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The SARS-CoV-2 spike protein non-RBD epitopes and other viral antigens represent a broad set of targets for the development of vaccines and therapeutics against COVID-19. While the Receptor Binding Domain (RBD) of the spike protein is the primary target for most neutralizing antibodies, non-RBD regions such as the N-terminal domain (NTD) and the S2 subunit are critical for viral attachment and membrane fusion (Huang et al., 2020). Other structural proteins, including the Nucleocapsid (N), Membrane (M), and Envelope (E) proteins, play essential roles in viral RNA packaging, assembly, and budding (Yadav et al., 2021). Targeting these conserved regions is a key strategy to overcome the mutational escape observed in RBD-focused therapies. Vaccines utilizing inactivated virus or multi-antigen platforms aim to elicit a broader immune response, including T-cell activation against the N and M proteins, which are less prone to mutation than the spike protein (Shah et al., 2021). Therapeutic monoclonal antibodies targeting the S2 subunit or conserved NTD epitopes offer potential pan-sarbecovirus protection (Chi et al., 2020). These antigens are also vital for diagnostic purposes, where anti-N antibodies are used to distinguish natural infection from S-protein-based vaccination.
Inhibition of viral-host membrane fusion via the S2 subunit, blocking of auxiliary attachment factors in the N-terminal domain (NTD), and induction of broad-spectrum humoral and cellular immunity against structural proteins (N, M, E) to prevent viral replication and clear infected cells.
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