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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{triangledown}

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 {alpha}-Gal epitope (Gal{alpha}1-3Galß1-4GlcNAc-R). This epitope interacts with anti-Gal, the most abundant antibody in humans (1% of immunoglobulins). Influenza virus vaccine expressing {alpha}-Gal epitopes is opsonized in situ by anti-Gal immunoglobulin G. The Fc portion of opsonizing anti-Gal interacts with Fc{gamma} 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 {alpha}1,3galactosyltransferase ({alpha}1,3GT) knockout mice, which produce anti-Gal, using the influenza virus strain A/Puerto Rico/8/34-H1N1 (PR8). Synthesis of {alpha}-Gal epitopes on carbohydrate chains of PR8 virus (PR8{alpha}gal) was catalyzed by recombinant {alpha}1,3GT, the glycosylation enzyme that synthesizes {alpha}-Gal epitopes in cells of nonprimate mammals. Mice immunized with PR8{alpha}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 {alpha}-Gal epitopes. Mice immunized with PR8{alpha}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.

* 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

{triangledown} Published ahead of print on 3 July 2007.

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.



This article has been cited by other articles:

  • Wijga, S., Parmentier, H. K., Nieuwland, M. G. B., Bovenhuis, H. (2009). Genetic parameters for levels of natural antibodies in chicken lines divergently selected for specific antibody response. Poult. Sci. 88: 1805-1810 [Abstract] [Full Text]  
  • Parmentier, H. K., De Vries Reilingh, G., Lammers, A. (2008). Decreased Specific Antibody Responses to {alpha}-Gal-Conjugated Antigen in Animals with Preexisting High Levels of Natural Antibodies Binding {alpha}-Gal Residues. Poult. Sci. 87: 918-926 [Abstract] [Full Text]  


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