Chapter 9 - Anti-Gal-Mediated Amplification of Viral Vaccine Efficacy

Abstract

The natural anti-Gal antibody may be harnessed for increasing the efficacy of viral vaccines as well as other vaccines, if the vaccine is engineered to carry the α-gal epitope. The binding of anti-Gal, present in large amounts in humans, to the α-gal epitopes on the vaccinating virus or on the glycoprotein vaccines results in formation of immune complexes. These immune complexes activate the complement system and generate complement cleavage chemotactic factors that recruit macrophages and dendritic cells to the immunization site. These antigen-presenting cells (APC) bind via their Fc receptors, the Fc portion of anti-Gal immunocomplexed with the vaccine and are induced to effectively internalize the vaccine, transport it to the regional lymph nodes, process, and present the immunogenic peptides for effective activation of cytotoxic T cells and helper T cells. Studies on immunization of anti-Gal producing α1,3galactosyltransferase knockout mice (GT-KO) with inactivated influenza virus presenting α-gal epitopes and with gp120 of HIV carrying α-gal epitopes indicated that anti-Gal-mediated targeting of vaccines to APC results in amplification of the antibody response by 30- to 200-fold and the cellular immune response by 10- to 30-fold. Synthesis of α-gal epitopes on carbohydrate chains of enveloped virus glycoproteins or on recombinant virus glycoproteins is feasible by using rα1,3GT and uridine diphosphate galactose (UDP-Gal). If the carbohydrate chains are capped with sialic acid, addition of neuraminidase removes the sialic acid and exposes the penultimate LacNAc (Galβ1-4GlcNAc-R), which is the acceptor for synthesis of α-gal epitopes by α1,3GT. Increased immunogenicity of vaccinating proteins lacking carbohydrate chains (e.g., core and matrix viral proteins) can be achieved by producing fusion proteins with glycoproteins carrying multiple α-gal epitopes, such as gp120 of HIV or hemagglutinin of influenza virus.