This study describes a method for increasing immunogenicity of influenza virus vaccines by exploiting the natural anti-Gal antibody for effective targeting vaccines to antigen presenting cells (APC). This method is based on enzymatic engineering of carbohydrate chains on viral envelope hemagglutinin (HA) to carry the alpha-gal epitope (Galalpha1-3Galbeta1-4GlcNAc-R). This epitope interacts with anti-Gal, the most abundant antibody in humans (1% of immunoglobulins). Vaccinating influenza virus expressing alpha-gal epitopes is opsonized in situ by anti-Gal IgG. The Fc portion of opsonizing anti-Gal interacts with Fcgamma receptors on APC and induces effective uptake of the vaccinating virus by APC. APC internalizing the opsonized virus transport it to draining lymph nodes for stimulation of influenza virus specific T cells, thereby eliciting a protective immune response. Efficacy of such flu vaccine is demonstrated in alpha1,3galactosyltransferase (alpha1,3GT) knockout mice which produce anti-Gal and using the influenza virus strain A/Puerto Rico/8/34- H1N1 (PR8). alpha-Gal epitope synthesis on carbohydrate chains of PR8 virus (PR8alphagal) was catalyzed by recombinant alpha1,3GT, the glycosylation enzyme synthesizing alpha-gal epitopes in cells of non-primate mammals. Mice immunized with PR8alphagal displayed much higher numbers of PR8 specific CD8+ and CD4+ T cells (intracellular cytokine staining and ELISPOT) and produced anti-PR8 antibodies with much higher titers than mice immunized with PR8 lacking alpha-gal epitopes. Mice immunized with PR8alphagal also displayed a much higher protection than PR8 immunized mice following challenge with lethal dose of live PR8 virus. We suggest that a similar method for increased immunogenicity may be applicable to avian flu vaccines.