Serological differentiation between COVID-19 and SARS infections

Emerg Microbes Infect. 2020 Dec;9(1):1497-1505. doi: 10.1080/22221751.2020.1780951.


In response to the coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, multiple diagnostic tests are required for acute disease diagnosis, contact tracing, monitoring asymptomatic infection rates and assessing herd immunity. While PCR remains the frontline test of choice in the acute diagnostic setting, serological tests are urgently needed. Unlike PCR tests which are highly specific, cross-reactivity is a major challenge for COVID-19 antibody tests considering there are six other coronaviruses known to infect humans. SARS-CoV is genetically related to SARS-CoV-2 sharing approximately 80% sequence identity and both belong to the species SARS related coronavirus in the genus Betacoronavirus of family Coronaviridae. We developed and compared the performance of four different serological tests to comprehensively assess the cross-reactivity between COVID-19 and SARS patient sera. There is significant cross-reactivity when N protein of either virus is used. The S1 or RBD regions from the spike (S) protein offers better specificity. Amongst the different platforms, capture ELISA performed best. We found that SARS survivors all have significant levels of antibodies remaining in their blood 17 years after infection. Anti-N antibodies waned more than anti-RBD antibodies, and the latter is known to play a more important role in providing protective immunity.

Keywords: COVID-19; SARS; SARS-CoV-2; antibody; serology.

Publication types

  • Clinical Trial
  • Comparative Study

MeSH terms

  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology*
  • Betacoronavirus / immunology*
  • Betacoronavirus / isolation & purification
  • COVID-19
  • COVID-19 Testing
  • Clinical Laboratory Techniques / methods*
  • Coronavirus Infections / diagnosis*
  • Coronavirus Nucleocapsid Proteins
  • Cross Reactions
  • Diagnosis, Differential
  • Enzyme-Linked Immunosorbent Assay / methods
  • HEK293 Cells
  • Humans
  • Immunoprecipitation
  • Nucleocapsid Proteins / immunology
  • Pandemics
  • Phosphoproteins
  • Pneumonia, Viral / diagnosis*
  • Protein Domains / immunology
  • SARS-CoV-2
  • Serologic Tests / methods*
  • Severe Acute Respiratory Syndrome / diagnosis*
  • Severe acute respiratory syndrome-related coronavirus / immunology*
  • Severe acute respiratory syndrome-related coronavirus / isolation & purification
  • Spike Glycoprotein, Coronavirus / immunology


  • Antibodies, Viral
  • Coronavirus Nucleocapsid Proteins
  • Nucleocapsid Proteins
  • Phosphoproteins
  • Spike Glycoprotein, Coronavirus
  • nucleocapsid phosphoprotein, SARS-CoV-2
  • spike protein, SARS-CoV-2

Grants and funding

This work is supported in part by the Singapore Singapore Medical Research Council (NMRC) grants STPRG-FY19-001 and COVID19RF-003, and Singapore National Research Foundation (NRF) grant NRF2016NRF-NSFC002-013.