SARS-CoV-2 Vaccines Based on the Spike Glycoprotein and Implications of New Viral Variants

Abstract

Coronavirus 19 Disease (COVID-19) originating in the province of Wuhan, China in 2019, is caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), whose infection in humans causes mild or severe clinical manifestations that mainly affect the respiratory system. So far, the COVID-19 has caused more than 2 million deaths worldwide. SARS-CoV-2 contains the Spike (S) glycoprotein on its surface, which is the main target for current vaccine development because antibodies directed against this protein can neutralize the infection. Companies and academic institutions have developed vaccines based on the S glycoprotein, as well as its antigenic domains and epitopes, which have been proven effective in generating neutralizing antibodies. However, the emergence of new SARS-CoV-2 variants could affect the effectiveness of vaccines. Here, we review the different types of vaccines designed and developed against SARS-CoV-2, placing emphasis on whether they are based on the complete S glycoprotein, its antigenic domains such as the receptor-binding domain (RBD) or short epitopes within the S glycoprotein. We also review and discuss the possible effectiveness of these vaccines against emerging SARS-CoV-2 variants.

Keywords: RBD; SARS-CoV-2 variants; resistance to neutralization; spike glycoprotein; vaccine design.

Figure 1

Structural characteristics of SARS-CoV-2 virion. Nucleocapsid (N) protein is associated to the single-stranded genomic RNA (ssRNA), which is covered by an outer envelope of the main structural proteins: S glycoprotein (S), membrane protein (M) and envelope protein (E), which are found in the lipid membrane of the virion.

Figure 2

Structural characteristics of the trimeric S glycoprotein of SARS-CoV-2. (A) Schematic representation of the composition and arrangement of domains present in the SARS-CoV-2 S glycoprotein. Signal sequence (SS), N-terminal domain (NTD), receptor-binding domain (RBD), subdomain 1 and 2 (SD1/2), furin cleavage site (S1/S2, arrow), protease cleavage site 2′ (S2′, arrow), fusion peptide (FP), heptad repeat 1 (HR1), central helix (CH), connector domain (CD), heptad repeat 2 (HR2), transmembrane domain (TM), cytoplasmic tail (CT). (B) Side view of the SARS-CoV-2 S glycoprotein monomer (PDB: 7DK3) in open state using the same color representation as in panel A (left). Side (middle) and top (right) views of the oligomeric conformation. The second (grey) and third (black) sub-units of the trimer are shown in the closed conformation.

Figure 3

Immunogenic peptides used in a peptide vaccine against SARS-CoV-2. (A) Structural representation of a SARS-CoV-2 S glycoprotein monomer in closed state (PDB: 7DK3), showing the location of the epitopes and sequences used for the design of a peptide vaccine against SARS-CoV-2 (cyan, red and green). (B) Structural representation of the trimer formed by three protomers of the S glycoprotein (white, grey and black), and location of the antigenic epitopes in the oligomeric conformation.

Figure 4

Structural mutations of the S glycoprotein in the SARS-CoV-2 variants: B.1.1.7., B.1.351, P.1, B.1.617 and his sub-lineages. (A) Schematic representation of the S glycoprotein (PDB:7DK3) and the changes present in variants. The amino acid mutations for the sub-lineages of B.1.617 are shown in red. (B) Structural representation of the S glycoprotein, showing deletion sites (del) (green dots) and mutation sites (blue dots) for each of the panel (A) variants. Some mutations are not shown because they are in unresolved regions.

Figure 5

Association of neutralizing antibodies (nAbs) to RBD and mutations of variants B.1.1.7, B.1.351, P.1 and B.1.617 (A) General structure of the interaction of the nAb C119 blocking the binding site of ACE2 in RBD (PDB: 7K8W). (B) Interaction surface of the C119 antibody blocking the ACE2 binding site in RBD (PDB: 7K8W). (C) Regions in RBD that interact with nAbs of different classes. Class I: B38 Antibody (PDB: 7BZ5) (Red), C119 Antibody (PDB: 7K8W) (Sand), S309 Antibody (PDB: 7BEP) (Green), CR3022 Antibody (PDB: 6W41) (Blue). (D) RBD residues (yellow) interacting with class I, II, III and IV nAbs. The mutated amino acids of the variants B.1.1.7., B.1.351, P.1 and B.1.617 are highlighted in a red box.