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Journal of Virology, September 2007, p. 9131-9141, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00647-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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 Galili^1*

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 (Gal1-3Galß1-4GlcNAc-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 (PR8_gal) was catalyzed by recombinant 1,3GT, the glycosylation enzyme that synthesizes -Gal epitopes in cells of nonprimate mammals. Mice immunized with PR8_gal 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 PR8_gal 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.

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* Corresponding author. Mailing address: Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, LRB, Worcester, MA 01605. Phone: (508) 856-4188. Fax: (508) 856-4106. E-mail: Uri.Galili{at}umassmed.edu

Published ahead of print on 3 July 2007.

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Journal of Virology, September 2007, p. 9131-9141, Vol. 81, No. 17
0022-538X/07/$08.00+0     doi:10.1128/JVI.00647-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

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