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Antibody Testing Can Identify SARS-CoV-2 Infection, Guide Epidemiologic Studies

Key findings

  • This study characterized the antibody profile against the receptor-binding domain (RBD) region of the SARS-CoV-2 spike protein in patients with COVID-19
  • The presence of IgG antibodies targeting SARS-CoV-2 RBD was a highly specific (100%) and sensitive (97%) marker of infection after 14 days from onset of illness
  • IgG seropositivity was sustained in patients up to 75 days (last time point measured), and IgG concentration was highly correlated with titers of neutralizing antibodies
  • IgM and IgA responses to RBD were short-lived, with many individuals becoming seronegative within two months of illness onset
  • SARS-CoV-2 RBD did not cross-react with common cold coronaviruses, allowing additional confidence in the specificity of the assay

A widespread misperception is that antibody testing is not useful in the context of COVID-19. This may stem from the poor performance of some commercial serologic tests and confusion about the role of antibodies as biomarkers of past infection versus protective immunity.

By studying large numbers of cases and controls, researchers in the Division of Infectious Diseases at Massachusetts General Hospital have shown that antibody responses to the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 are highly accurate in identifying recently infected individuals. Anita S. Iyer, PhD, research fellow in Medicine, Richelle C. Charles, MD, physician, Jason B. Harris, MD, a pediatric infectious disease attending, and Ariana Nodoushani, research technician, posted the results on medRxiv, a non-peer-reviewed preprint server.

Study Cohorts

Using enzyme-linked immunosorbent assay (ELISA), the researchers measured RBD antibody responses in:

  • 259 symptomatic patients who tested positive for SARS-CoV-2 by polymerase chain reaction (PCR) at Mass General between March and April 2020
  • 1,515 healthy and 33 febrile controls whose samples were collected between September 2015 and December 2019, prior to the COVID-19 pandemic

Predictive Capacity

Between 14 and 28 days from symptom onset, IgG, IgA or IgM antibody responses to RBD were all accurate in identifying recently infected individuals with 100% specificity and sensitivities of 97%, 91% and 81%, respectively.

Even models incorporating all antibody types had limited predictive capacity during the first week of symptoms. Thus, the detection of RBD antibodies by ELISA is unlikely to contribute much to the early diagnosis of COVID-19.

Time to Seroconversion and Seroreversion

94 cases had samples taken >20 days post-symptoms, and most had evidence of seroconversion for all isotypes. The median time to seroconversion from symptom onset was comparable across isotypes.

Of seroconverted cases with samples taken ≥40 days post-symptoms, most eventually had IgM and IgA seronegativity (21of 27 and 18 of 27, respectively). Only 1 of 29 seroreverted for IgG.

The estimated median time to seroreversion was 47 days for IgM and 51 days for IgA. The first 5% of cases seroreverted within 24 and 30 days, respectively. Early seroreversion of IgM and IgA responses could be useful for distinguishing a previous infection from acute COVID-19.

Neutralizing Antibodies

All 15 cases tested had neutralizing antibodies targeting the spike protein of SARS-CoV-2 (tested on days 0–75 post-symptoms). Neutralizing antibody titers were correlated with IgG concentration and remained detectable after the decline of IgA and IgM responses.


Reassuringly, SARS-CoV-2 RBD did not cross-react with any of the three coronaviruses that cause the common cold.

Clinical Applications

These results strongly support using anti-RBD antibodies as a marker of recent SARS-CoV-2 infection. Besides being appropriate for clinical settings, this approach could be used in population-based studies of previous infection. Importantly, though, the assay does not provide information about whether individuals are protected from subsequent re-infection.

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