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Immunogenicity of Influenza Virus Vaccine Is Increased by Anti-Gal-Mediated Targeting to Antigen-Presenting Cells
Ussama M. Abdel-Motal,1 Heath M. Guay,2 Kim Wigglesworth,1 Raymond M. Welsh,2 and Uri Galili1*
Department of Medicine,1 Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 016052
Received 26 March 2007/ Accepted 15 June 2007
This study describes a method for increasing the immunogenicity of influenza virus vaccines by exploiting the natural anti-Gal antibody to effectively target vaccines to antigen-presenting cells (APC). This method is based on enzymatic engineering of carbohydrate chains on virus envelope hemagglutinin to carry the -Gal epitope (Gal1-3Gal?1-4GlcNAc-R). This epitope interacts with anti-Gal, the most abundant antibody in humans (1% of immunoglobulins). Influenza virus vaccine expressing -Gal epitopes is opsonized in situ by anti-Gal immunoglobulin G. The Fc portion of opsonizing anti-Gal interacts with Fc receptors on APC and induces effective uptake of the vaccine virus by APC. APC internalizes the opsonized virus to transport it to draining lymph nodes for stimulation of influenza virus-specific T cells, thereby eliciting a protective immune response. The efficacy of such an influenza vaccine was demonstrated in 1,3galactosyltransferase (1,3GT) knockout mice, which produce anti-Gal, using the influenza virus strain A/Puerto Rico/8/34-H1N1 (PR8). Synthesis of -Gal epitopes on carbohydrate chains of PR8 virus (PR8gal) was catalyzed by recombinant 1,3GT, the glycosylation enzyme that synthesizes -Gal epitopes in cells of nonprimate mammals. Mice immunized with PR8gal displayed much higher numbers of PR8-specific CD8+ and CD4+ T cells (determined by intracellular cytokine staining and enzyme-linked immunospot assay) and produced anti-PR8 antibodies with much higher titers than mice immunized with PR8 lacking -Gal epitopes. Mice immunized with PR8gal also displayed a much higher level of protection than PR8 immunized mice after being challenged with lethal doses of live PR8 virus. We suggest that a similar method for increasing immunogenicity may be applicable to avian influenza vaccines.
(Babelfish translation from parts of:
http://www.faz.net/s/Rub7F74ED2FDF2B...~Scontent.html
)
Also Immunogenitaet of the bird flu virus riserable More survived than ninety per cent of the mice, which had received a protective inoculation with killed, sugar-coated Influenzaviren, a following infection with living Influenzaviren. On the other hand endured of the animals only ten per cent the attack by the Influenzaviren, inoculated with not modified viruses. Further results point on the fact that also the Immunogenitaet of the bird flu virus H5N1 can be increased with the help of an artificial sugar covering. The fact that humans can get sick despite protective inoculation at flu is to be due not only to emerging new exciter variants, but also to an often insufficient immune protection. That hangs, as Galili states, so that together that Influenzaviren do not possess surface textures, by which guard cells could recognize her easily. Probably only those set coincidentally and thus rather rarely in guard cells penetrated flu exciter the defence reactions in motion. The trick to disguise viruses as bacteria could make not only protective inoculations more effective against the flu, but also improve the immunological protection from many other virus illnesses.
Immunogenicity of Influenza Virus Vaccine Is Increased by Anti-Gal-Mediated Targeting to Antigen-Presenting Cells
Ussama M. Abdel-Motal,1 Heath M. Guay,2 Kim Wigglesworth,1 Raymond M. Welsh,2 and Uri Galili1*
Department of Medicine,1 Department of Pathology, University of Massachusetts Medical School, Worcester, Massachusetts 016052
Received 26 March 2007/ Accepted 15 June 2007
This study describes a method for increasing the immunogenicity of influenza virus vaccines by exploiting the natural anti-Gal antibody to effectively target vaccines to antigen-presenting cells (APC). This method is based on enzymatic engineering of carbohydrate chains on virus envelope hemagglutinin to carry the -Gal epitope (Gal1-3Gal?1-4GlcNAc-R). This epitope interacts with anti-Gal, the most abundant antibody in humans (1% of immunoglobulins). Influenza virus vaccine expressing -Gal epitopes is opsonized in situ by anti-Gal immunoglobulin G. The Fc portion of opsonizing anti-Gal interacts with Fc receptors on APC and induces effective uptake of the vaccine virus by APC. APC internalizes the opsonized virus to transport it to draining lymph nodes for stimulation of influenza virus-specific T cells, thereby eliciting a protective immune response. The efficacy of such an influenza vaccine was demonstrated in 1,3galactosyltransferase (1,3GT) knockout mice, which produce anti-Gal, using the influenza virus strain A/Puerto Rico/8/34-H1N1 (PR8). Synthesis of -Gal epitopes on carbohydrate chains of PR8 virus (PR8gal) was catalyzed by recombinant 1,3GT, the glycosylation enzyme that synthesizes -Gal epitopes in cells of nonprimate mammals. Mice immunized with PR8gal displayed much higher numbers of PR8-specific CD8+ and CD4+ T cells (determined by intracellular cytokine staining and enzyme-linked immunospot assay) and produced anti-PR8 antibodies with much higher titers than mice immunized with PR8 lacking -Gal epitopes. Mice immunized with PR8gal also displayed a much higher level of protection than PR8 immunized mice after being challenged with lethal doses of live PR8 virus. We suggest that a similar method for increasing immunogenicity may be applicable to avian influenza vaccines.
(Babelfish translation from parts of:
http://www.faz.net/s/Rub7F74ED2FDF2B...~Scontent.html
)
Also Immunogenitaet of the bird flu virus riserable More survived than ninety per cent of the mice, which had received a protective inoculation with killed, sugar-coated Influenzaviren, a following infection with living Influenzaviren. On the other hand endured of the animals only ten per cent the attack by the Influenzaviren, inoculated with not modified viruses. Further results point on the fact that also the Immunogenitaet of the bird flu virus H5N1 can be increased with the help of an artificial sugar covering. The fact that humans can get sick despite protective inoculation at flu is to be due not only to emerging new exciter variants, but also to an often insufficient immune protection. That hangs, as Galili states, so that together that Influenzaviren do not possess surface textures, by which guard cells could recognize her easily. Probably only those set coincidentally and thus rather rarely in guard cells penetrated flu exciter the defence reactions in motion. The trick to disguise viruses as bacteria could make not only protective inoculations more effective against the flu, but also improve the immunological protection from many other virus illnesses.