Abstract
The many carbohydrate chains on Covid-19 coronavirus SARS-CoV-2 and its S-protein form a glycan-shield that masks antigenic peptides and decreases uptake of inactivated virus or S-protein vaccines by APC. Studies on inactivated influenza virus and recombinant gp120 of HIV vaccines indicate that glycoengineering of glycan-shields to present α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) enables harnessing of the natural anti-Gal antibody for amplifying vaccine efficacy, as evaluated in mice producing anti-Gal. The α-gal epitope is the ligand for the natural anti-Gal antibody which constitutes ~1% of immunoglobulins in humans. Upon administration of vaccines presenting α-gal epitopes, anti-Gal binds to these epitopes at the vaccination site and forms immune complexes with the vaccines. These immune complexes are targeted for extensive uptake by APC as a result of binding of the Fc portion of immunocomplexed anti-Gal to Fc receptors on APC. This anti-Gal mediated effective uptake of vaccines by APC results in 10–200-fold higher anti-viral immune response and in 8-fold higher survival rate following challenge with a lethal dose of live influenza virus, than same vaccines lacking α-gal epitopes. It is suggested that glycoengineering of carbohydrate chains on the glycan-shield of inactivated SARS-CoV-2 or on S-protein vaccines, for presenting α-gal epitopes, will have similar amplifying effects on vaccine efficacy. α-Gal epitope synthesis on coronavirus vaccines can be achieved with recombinant α1,3galactosyltransferase, replication of the virus in cells with high α1,3galactosyltransferase activity as a result of stable transfection of cells with several copies of the α1,3galactosyltransferase gene (GGTA1), or by transduction of host cells with replication defective adenovirus containing this gene. In addition, recombinant S-protein presenting multiple α-gal epitopes on the glycan-shield may be produced in glycoengineered yeast or bacteria expression systems containing the corresponding glycosyltransferases. Prospective Covid-19 vaccines presenting α-gal epitopes may provide better protection than vaccines lacking this epitope because of increased uptake by APC.
Highlights
Increasing numbers of research groups are developing prophylactic vaccines against infection by the Covid-19 coronavirus SARSCoV-2
Since the proposed glycoengineering was found to increase immunogenicity of viral vaccines such as influenza virus and gp120 of HIV up to 100–200 fold, this review suggests that the glycoengineering methods presented here may greatly increase immunogenicity of vaccines containing attenuated or inactivated SARS-CoV-2, or the S-protein of this virus
The increased antibody and T cells responses in mice immunized with the recombinant gp120agal vs. gp120 is similar to the increased immune response observed with PR8agal vaccine vs. PR8 vaccine. These findings suggest that replacing the sialic acid of S-protein split, subunit, or recombinant vaccines with a-gal epitopes to form
Summary
Increasing numbers of research groups are developing prophylactic vaccines against infection by the Covid-19 coronavirus SARSCoV-2. Glycoengineering of the glycan-shield, as described in this review, is likely to convert this shield from an obstacle for uptake of vaccine by APC into a portion of the S-protein molecule that effectively targets it for extensive uptake by APC, thereby amplifying immunogenicity by increasing processing and presentation of SARS-CoV-2 antigens by the APC This conversion is achieved by replacing sialic acid on the glycan-shield of the S-protein vaccine with terminal galactose linked a1-3 to the glycans in order to form multiple a-gal epitopes with the structure Gala1-3Galb1-4GlcNAc-R on the S-protein (called here S-proteinagal) (Fig. 1). Step 1- Administration of inactivated virus or viral envelope glycoprotein vaccines presenting a-gal epitopes into humans will result in rapid formation of immune complexes with the natural anti-Gal antibody of the vaccinated individual These immune complexes will activate the complement system for the formation of chemotactic complement cleavage peptides (e.g. C5a) that induce rapid recruitment of APC as dendritic cells and macrophages to the immunization sites, as observed in tumors converted into vaccines by intratumoral injection of a-gal glycolipids [66]. The presented viral peptides will activate specific T cells with the corresponding T cell receptors (TCR) to proliferate and initiate effective anti-virus T cell and antibody immune response
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