Severe acute respiratory syndrome-coronavirus-2 spike (S) protein based vaccine candidates: State of the art and future prospects

Abstract

Coronavirus disease 2019 (Covid-19) is caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) which is responsible for a global pandemic that started in late 2019 in Wuhan, China. To prevent the worldwide spread of this highly pathogenic virus, development of an effective and safe vaccine is urgently needed. The SARS-CoV-2 and SARS-CoV share a high degree of genetic and pathologic identity and share safety and immune-enhancement concerns regarding vaccine development. Prior animal studies with first generation (whole virus-based) preparations of SARS-CoV vaccines (inactivated and attenuated vaccine modalities) indicated the possibility of increased infectivity or eosinophilic infiltration by immunization. Therefore, development of second and third generation safer vaccines (by using modern vaccine platforms) is actively sought for this viral infection. The spike (S) protein of SARS-CoVs is the main determinant of cell entry and tropism and is responsible for facilitating zoonosis into humans and sustained person-to-person transmission. Furthermore, 'S' protein contains multiple neutralizing epitopes that play an essential role in the induction of neutralizing antibodies (nAbs) and protective immunity. Moreover, T-cell responses against the SARS-CoV-2 'S' protein have also been characterized that correlate to the IgG and IgA antibody titres in Covid-19 patients. Thus, S protein is an obvious candidate antigen for inclusion into vaccine platforms against SARS-CoV-2 viral infection. This manuscript reviews different characteristics of S protein, its potency and 'state of the art' of the vaccine development strategies and platforms using this antigen, for construction of a safe and effective SARS-CoV-2 vaccine.

Keywords: RBD; SARS-CoV-2; spike; vaccine.

FIGURE 1

Genome composition of SARS‐CoV‐2. (a) The coding sequence for SARS‐CoV‐2 proteins. The orf1ab encodes the pp1ab protein that contains 15 nsps (nsp1‐nsp10 and nsp12‐nsp16). The orf1a encodes the pp1a protein that contains ten nsps (nsp1‐nsp10). SARS‐CoV‐2 encodes four structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N) and eight accessory proteins 3a, 3b, p6, 7a, 7b, 8b, 9b, and ORF14. (b) Schematic of SARS‐CoV‐2 S protein. Similar to SARS‐CoV, S protein of SARS‐CoV‐2 also consists of (a) a signal peptide (SP; amino acids 1–19) located at the N terminus, (b) an extracellular domain (amino acids 20–1213) containing S1 (N‐terminal domain [NTD]: amino acids 20–286; C‐terminal domain [CTD]/RBD: amino acids 319‐541) and S2 (fusion peptide [FP] and Heptad repeat [HR1 and HR2]: amino acids 686–1213), (c) a transmembrane domain (TM: amino acids 1214–1236) and (d) a short cytoplasmic domain (CT: amino acids 1237–1273)., The D614G amino acid change in S protein is caused by an A‐to‐G nucleotide mutation at position 23,403 in the Wuhan reference strain. The residue numbers of each region denote their positions in the S protein of SARS‐CoV‐2. CT, cytoplasmic domain; FP, fusion peptide; HR1/2, heptad repeat 1/2; NTD, N‐terminal domain; RBD, receptor‐binding domain; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus‐2; SP, signal peptide; TM, transmembrane domain. The positions of N‐linked glycosylation sequons are shown as branches

FIGURE 2

Structure of SARS‐CoV‐2 S protein in the pre‐fusion conformation. In the top row, the ribbon diagram shows single protomer of SARS‐CoV‐2 S consists the RBD (green) in the down conformation (closed RBD; left) and surface diagrams show side (centre) and apical (right) views of the structure of SARS‐CoV‐2 S trimer with three RBD (green and grey) in the down conformation (closed SARS‐CoV‐2 S trimer). In the bottom row, ribbon diagram shows single protomer of SARS‐CoV‐2 S consists the RBD (green) in the up conformation (opened RBD; left) and surface diagrams show side (centre) and apical (right) views of the structure of SARS‐CoV‐2 S trimer with single RBD (green) in the up conformation (opened SARS‐CoV‐2 S trimer). The structure of the SARS‐CoV‐2 S protein (PBD ID: 6VSB) were analysed and modelled with molecular visualization software VMD (Version 1.9.3). RBD, receptor‐binding domain; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus‐2

FIGURE 3

Immune response to SARS‐CoV‐2. Dendritic cells as APC present viral antigens to CD4+ T cells and induce the production of IgG, IgM and IgA to prevent viral entrance. Furthermore, cytokine storm starts in severe cases that might be correlated with disease severity. It was shown that antibodies and CD4+ T cells generated in 100% of recovering Covid‐19 patients. The CD8+T cells also detected in 70% of recovering COVID patients which secrete perforin and granzyme to kill virally infected cells. It was found CD4+ T‐cell responses to S protein, the main target of most vaccine efforts, were robust, and correlated with the magnitude of the anti‐SARS‐CoV‐2 IgG and IgA titres. T cell responses are focused not only on S but also on M, N, and other ORFs. APC, antigen‐presenting cell; Covid‐19, coronavirus disease 2019; SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus‐2

FIGURE 4

Potential and developing candidates of SARS‐CoV‐2 vaccine platforms. SARS‐CoV‐2, severe acute respiratory syndrome‐coronavirus‐2