Epitope mapping of neutralising anti-SARS-CoV-2 monoclonal antibodies: Implications for immunotherapy and vaccine design

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. This disease has currently affected more than 346 million people and resulted in more than 5.5 million deaths in many countries. Neutralising monoclonal antibodies (MAbs) against the SARS-CoV-2 virus could serve as prophylactic/therapeutic agents in COVID-19 infection by providing passive protection against the virus in individuals. Until now, no Food and Drug Administration/European Medicines Agency-approved neutralising MAb against SARS-CoV-2 virus exists in the market, though a number of MAbs have been authorised for emergency use. Therefore, there is an urgent need for development of efficient anti-SARS-CoV-2 neutralising MAbs for use in the clinic. Moreover, neutralising anti-SARS-CoV-2 MAbs could be used as beneficial tools for designing epitope-based vaccines against the virus. Given that the target epitope of a MAb is a crucial feature influencing its neutralising potency, target epitopes of neutralising anti-SARS-CoV-2 MAbs already reported in the literature and reactivity of these MAbs with SARS-CoV-2 variants are reviewed herein.

Keywords: COVID-19; RBD; SARS-CoV-2 virus; epitope mapping; immunotherapy; neutralising monoclonal antibody.

FIGURE 1

Structure of SARS‐CoV‐2 virus and spike Protein (a) Schematic representation of SARS‐CoV‐2 particle and structural proteins of the virus (b) Primary structure of spike protein (c) Diagram of S protein structure in the closed and open conformations (adapted from the Protein Database, ¹¹³ , ¹¹⁴ ). SARS‐CoV‐2: Severe acute respiratory syndrome coronavirus 2, S: Spike; NTD: N‐terminal domain; RBD: Receptor binding domain; SD: Subdomain; UH: Upstream helix; FP: Fusion peptide; HR: Heptad repeat; SH: Stem helix; TM: Transmembrane; CT: Cytoplasmic tail

FIGURE 2

Prevention of virus binding to its receptor on target cell by neutralising antibodies. Binding of (a) non‐neutralising antibodies and (b) neutralising antibodies to spike protein. ACE2: Angiotensin‐converting enzyme two

FIGURE 3

SARS‐CoV‐2 neutralising monoclonal antibodies (MAbs) grouped based on targeting regions of the spike protein. SARS‐CoV‐2 trimeric spike protein is illustrated showing S1 domain regions: the N‐terminal domain (NTD) (salmon), Receptor binding domain (RBD) (slate), receptor‐binding motif (RBM) (bright orange), SD1 (palegreen), and SD2 (yellow) and S2 domain regions: Upstream helix (UH) (violet), Fusion peptide (FP) (aquamarine), HR1 (blue), SD3 (orange) and Stem helix (SH) (red). SARS‐CoV‐2: Severe acute respiratory syndrome coronavirus 2, S: Spike; NTD: N‐terminal domain; RBD: Receptor binding domain; RBM: Receptor‐binding motif, SD: Subdomain; UH: Upstream helix; FP: Fusion peptide; HR: Heptad repeat; SH: Stem helix; TM: Transmembrane; CT: Cytoplasmic tail

FIGURE 4

Assignment of epitope residues of spike protein for binding to Angiotensin‐converting enzyme 2 (ACE2) and SARS‐CoV‐2 neutralising monoclonal antibodies (MAbs). Epitope residues of (a) Receptor binding domain (RBD), (b) N‐terminal domain (NTD), (c) Furin cleavage site, and (d) SH‐targeting neutralising MAbs are highlighted in different colours. ACE2: Angiotensin‐converting enzyme 2, SARS‐CoV‐2: Severe acute respiratory syndrome coronavirus 2; NTD: N‐terminal domain; RBD: Receptor binding domain; SH: Stem helix

FIGURE 5

Assignment of epitope residues of (a) Receptor binding domain (RBD), (b) N‐terminal domain (NTD), (c) SD2, and (d) SH‐targeted by neutralising monoclonal antibodies (MAbs) illustrated in Figure 4. NTD: N‐terminal domain; RBD: Receptor binding domain; RBM: Receptor‐binding motif, SD2: Subdomain two; SH: Stem helix

FIGURE 6

Spike amino acid mutations in Alpha, Beta, Gamma, Delta, and Omicron VOCs. VOCs: variants of concern (VOC)