The Challenges of Vaccine Development against Betacoronaviruses: Antibody Dependent Enhancement and Sendai Virus as a Possible Vaccine Vector

Abstract

To design an effective and safe vaccine against betacoronaviruses, it is necessary to use their evolutionarily conservative antigenic determinants that will elicit the combination of strong humoral and cell-mediated immune responses. Targeting such determinants minimizes the risk of antibody-dependent enhancement of viral infection. This phenomenon was observed in animal trials of experimental vaccines against SARS-CoV-1 and MERS-CoV that were developed based on inactivated coronavirus or vector constructs expressing the spike protein (S) of the virion. The substitution and glycosylation of certain amino acids in the antigenic determinants of the S-protein, as well as its conformational changes, can lead to the same effect in a new experimental vaccine against SARS-CoV-2. Using more conservative structural and accessory viral proteins for the vaccine antigenic determinants will help to avoid this problem. This review outlines approaches for developing vaccines against the new SARS-CoV-2 coronavirus that are based on non-pathogenic viral vectors. For efficient prevention of infections caused by respiratory pathogens the ability of the vaccine to stimulate mucosal immunity in the respiratory tract is important. Such a vaccine can be developed using non-pathogenic Sendai virus vector, since it can be administered intranasally and induce a mucosal immune response that strengthens the antiviral barrier in the respiratory tract and provides reliable protection against infection.

Keywords: ADE; COVID-19; SARS-CoV-1; SARS-CoV-2; Sendai virus; antibody-dependent enhancement; conservative antigenic determinants; murine respirovirus; vaccine vector.

Fig. 1.

Scheme of antibody-dependent infection enhancement (ADE) for SARS-CoV-1. On the left, a scenario of the correct immune response is shown, when specific neutralizing and protective antibodies contribute to the elimination of the virus from the body. According to this scenario viruses are phagocytosed as stable antigen–antibody complexes and destroyed by macrophages or other immune cells. On the right is an immunopathology scenario that occurs when the antigen of the virus changes and, because of this change, IgG antibodies form imperfect complexes with the virus. The unstable antibody–virus complex binds to the FсγRII receptor of immune cells and is absorbed by these cells. Further, inside the cell, the virus leaves the endosome, already without the antibody, and begins the replicative cycle [5, 10, 12].

Fig. 2.

S-protein conformations in the homotrimer. (a) All S1 subunits are in a closed conformation. (b) One subunit is in an open conformation, and one is in a closed conformation. (c) Conformations of the S-protein in the trimer and the protein domain structure are shown schematically. The receptor-binding domain (RBD, blue), together with the N-terminal domain (yellow), is part of the S1 subunit. In the S1 subunit (blue) there is a proteolytic cleavage site for furin, and within the S2 subunit (brown) is a TMPRSS2 protease cleavage site [15]. Images are taken from the PDB database [16].

Fig. 3.

Models of S- and N-protein structures of betacoronaviruses. Conservative and variable amino acids (AA) are shown in different colors. Protein structures reproduced from the preprint [21]. It is assumed that the high variability of the S-protein is due to its surface exposure on the virion and, as a result, fast antigenic drift under the pressure of immune surveillance. In contrast the N-protein, which is mainly located inside the virion and less visible for humoral immunity is more conservative.

Fig. 4.

The organization of the genomes of the SARS-CoV-2 and Sendai viruses. Above—the genome of SARS-CoV-2 virus and the amino acids variability histogram. The variability scale shows the proportion of non-identical amino acids in each position in the database, collected from December 2019 to June 2020 [97] and includes 2921 viral variants. The first amino acid sequence of proteins encoded by the SARS-CoV-2 genome, published in the database, was taken as a standard. The variability of the amino acid at each position was calculated as the proportion of amino acids found in the database that were not identical to the reference one for all proteins in the translated part of the genome. Below is the genome of the Sendai virus and potential sites for the transgene’s introduction [56, 57]. Transgenes may encode conservative antigenic determinants of SARS-CoV-2 [41, 44, 98]. The encoded proteins are indicated in Latin letters. The numbers that are above the scheme of the Sendai virus genome indicate the length of individual genes, and numbers below—the size of the corresponding proteins.