Development of synthetic antigen vaccines for COVID-19

Abstract

The current pandemic called COVID-19 caused by the SARS-CoV-2 virus brought the need for the search for fast alternatives to both control and fight the SARS-CoV-2 infection. Therefore, a race for a vaccine against COVID-19 took place, and some vaccines have been approved for emergency use in several countries in a record time. Ongoing prophylactic research has sought faster, safer, and precise alternatives by redirecting knowledge of other vaccines, and/or the development of new strategies using available tools, mainly in the areas of genomics and bioinformatics. The current review highlights the development of synthetic antigen vaccines, focusing on the usage of bioinformatics tools for the selection and construction of antigens on the different vaccine constructions under development, as well as strategies to optimize vaccines for COVID-19.

Keywords: SARS-CoV-2; adjuvants; immunoinformatics; in silico; nucleic acid vaccines.

Figure 1.

Mechanism of action of DNA and mRNA vaccines and the pathways for activating the cellular and humoral response. DNA vaccines are commonly delivered by electroporation through transient pores formed in the membrane (1). Thus, the DNA reaches the cell cytoplasm and then the nucleus, where it will be transcribed (2). Then the mRNA goes to the cytoplasm, where it is translated in the vaccine peptide (3). Another strategy is the direct delivery of the mRNA (mRNA vaccine) encapsulated in lipid nanoparticles in the cell cytoplasm (4). After the endosome escape, the mRNA is translated in the cytoplasm, followed by the vaccine antigen processing in the proteasomes (5), where they are cleaved into smaller peptides. Next, the peptides are transported by the TAP transporter (not shown) into the endoplasmic reticulum, where they are linked to the MHC-I (6) for TCD8 lymphocyte presentation at the cell surface (7), activating the cytotoxic response and generating effective and memory cells. While the cytotoxic response is triggered through the processing of intracellular antigens, the helper response, as a general rule, is triggered through the exogenous pathway, in which transfected somatic cells – such as myocytes at the injection site – produce the vaccine peptide (8). The peptides can be released outside the cell and be directly engulfed by DCs, or they can be internalized by the apoptotic or necrotic bodies, provoked by an inflammatory environment caused by the electroporation. Thus, the fusion of endocytic vesicles – containing the peptides processed by the lysosomal pathway – with vesicles containing MHC-II molecules of DCs (9), allows the presentation of epitopes to the TCD4 lymphocytes at the cell surface (10), with the activation of helper response and generation of memory cells. The TCD4+ lymphocytes, in turn, play a fundamental role in the activation (11) and maturation of B cell affinity inside the germinal centers (12) for the activation of the humoral response (T cell-dependent B cell activation) generating plasmatic cells that can produce high-affinity neutralizing antibodies, as well as memory cells. Another possible activation pathway for humoral response, but with the induction of a weaker immune response, is the direct linkage to the vaccine antigen with B cell receptors (BCRs) (T-cell independent B cell activation).

Figure 2.

Structure of a hypothetical synthetic multiepitope vaccine construct containing adjuvant and linkers sequences. In this example, the construct contains sequences that act as adjuvants, which are capable of increasing the immunogenicity of nucleic acid vaccines. Moreover, linker sequences were added between each epitope in order to provide proteasomal and lysosomal processing sites, and TAP transporter binding sites. Concerning the epitopes, in this construction MHC-I, MHC-II ligands, and linear B cell epitopes were added in order to induce both cellular and humoral responses. The epitopes shown in purple are intended for binding to MHC-I molecules and must have between 8 and 11 amino acids. In light blue, the MHC-II ligands are found, these must feature more than 11 amino acids. Meanwhile, the epitopes for B cell activation are shown in gray and contain larger-sized epitopes, up to about 16 aa. LK: Linker, ADJ: Adjuvant.

Figure 3.

Summary showing, step by step, the criteria for the development of a COVID-19 vaccine through the construction of synthetic antigens.