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Discovery of Key Protein Sites on the SARS-CoV-2 Virus that can Potentially Improve COVID-19 Diagnosis and Therapeutics

A collaborative study among medical professionals and scientists from the National Centre for Infectious Diseases (NCID) and A*STAR’s Singapore Immunology Network (SIgN) unveiled four crucial epitopes on the crown of the SARS-CoV-2 virus to which patient-derived antibodies can bind.

In line with the national efforts to combat COVID-19, research teams from Singapore have discovered four key epitopes on the SARS-CoV-2 virus which COVID-19 patient-derived antibodies can interact with. The applications of this new knowledge can help curb the spread of the virus to others. Discoveries from two cooperative studies by scientists and medical professionals from the National Centre for Infectious Diseases (NCID) and the Singapore Immunology Network (SIgN) A*STAR have been published in Nature Communications and EBioMedicine.

Epitopes are specific amino acid sequences on invading pathogens (viruses and bacteria) acting as infection recognition patterns, which the antibodies produced in the human body can interact with and bind to specifically. Epitopes are important for the recognition of foreign pathogens by the human immune system and the mounting of an immune response to first contain and eventually rid the body of the pathogen.

The researchers found that patient-derived antibodies can accurately detect these four epitopes – S14P5, S21P2, S20P2 and N4P5 located on spike proteins of the SARS-CoV-2 virus’ characteristic crown. N4P5 in particular, demonstrated the greatest specificity and sensitivity (100% and >96% respectively) against the SARS-CoV-2 virus.

The study also showed that patients recovering from the COVID-19 infection produced antibodies that could specifically detect the four key epitopes. By extension, the presence of such antibodies against any of the epitopes (S14P5, S21P2, S20P2 and N4P5) likely indicates and identifies the person who had prior exposure to SARS-CoV-2. The presence of these four epitopes, and the strength of response they elicit in humans (measured by the amount of human Immunoglobulin G, IgG produced) can be used to denote the degree of immunopathology in COVID-19 patients. The use of these crucial epitopes, either individually or together for the formulation of point-of-care-tests (POCTs), makes them accurate determiners of COVID-19 infection in patients due to their high specificity and sensitivity.

Additionally, the blood sera extracted from COVID-19 patients could prevent more than 50 percent of the entry of the SARS-CoV-2 pseudovirus, which are artificially created viruses without the ability to replicate in human hosts, used solely for the purpose of laboratory testing. The same test, when performed with blood serum from SARS patients, could not prevent the entry of the SARS-CoV-2 pseudovirus. This suggests that antibodies produced by COVID-19 patients circulating in their blood serum is not produced in SARS patients, and distinctly interact with S14P5 and S21P2 epitopes specific to the SARS-CoV-2 virus.

Specifically, the discovery of these four epitopes S14P5, S21P2, S20P2 and N4P5 opens new doors to many possible future studies. This discovery can improve detection accuracy and facilitate innovative efforts for future diagnostics, vaccines, and treatments for COVID-19.

The four epitopes can be used for the following purposes:

  • More accurate diagnosis of SARS-CoV-2-positive patients through examination of their blood serum, thereby eliminating false negatives from the PCR test.
  • Further streamlining of studies on infectious properties of SARS-CoV-2 and its mechanisms of action by shifting the focus onto investigating antibody interaction with the four key epitopes.
  • Approximation of the COVID-19 infection immunity within a population by determining the number of people who have antibodies against the four epitopes identified in these studies.
  • Facilitation of the creation of viable vaccines and therapeutics through using the four epitopes as a base and exploring options with monoclonal and polyclonal antibodies which can also bind and detect the four epitopes.

Professor Leo Yee Sin, the Executive Director of NCID commented, “SARS-CoV-2 is the novel causative agent of COVID-19. This seventh human coronavirus has challenged the entire scientific world with numerous unresolved questions awaiting scientists to unravel. Antibodies are key to our bodies’ defence mechanisms against viruses. We are pleased to share this internationally leading work by the local research team which focuses on a powerful aspect of finding out how humans can generate specific antibodies targeted against SARS-CoV-2. The implications are manifold as explained by the studies.”

These two studies were made possible with funding from the COVID-19 Research Fund, under the National Research Foundation Singapore (NRF) and endorsed by the Ministry of Health (MOH). Additional funding was provided by A*STAR’s core research grants and A*ccelerate’s GAP-funding.

According to Professor Lisa Ng, Senior Principal Investigator of SIgN, A*STAR, “The identification of these specific targets on the virus is a crucial advance in the development of better diagnostics and treatments for COVID-19. There is also potential to use these targets against similar coronaviruses to address other viral outbreaks. We are pleased to have leveraged our immunological experience in this research, in collaboration with renowned infectious disease and healthcare agencies in Singapore.”.

Moving forward, the four epitopes will form the basis for a multi-centre collaboration and subsequently contribute to the establishment of the WHO International Standard for COVID-19 antibody and Reference Panel. More research work will be carried out with the aim of devising novel and effective diagnostics, vaccines, and treatment options for COVID-19. [APBN]