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CAP Statement on the Current Role of Serologic Testing for SARS-CoV-2

NORTHFIELD, IL—College of American Pathologists (CAP) President Patrick Godbey, MD, FCAP issued the following statement regarding the Current Role of Serologic Testing for SARS-CoV-2:

Highlights

There are still significant unknowns with respect to SARS-CoV-2 antibody testing, ranging from uncertainty regarding the accuracy of many commercially available assays to the clinical significance of positive results. Importantly, serologic testing is not currently recommended for detection of an active SARS-CoV-2 infection. Clinical laboratories should continue to employ the use of SARS-CoV-2 molecular tests performed from respiratory specimens for the diagnosis of acute COVID-19 infection in symptomatic patients. It is important for clinical laboratories to understand and communicate to providers that SARS-CoV-2 serology tests should not replace nucleic acid amplification tests for diagnosis of acute infection. Tests to detect SARS-CoV-2 antigen are beginning to come to market, but the clinical performance characteristics of these antigen tests have not been well studied, yet.

The clinical and social implications of a detectable antibody response to SARS-CoV-2 remain unclear at this time, primarily because it is not yet known whether antibody presence correlates with longstanding protective immunity (as of May 2020). At this time, serology is best used for epidemiologic purposes, identifying possible donors of convalescent plasma, and for verification of vaccine response.

Currently, neither changes in the use of personal protective equipment or adherence to social distancing practices can be made based on serologic test results.

Background

There are currently three types of laboratory tests available for the detection of the novel (new) coronavirus SARS-CoV-2 and the disease it causes, coronavirus disease 2019 or COVID-19. Nucleic acid amplifications tests detect the RNA of SARS-CoV-2, and thus indicate the presence of an active or recent infection. Serology tests detect the presence of antibodies against the SARS-CoV-2 virus and provide evidence that a person’s immune system has mounted a response to the viral antigens. Antigen tests to directly detect viral antigens in a specimen are beginning to come to market, but their performance characteristics are not well-studied, yet. Often, direct antigen assays have lower sensitivity than nucleic acid amplification tests. The following information summarizes the status of serology testing.

Serology (or antibody) tests are designed to determine if a person has been exposed to (infected with or vaccinated against) SARS-CoV-2 at some point in time. Antibodies to SARS-CoV-2 will be produced if a person had COVID-19 or if an individual had an asymptomatic or mild infection with SARS-CoV-2. Interestingly, several studies suggest that not all individuals will mount antibody response post infection. Serologic testing alone should not be relied upon to detect active infection as antibodies can take days to weeks to develop and testing too soon following infection may lead to a false-negative result. Perhaps the most important limitation associated with SARS-CoV-2 serologic testing at this time is the lack of information regarding whether detected antibodies are associated with protective immunity, and if they are, for how long that immunity lasts. The correlate of protective immunity has not yet been established. One way to determine whether immunity is generated is through monitoring the rate of infection following vaccination – an aspect that will be closely followed in upcoming vaccine trials.

Even for serology assays with high specificity (>99%) and low rates of false-positive results, the positive predictive value (PPV) may be low if SARS-CoV-2 infections in the region have been rare. False positive serology results obtained during surveillance testing could falsely inflate the case count, which could skew fatality rate calculations. The accuracy of serology testing is particularly important for public health response strategies, which may use the information to guide public health recommendations.

Questions About Serology Testing

How should serologic testing be used?

Laboratories are encouraged to follow recommendations and guidelines as put out by various national and international groups, including the American Society for Microbiology (ASM), Infectious Diseases Society of America (IDSA), and others.

The following are current applications for serology testing:

  • Seroprevalence and epidemiologic studies
  • Identification if an individual has been infected in the past
  • Identification of individuals with prior COVID-19 infection who may serve as potential convalescent plasma donors
    • Commercially available serologic assays may be used to screen potential donors. The FDA currently recommends using neutralization assays to confirm that seropositive donors have a SARS-CoV-2 neutralizing antibody titer of at least 1:160. However, such assays are not currently commercially available. Although some studies show correlation between commercial assays and neutralizing antibody tests, additional data is necessary before commercial tests can be used routinely to determine neutralizing antibody titers. Currently, serum from potential convalescent plasma donors is recommended to be stored for retrospective testing by neutralization assays as they become available.
  • Monitoring immune response during vaccine clinical trials

What tests are available for serology testing?

The FDA has authorized several serology tests through the Emergency Use Authorization (EUA) process. These assays include lateral flow assays and instrument-based immunoassays. More assays are being authorized daily, and laboratories are encouraged to access the FDA’s Coronavirus website for the most updated information on FDA EUAs.

There are many serological tests on the market that have not gone through the EUA process. The FDA’s Policy for Coronavirus Disease-2019 Tests During the Public Health Emergency allowed for kits to be submitted to the FDA that had been validated but had not gone through the EUA process and carried certain disclaimer language. However, on May 4, 2020, the FDA updated its policy to provide more oversight for serologic tests and unveiled a new “umbrella” pathway for EUA. It is important to remember that any test kits that do not have FDA EUA must be validated and performed in a high-complexity, CLIA-certified laboratory.

What are the known challenges and knowledge gaps with SARS-CoV-2 serology?

  • The relevance of isotype-specific (IgM, IgG, IgA) assays versus total antibody detection
  • The importance of semi-quantitative results when selecting convalescent plasma donors
  • Assays’ cross-reactivity with other antibodies
  • Specificity and sensitivity of each assay
  • The unknown level and duration of protective immunity provided by detectable antibodies
  • The clinical relevance, sensitivity, and specificity of antibodies targeting specific SARS-CoV-2 antigens (eg, spike protein, nucleocapsid protein)

About the College of American Pathologists

As the world’s largest organization of board-certified pathologists and leading provider of laboratory accreditation and proficiency testing programs, the College of American Pathologists (CAP) serves patients, pathologists, and the public by fostering and advocating excellence in the practice of pathology and laboratory medicine worldwide. As a 501(c)(6) membership organization, the CAP is the only entity representing pathologists with unrestricted advocacy capability and a political action committee, PathPAC. For more information, visit yourpathologist.org to watch pathologists at work and see the stories of the patients who trust them with their care. Read the CAP Annual Report.

References:

  1. https://www.cdc.gov/coronavirus/2019-ncov/covid-data/serology-surveillance/index.html
  2. https://www.idsociety.org/globalassets/idsa/public-health/covid-19/idsa-covid-19-antibody-testing-primer.pdf
  3. https://www.who.int/news-room/commentaries/detail/immunity-passports-in-the-context-of-covid-19
  4. https://www.fda.gov/vaccines-blood-biologics/investigational-new-drug-ind-or-device-exemption-ide-process-cber/recommendations-investigational-covid-19-convalescent-plasma
  5. https://www.ccjm.org/content/covid-19-curbside-consults
  6. https://www.fda.gov/medical-devices/emergency-situations-medical-devices/emergency-use-authorizations#covid19ivd
  7. The College of American Pathologists: Clarifying Tests for COVID-19