Nochi Tomonori, Yuki Yoshikazu, Katakai Yuko, Shibata Hiroaki, Tokuhara Daisuke, Mejima Mio, Kurokawa Shiho, Takahashi Yuko, Nakanishi Ushio, Ono Fumiko, Mimuro Hitomi, Sasakawa Chihiro, Takaiwa Fumio, Terao Keiji, Kiyono Hiroshi
Division of Mucosal Immunology, Department of Microbiology and Immunology, University of Tokyo, Japan.
J Immunol. 2009 Nov 15;183(10):6538-44. doi: 10.4049/jimmunol.0901480. Epub 2009 Oct 30.
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.
我们之前的研究表明，用表达霍乱毒素（CT）B亚基的水稻疫苗（MucoRice-CT-B）对小鼠进行口服免疫，可在全身和黏膜部位诱导产生具有毒素中和活性的CT特异性免疫反应。在本研究中，我们检测了该疫苗能否在非人灵长类动物中诱导CT特异性抗体反应。口服MucoRice-CT-B在我们免疫的三只食蟹猴中诱导产生了高水平的CT中和血清IgG抗体。尽管抗体水平逐渐下降，但可检测水平至少维持了6个月，口服一剂水稻疫苗加强免疫后，高滴度抗体迅速恢复。相比之下，即使多次免疫后也未诱导出针对水稻储存蛋白的血清IgE抗体。此外，在免疫前，食蟹猴体内存在与CT以及产肠毒素大肠杆菌产生的同源不耐热肠毒素均发生反应且具有毒素中和活性的肠道分泌型IgA（SIgA）抗体。SIgA抗体存在于1月龄至29岁的食蟹猴中，在用MucoRice-CT-B口服疫苗接种后或随后口服天然形式的CT后，其水平并未升高。这些结果表明，即使在非人灵长类动物中预先存在与CT和不耐热肠毒素反应的肠道SIgA抗体的情况下，口服MucoRice-CT-B仍能有效诱导CT特异性、中和性血清IgG抗体反应。
