and/or IgM antibody to SARS-CoV-2 indicates that the patient has developed an immune response to the virus.3,5-8 Although the immune response may protect against reinfection, this has yet to be conclusively established.16,17 It is not known how long antibodies to the virus will protect someone, if at all.17 Cases of reinfection with COVID-19 have been reported but remain rare.17​,18

Question 11. What are the indications for use of the SARS-CoV-2 Serology (COVID-19) Antibody (IgG/IgM), Immunoassay Panel (test code 31672)?

Testing for SARS-CoV-2 IgG/IgM, including in individuals who may be asymptomatic or are ≥10 days after SARS-CoV-2 exposure or post-symptom onset, can play an important role in the fight against COVID-19.8,17 At Quest, our SARS-CoV-2 IgG/IgM testing assesses IgG to SARS-CoV-2 nucleocapsid protein and IgM to SARS-CoV-2 spike protein.5,6 Our SARS-CoV-2 IgG/IgM panel can be used to

  • Identify SARS-CoV-2-infected persons with negative results on nucleic acid amplification (NAAT) /PCR tests, especially patients who present late with RNA levels below the detection limit of a NAAT/PCR assay, or when respiratory tract sampling is not possible2,5,6,9,11,12,14

  • Identify whether people have been infected with SARS-CoV-2 and have mounted an immune response2,5,6,9,11,12,14

  • Assess how many people have been infected with SARS-CoV-2 in a population, through seroprevalence surveys2,9,11

  • Help identify individuals who may be able to donate convalescent plasma as a possible treatment for those who are seriously ill from COVID-192,9,11

Question 12. Are SARS-CoV-2 IgM and/or IgG tests helpful in assessing immunity after vaccination?

Not at present. At the date of this publication, no SARS-CoV-2 IgG and IgM assays, under FDA EUA, have an intended use/labelling for evaluating SARS-CoV-2 vaccine efficacy.4,8 Clinical researchers continue to investigate what constitutes SARS-CoV-2 protective immunity and long-term vaccine efficacy. This is an area of active clinical research.4,8,17

Question 13. What proportion of the general population has pre-existing IgM and/or IgG reactivity to SARS-CoV-2 antibody tests?

Manufacturers’ validation of SARS-CoV-2 IgG assays utilized by Quest reported less than 1% positivity in specimens from pre-COVID times (2010, 2017, and 2019).3,5-7

In an antibody cross-reactivity study of 143 specimens from 30 different categories of infectious disease and autoimmune disease, only 1 specimen (with rheumatoid factor) had a SARS-CoV-2 IgM-positive result.6 In a medical condition cross-reactivity study using 65 specimens from 13 different categories, only 1 specimen (from a hemodialysis patient) tested positive for SARS-CoV-2 IgM.6

The cross-reactivity of the Quest SARS-CoV-2 IgG (ELISA or CMIA) and SARS-CoV-2 IgM immunoassays (CMIA) is <1%.3,5-7

Question 14. What is the role of antibody neutralization assays, and are they available to assess immunity to SARS-CoV-2?

Neutralization assaysare performed to help assess the ability of neutralizing antibodies (NAbs) in patient serum to neutralize virus infectivity in vitro.18 These tests are potentially useful to assess whether past infection (or potentially vaccination) has provided protection against infection. In these tests, serial dilutions of patient serum are incubated with known infectious virus concentrations and then added to virus susceptible cell lines.18 After incubation, infected cells are quantified to determine the effectiveness of patient antibodies in neutralizing the virus.18,19 The presence of NAbs may suggest in vivo immunity to viral infection, and convalescent serum with NAbs is being studied as a treatment for severe COVID-19.18-21 Testing for NAbs is only available at some specially equipped public health laboratories and research facilities. SARS-CoV-2 NAbs testing is not performed at Quest.

Question 15. Does a positive SARS-CoV-2 antibody result mean the patient does not need the vaccine?

No, a positive result does not have implications for vaccination. At this time, the CDC and ACIP guidance states that previous SARS-CoV-2 infection, whether symptomatic or asymptomatic, is not considered a contraindication to vaccination, and that serologic testing for SARS-CoV-2 antibodies is not recommended prior to vaccination.17

References

  1. Serology tests for COVID-19. COVID-19 Testing Toolkit. Updated February 9, 2021. Accessed February 14, 2021. https://www.centerforhealthsecurity.org/resources/COVID-19/serology/Serology-based-tests-for-COVID-19.html Serology based tests for COVID-19. Center for Health Security
  2. FAQs on testing for SARS CoV-2. US Food and Drug Administration. Accessed January 22, 2021. https://www.fda.gov/medical-devices/emergency-situations-medical-devices/faqs-diagnostic-testing-sars-cov-2
  3. VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG. Instructions for use. Ortho-Clinical Diagnostics; 2020. Accessed January 21, 2021. https://www.fda.gov/media/137363/download
  4. EUA authorized serology test performance. US Food and Drug Administration. Updated October 14, 2020. Accessed January 21, 2021. https://www.fda.gov/medical-devices/emergency-situations-medical-devices/eua-authorized-serology-test-performance
  5. SARS-CoV-2 IgG. Package insert. Abbott Laboratories; 2020. Accessed January 21, 2021. https://www.fda.gov/media/137383/download
  6. AdviseDx SARS-CoV-2 IgM. Package insert. Abbott Laboratories; 2020. Accessed January 21, 2021. https://www.fda.gov/media/142940/download
  7. Atellica® IM SARS-CoV-2 IgG (COV2G) and ADVIA® Centaur SARS-CoV-2 IgG (COV2G). Instructions for use. Siemens Healthcare Diagnostics Inc; 2020. Accessed February 14, 2021. https://www.fda.gov/media/140704/downloadhttps://www.fda.gov/media/140699/download;
  8. Important information on the use of serologic (antibody) tests for COVID-19–letter to health care providers. US Food and Drug Administration. Updated April 17, 2020. Accessed January 21, 2021. https://www.fda.gov/medical-devices/letters-health-care-providers/important-information-use-serological-antibody-tests-covid-19-letter-health-care-providers
  9. Espejo AP, Akgun Y, Al Mana AF, et al. Review of current advances in serologic testing for COVID-19. Am J Clin Pathol. 2020;154(3):293-304. doi:10.1093/ajcp/aqaa112
  10. Li Z, Yi Y, Luo X, et al. Development and clinical application of a rapid IgM‐IgG combined antibody test for SARS‐CoV‐2 infection diagnosis. J Med Virol.2020;92(9):1518-1524. doi:10.1002/jmv.25727
  11. Interim guidelines for COVID-19 antibody testing. Centers for Disease Control and Prevention. Updated August 1, 2020. Accessed January 22, 2021. https://www.cdc.gov/coronavirus/2019-ncov/lab/resources/antibody-tests-guidelines.html#anchor_1590264293982
  12. Fact sheet for healthcare providers: SARS-CoV-2 IgG assay - Abbott Laboratories Inc. US Food and Drug Administration. Updated April 26, 2020. Accessed January 22, 2021. https://www.fda.gov/media/137381/download
  13. Fact sheet for healthcare providers: Ortho-Clinical Diagnostics, Inc VITROS Immunodiagnostic Products Anti-SARS-CoV-2 IgG Reagent Pack. US Food and Drug Administration. Updated January 22, 2021. Accessed November 5, 2020. https://www.fda.gov/media/137361/download
  14. Fact sheet for healthcare providers: Abbott Laboratories AdviseDx SARS-CoV-2 IgM. US Food and Drug Administration. Updated October 9, 2020. Accessed January 22, 2021. https://www.fda.gov/media/142938/download
  15. Fact sheet for healthcare providers: Siemens Healthcare Diagnostics Inc. Atellica® IM SARS-CoV-2 IgG (COV2G). SARS-CoV-2 IgG semi-quantitative and ADVIA Centaur® SARS-CoV-2 IgG (COV2G). US Food and Drug Administration. Updated July 31, 2020. Accessed January 22, 2021.  https://www.fda.gov/media/140702/download; https://www.fda.gov/media/140698/download
  16. COVID-19 vaccine – frequently asked questions. The New England Journal of Medicine. Accessed January 22, 2021. https://www.nejm.org/covid-vaccine/faq
  17. Interim considerations for COVID-19 vaccination of healthcare personnel and long-term care facility residents. Centers for Disease Control and Prevention. Reviewed December 3, 2020. Accessed January 22, 2021. https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/covid-19/clinical-considerations.html
  18. Reinfection with COVID-19. Centers for Disease Control and Prevention. Updated October 27, 2020. Accessed January 22, 2021. https://www.cdc.gov/coronavirus/2019-ncov/your-health/reinfection.html
  19. Ju B, Zhang Q, Ge J, et al. Human neutralizing antibodies elicited by SARS-CoV-2 infection. Nature. 2020;584(7819):115-119. doi:10.1038/s41586-020-2380-z
  20. Mo H, Zeng G, Ren X, et al. Longitudinal profile of antibodies against SARS-coronavirus in SARS patients and their clinical significance. Respirology. 2006;11(1):49-53. doi:10.1111/j.1440-1843.2006.00783.x
  21. IDSA COVID-19 antibody testing primer. Infectious Diseases Society of America. Updated April 22, 2020. Accessed April 23, 2020. https://www.idsociety.org/globalassets/idsa/public-health/covid-19/idsa-covid-19-antibody-testing-primer.pdf
This FAQ is provided for informational purposes only and is not intended as medical advice. A clinician’s test selection and interpretation, diagnosis, and patient management decisions should be based on his/her education, clinical expertise, and assessment of the patient.
Document FAQS.219 Version: 3
Version 3: Effective 02/15/2021 to present
Version 2: Effective 11/09/2020 to 02/15/2021
Version 1: Effective 05/26/2020 to 11/09/2020
Version 0: Effective 04/24/2020 to 05/26/2020