Mutations of SARS-CoV-2 spike protein: Implications on immune evasion and vaccine-induced immunity

Abstract

Responsible for more than 4.9 million deaths so far, COVID-19, caused by SARS-CoV-2, is instigating devastating effects on the global health care system whose impacts could be longer for the years to come. Acquiring a comprehensive knowledge of host-virus interaction is critical for designing effective vaccines and/or drugs. Understanding the evolution of the virus and the impact of genetic variability on host immune evasion and vaccine efficacy is helpful to design novel strategies to minimize the effects of the emerging variants of concern (VOC). Most vaccines under development and/or in current use target the spike protein owning to its unique function of host receptor binding, relatively conserved nature, potent immunogenicity in inducing neutralizing antibodies, and being a good target of T cell responses. However, emerging SARS-CoV-2 strains are exhibiting variability on the spike protein which could affect the efficacy of vaccines and antibody-based therapies in addition to enhancing viral immune evasion mechanisms. Currently, the degree to which mutations on the spike protein affect immunity and vaccination, and the ability of the current vaccines to confer protection against the emerging variants attracts much attention. This review discusses the implications of SARS-CoV-2 spike protein mutations on immune evasion and vaccine-induced immunity and forward directions which could contribute to future studies focusing on designing effective vaccines and/or immunotherapies to consider viral evolution. Combining vaccines derived from different regions of the spike protein that boost both the humoral and cellular wings of adaptive immunity could be the best options to cope with the emerging VOC.

Keywords: Immunity; Mutation; RBD; SARS-CoV-2; Spike protein; Vaccine.

Fig. 1

Structure of trimeric SARS-CoV-2 spike protein (PDB entry: 7JWY) [274]. The SARS-CoV-2 S1 subunit (with S1 core domain in magenta and RBD in light purple) and S2 subunit (with S2 core domain in red and fusion peptide fragment in yellow) are presented. (A-B) Pre-fusion stabilized closed conformation of Spike trimer (7JWY), with a close-up view of the interaction between G614 from one SD2 Spike monomer and K835, Y837, and K854 from the neighbor FP fragment (yellow). (C-D) Partial open conformation of Spike trimer (6XM4), highlighting the loss of the binding lead by conformational changed, which allows the open conformation and favors the binding with ligand (ACE2). D614 G is involved in the stabilization of FP and the tight pre-fusion closed conformation of SARS-Co-2 S protein. Any mutation of D614 destabilizes the intradomain interaction, favors an open conformation, and increase the viral infectivity.

Fig. 2

Complex structure of SARS-CoV-2 RBD with human ACE2 (PDB entry: 6VW1) [111]. (A) Structure showing the binding of RBD (magentas) with human ACE2 (cyan) and (B) the binding interface of the RBD (magentas) and human ACE2 (cyan). The key residues at the binding interface between the RBD (red highlighted N501, Q493, S494, L455, and F486) and human ACE2 (blue highlighted K353, D38, E35, K31, and M82) are presented by red highlighted sticks.

Fig. 3

Cartoon (upper) and surface (lower) representation of a structure of a typical antibody (P2B-2F6 mAb) bound onto the RBD of SARS-CoV-2(PDB entry: 7BWJ) [275]. (A) Overall structure of the antibody (light chain (magentas) and heavy chain (cyan)) binding with RBD (green). (B) The epitope residues are all in the RBD receptor-binding motif, including residues K444, G446, G447, N448, Y449, N450, L452, V483, E484, G485, F490 and S494. P2B-2F6 attachment uses hydrophobic interactions around RBD residues Y449, L452 and F490 and hydrophilic interactions at the interface. RBD residues at the binding interface engaged in the complex are colored in yellow (bind with light chain residues in red) and in bright orange (bind with heavy chain residues in dark blue) [276]. Mutations on these epitopes are reported to affect the antigenicity and susceptibility of RBD to neutralizing antibodies. Specially A475 V and F490 L substitution mutations resulted in increased resistance to mAbs and COVID-19 convalescent sera [95].

Fig. 4

Representation of the antibody binding interface susceptible for mutations compromising immune response (modified from PDB: 7DK3) with one RBD (RBD Chain C) in ‘’open’’ conformation [177]. RBD interface engaged in the complex with common antibodies are colored regarding specific antibody groups described in [99].

Fig. 5

Structural basis of variant related SARS-CoV-2 T-cell epitope presentation by HLA-I. (A) The KIADYNYKL epitope was presented by a HLA-A*02:01 HLA (PDB 7KEU). (B) NYN epitope in complex with HLA-A*24:02 (PDB 7F4W).