Summary The search for potential antibody-based diagnostics, vaccines, and treatments for the pandemic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has focused almost exclusively on the spike (S) and nucleocapsid (N) proteins. The coronavirus membrane (M) proteins, ORF3a and ORF8, are humoral immunogens in other coronaviruses (CoVs), but remain largely uninvestigated for SARS-CoV-2. Here, we use ultradense peptide microarray mapping to show that SARS-CoV-2 infection induces robust antibody responses to epitopes throughout the SARS-CoV-2 proteome, particularly in M, in which 1 epitope achieved excellent diagnostic accuracy. We mapped 79 B cell epitopes across the SARS-CoV-2 proteome and demonstrated that antibodies that develop in response to SARS-CoV-2 infection bind to homologous peptide sequences in the other 6 known human CoVs. We also confirmed reactivity against 4 of our top-ranking epitopes using enzyme-linked immunosorbent assay (ELISA). Disease severity was correlated with increased reactivity to 9 SARS-CoV-2 epitopes in S, M, N, and ORF3a in our population. Our results demonstrate previously unknown highly reactive B cell epitopes throughout the proteome of SARS-CoV-2 and other CoV proteins. |
All coronaviruses produce four primary structural proteins and multiple non-structural proteins. However, most antibody-based research on SARS-CoV-2 has focused on the nucleocapsid and spike proteins. A study published in PLOS Biology by Anna Heffron, Irene Ong and colleagues at the University of Wisconsin-Madison, USA, suggests that immune responses may develop against other proteins produced by the SARS-CoV-2 virus.
The efficacy of spike protein-based vaccines is variable and not all people infected with SARS-CoV-2 produce detectable antibodies against the spike or nucleocapsid proteins. Therefore, expanded antibody-based options have the potential to play an important role in improving vaccines, diagnostics and therapeutics, particularly given the emergence of new variants.
To investigate whether SARS-CoV-2 infection induces strong antibody responses against all SARS-CoV-2 proteins, the researchers mapped 79 "epitopes," specific regions of the viral proteome that antibodies recognize and bind to. They also tested whether antibodies that develop in response to SARS-CoV-2 or existing antibodies from previous coronavirus exposures could bind to any of the proteins in the other six known human coronaviruses to identify potential cross-reactive epitopes.
In addition to the spike and nucleocapsid proteins, the authors located previously unknown highly reactive B cell epitopes across the range of proteins in SARS-CoV-2 and other coronaviruses, expanding the potential for future development of vaccines and therapeutics. However, future research is needed to determine how long these antibodies remain and whether the responses of vaccinated people differ from those who contracted COVID-19 before vaccination. Dr. Ong and his colleagues will continue to investigate these issues in adults and children.
Although the authors did not directly profile variants of concern that have emerged since the beginning of the COVID-19 pandemic, a comparison of the original SARS-CoV-2 genome with some of the variants of concern identified numerous variations in regions that are in or within 3 amino acids of the identified antibody binding epitopes.
According to the authors, "our broad epitope-level resolution antibody reactivity profile in convalescent COVID-19 subjects, confirmed by independent assays, provides novel epitopes that could serve as important targets in the development of improved diagnostics, vaccines, and therapeutics." against SARS-CoV-2, variants of concern and dangerous human coronaviruses that may emerge in the future.”
