Clinical Validity of COVID-19 Serum Antibodies

Quick Takes

  • Antibody testing for SARS-CoV-2 is highly sensitive and specific only when performed ≥14 days after symptom onset.
  • Magnitude of IgG production correlates with severity of respiratory symptoms.
  • Serologic testing could be considered in patients suspected of COVID-19 who are SARS-CoV-2 negative by polymerase chain reaction testing.

Study Questions:

Is antibody testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) clinically useful?

Methods:

The authors reviewed data sets on all polymerase chain reaction (PCR) testing for SARS-CoV-2 performed by the Johns Hopkins microbiology laboratory during the first month of coronavirus disease 2019 (COVID-19) testing, and performed a case-control study in which they included a total of 628 persons: 115 hospitalized adults with confirmed SARS-CoV-2 PCR testing, and 513 persons not tested for SARS-CoV-2 who provided serum samples to the immunology laboratory. All samples obtained from these individual participants were then tested for the presence of IgG and IgA antibodies against the S1 domain of the SARS-CoV-2 spike protein by using a manual commercial enzyme-linked immunosorbent assay (ELISA) (Euroimmun), and a number of analyses performed to determine the sensitivity and specificity of antibody testing compared to PCR at different time points, the correlation with symptoms, and lastly whether antibody testing could be useful in PCR-negative patients at high suspicion for COVID-19.

Results:

Serum IgG antibodies against SARS-CoV-2 were significantly higher in COVID-19 case patients (median, 2.01 units [interquartile range, 0.16-44.33 units]) than in all persons in the control groups (median, 0.10 unit [interquartile range, 0.05-0.19 unit]; p < 0.001). Median time to seroconversion was 12 days after symptom onset for IgG, and all patients developed IgG by day 17. When measured ≥14 days after symptom onset, serum IgG to SARS-CoV-2 spike protein distinguished COVID-19 case patients from persons in the control group with a sensitivity of 0.976 (95% confidence interval [CI], 0.928-0.995) and a specificity of 0.988 (95% CI, 0.974-0.995). Sensitivity was much lower in samples collected prior to 14 days of symptoms. Antibody testing remained positive for up to 60 days. Similar kinetics were observed for the IgA isotype. Both IgG and IgA were significantly elevated in patients with severe respiratory symptoms compared to less severe cases. Among patients at high suspicion for COVID-19 but who tested negative (n = 6) by PCR, five of six had antibodies to SARS-CoV-2, and one had the sample collected prior to 14 days.

Conclusions:

Antibodies to SARS-CoV-2 can be useful when measured ≥14 days after symptom onset, notably in patients who test negative by PCR but remain at high suspicion for COVID-19.

Perspective:

There has been much discussion and anecdotal speculation on the sensitivity of antibody testing for SARS-CoV-2 and its clinical usefulness. This study makes the best of available laboratory and clinical data at Johns Hopkins to shed light on the kinetics of SARS-CoV-2 antibodies, clarifying that non-immunosuppressed patients who are symptomatic generate antibodies to SARS-CoV-2 approximately 14 days after symptom-onset, and who the pre-antibody testing can help in the setting of negative PCR testing and high suspicion of COVID-19, as long as testing occurs after 14 days of symptom onset. The correlation between magnitude of antibody generation and symptom severity is consistent with the hyperinflammatory pathophysiology of severe COVID-19. Accordingly, individuals exposed to SARS-CoV-2 who remain asymptomatic may not generate antibodies, making routine antibody testing for screening much less useful.

Clinical Topics: Prevention

Keywords: Antibody Specificity, Coronavirus, COVID-19, Immunoglobulin G, Kinetics, Polymerase Chain Reaction, Primary Prevention, severe acute respiratory syndrome coronavirus 2, Spike Glycoprotein, Coronavirus


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