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Infection and Immunity, September 2005, p. 5654-5665, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5654-5665.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Heteropentameric Cholera Toxin B Subunit Chimeric Molecules Genetically Fused to a Vaccine Antigen Induce Systemic and Mucosal Immune Responses: a Potential New Strategy To Target Recombinant Vaccine Antigens to Mucosal Immune Systems

Tetsuya Harakuni,1 Hideki Sugawa,2 Ai Komesu,1 Masayuki Tadano,3 and Takeshi Arakawa1*

Division of Molecular Microbiology, Center of Molecular Biosciences, University of the Ryukyus, 1 Senbaru, Nishihara, Okinawa 903-0213, Japan,1 Advanced Medical Biological Science Institute, Oozato, Okinawa 901-1202, Japan,2 Department of Molecular Virology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan3

Received 14 December 2004/ Returned for modification 17 February 2005/ Accepted 18 April 2005

Noninvasive mucosal vaccines are attractive alternatives to parenteral vaccines. Although the conjugation of vaccine antigens with the B subunit of cholera toxin (CTB) is one of the most promising strategies for vaccine delivery to mucosal immune systems, the molecule cannot tolerate large-protein fusion, as it severely impairs pentamerization and loses affinity for GM1-ganglioside. Here we report a new strategy, in which steric hindrance between CTB-antigen fusion subunits is significantly reduced through the integration of unfused CTB "molecular buffers" into the pentamer unit, making them more efficiently self-assemble into biologically active pentamers. In addition, the chimeric protein took a compact configuration, becoming small enough to be secreted, and one-step affinity-purified proteins, when administered through a mucosal route, induced specific immune responses in mice. Since our results are not dependent on the use of a particular expression system or vaccine antigen, this strategy could be broadly applicable to bacterial enterotoxin-based vaccine design.

* Corresponding author. Mailing address: Division of Molecular Microbiology, Center of Molecular Biosciences, University of the Ryukyus, Nishihara, Okinawa 903-0213, Japan. Phone and fax: 81-98- 895-8974. E-mail: tarakawa{at}comb.u-ryukyu.ac.jp.

Editor: J. D. Clements

Infection and Immunity, September 2005, p. 5654-5665, Vol. 73, No. 9
0019-9567/05/$08.00+0     doi:10.1128/IAI.73.9.5654-5665.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.





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