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*Division of Mucosal Immunology,
Division of Bacterial Infection, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan;
Corporation for Production and Research of Laboratory Primates, Japan;
Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Japan; and
¶Plant Biotechnology Department, National Institute of Agrobiological Sciences, Japan
We previously showed that oral immunization of mice with a rice-based vaccine expressing cholera toxin (CT) B subunit (MucoRice-CT-B) induced CT-specific immune responses with toxin-neutralizing activity in both systemic and mucosal compartments. In this study, we examined whether the vaccine can induce CT-specific Ab responses in nonhuman primates. Orally administered MucoRice-CT-B induced high levels of CT-neutralizing serum IgG Abs in the three cynomolgus macaques we immunized. Although the Ab level gradually decreased, detectable levels were maintained for at least 6 mo, and high titers were rapidly recovered after an oral booster dose of the rice-based vaccine. In contrast, no serum IgE Abs against rice storage protein were induced even after multiple immunizations. Additionally, before immunization the macaques harbored intestinal secretory IgA (SIgA) Abs that reacted with both CT and homologous heat-labile enterotoxin produced by enterotoxigenic Escherichia coli and had toxin-neutralizing activity. The SIgA Abs were present in macaques 1 mo to 29 years old, and the level was not enhanced after oral vaccination with MucoRice-CT-B or after subsequent oral administration of the native form of CT. These results show that oral MucoRice-CT-B can effectively induce CT-specific, neutralizing, serum IgG Ab responses even in the presence of pre-existing CT- and heat-labile enterotoxin-reactive intestinal SIgA Abs in nonhuman primates.
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1 This work was supported by grants from the "Development of Fundamental Technologies for Production of High-Value Materials Using Transgenic Plants" project of the Ministry of Economy, Trade and Industry (to H.K.); the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health and Labour (to H.K. and Y.Y.); GATES Grand Challenges Explorations (to H.K.); the Global COE Program "Center of Education and Research for the Advanced Genome-Based Medicine: For Personalized Medicine and the Control of Worldwide Infectious Diseases" (to H.K.); Research on Vaccine of Next Generation of The Ministry of Health, Labour and Welfare (to H.K. and K.T.); Research Fellowship of the Japan Society for the Promotion of Science (to T.N.); and the Research and Development Program for New Bio-industry Initiatives of the Bio-oriented Technology Research Advancement Institution (to Y.Y.).
2 Address correspondence and reprint requests to Dr. Hiroshi Kiyono, Division of Mucosal Immunology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4–6-1 Shirokanedai, Minato-ku, Tokyo, Japan. E-mail address: kiyono{at}ims.u-tokyo.ac.jp
3 Abbreviations used in this paper: CT, cholera toxin; CT-B, cholera toxin B subunit; PB, protein body; SIgA, secretory IgA Ab; LT, heat-labile enterotoxin; LT-B, heat-labile enterotoxin B subunit; WT, wild type; RT, room temperature; DC, dendritic cell.
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