Abstract
Adenovirus-based vectors are promising tools for genetic vaccination. However, several obstacles have to be overcome prior to a routine clinical application of adenovirus-based vectors as efficacious vectored vaccines. The linear trisaccharide epitope αGal (alpha-Gal) with the carbohydrate sequence galactose-α-1,3-galactosyl-β-1,4-N-acetylglucosamine has been described as a potent adjuvant for recombinant or attenuated vaccines. Humans and α-1,3-galactosyltransferase knockout mice do not express this epitope. Upon exposure of α-1,3-galactosyltransferase-deficient organisms to αGal in the environment, large amounts of circulating anti-Gal antibodies are produced consistently. Immunocomplexes formed between recombinant αGal-decorated vaccines and anti-Gal antibodies exhibit superior immunogenicity. We studied the effects of the trisaccharide epitope on CD8 T cell responses that are directed specifically to vector-encoded transgenic antigens. For that, covalently αGal-decorated adenovirus vectors were delivered to anti-Gal α-1,3-galactosyltransferase knockout mice. We generated replication-defective, E1-deleted adenovirus type 5 vectors that were decorated with αGal at the hexon hypervariable regions 1 or 5, at fiber knob, or at penton base. Surprisingly, none of the adenovirus immunocomplexes being formed from αGal-decorated adenovirus vectors and anti-Gal immunoglobulins improved the frequencies of CD8 T cell responses against the transgenic antigen ovalbumin. Humoral immunity directed to the adenovirus vector was neither increased. However, our data indicated that decoration of Ad vectors with the αGal epitope is a powerful tool to analyze the fate of adenovirus immunocomplexes in vivo.
Highlights
Vectored genetic vaccines which are based on replication-deficient adenovirus (Ad) are highly potent inducers of cellular and humoral immune responses. [1,2] Local delivery of Ad vectors causes transduction of a plethora of different cell types—somatic cells, as well as professional antigen-presenting dendritic cells. [3,4] Post-transduction de novo expression of transgenic antigen is followed by antigen processing, peptide presentation in the context of MHC class I molecules, and efficient activation of CD8 T cell responses
To enable covalent surface decoration of antigen-expressing Ad vectors with the trisaccharide αGal, thiol-reactive cysteines were inserted at distinct capsomer sites. αGal was first aminated at its reducing end according to Kochetkov, and the amination was confirmed by 1H-NMR
We hypothesized that formation of immunocomplexes composed of αGal-decorated Ad vectors and anti-Gal antibodies, which are naturally present in humans and can be induced in homozygous α-1,3GT KO mice, might lead to an improved uptake of Ad vectors and subsequent transduction of antigen-presenting cells, and an improved generation of CD8 T cells that are reactive to vector-encoded antigens
Summary
Vectored genetic vaccines which are based on replication-deficient adenovirus (Ad) are highly potent inducers of cellular and humoral immune responses. [1,2] Local delivery of Ad vectors causes transduction of a plethora of different cell types—somatic cells, as well as professional antigen-presenting dendritic cells. [3,4] Post-transduction de novo expression of transgenic antigen is followed by antigen processing, peptide presentation in the context of MHC class I molecules, and efficient activation of CD8 T cell responses. [3,4] Post-transduction de novo expression of transgenic antigen is followed by antigen processing, peptide presentation in the context of MHC class I molecules, and efficient activation of CD8 T cell responses. Ad vectors induce strong antigen-specific antibody responses. It had been found a characteristic of viral vectors, including adenoviral vectors, to induce a Th1-type immune response which is characterized by a more pronounced cellular immunity and conserved humoral responses. Distinct types of immunocomplexes and targeting of phagocyte surface receptors, such as Fc receptors and lectins by glycans, bispecific adaptor molecules and monoclonal antibodies, were observed to be favorable in immune response induction. Distinct types of immunocomplexes and targeting of phagocyte surface receptors, such as Fc receptors and lectins by glycans, bispecific adaptor molecules and monoclonal antibodies, were observed to be favorable in immune response induction. [10,11,12,13,14,15,16,17,18]
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