A novel neurotoxoid vaccine prevents mucosal botulism
A novel neurotoxoid vaccine prevents mucosal botulism
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DOI：
10.4049/jimmunol.174.4.2190
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发表时间：
2005-02-15
影响因子：
4.4
通讯作者：
Fujihashi, K
中科院分区：
文献类型：
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作者：
Kobayashi, R;Kohda, T;Fujihashi, K
肉毒杆菌中毒是一种典型的食源性和水源性疾病，发病率和死亡率都很高，在生物恐怖主义的时代，它构成的威胁呈指数级增加。由于肉毒杆菌神经毒素(BONT)很容易被恐怖分子使用气雾剂传播，或者可能被用来污染食物或水供应，美国疾病控制和预防中心以及国家过敏和传染病研究所已将其归类为A类毒剂。尽管开发一种安全有效的黏膜疫苗来对抗这种毒素显然是当务之急，但到目前为止，基本上还没有研究评估对这种疾病的黏膜免疫反应。为了弥合我们知识上的这一差距，我们用鼻腔剂量的A型BONT类毒素和一种名为E112K的霍乱毒素突变体对小鼠进行了为期4周的免疫。我们发现血浆中的BONT特异性免疫球蛋白抗体和外部分泌物(鼻液、唾液和粪便提取物)中的分泌型IgA抗体水平升高。用4×10(3)LD50的A型BoNT疫苗(BoNT/A)攻击鼻腔接种BoNT疫苗小鼠。给与相同剂量的幼鼠在2小时内死亡。为了进一步证实这种鼻腔疫苗的效果，我们测定了口服LD50。当小鼠口服5杯(2倍LD50)的祖细胞BoNT/A时，所有免疫的小鼠都能存活5天以上，而未免疫的小鼠则不能。鼻腔免疫小鼠的粪便提取液中含有中和分泌型IgA抗体。综上所述，这些结果表明鼻用Bot/A疫苗有效地预防了黏膜Bot中毒。
The threat posed by botulism, classically a food- and waterborne disease with a high morbidity and mortality, has increased exponentially in an age of bioterrorism. Because botulinum neurotoxin (BoNT) could be easily disseminated by terrorists using an aerosol or could be used to contaminate the food or water supply, the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases has classified it as a category A agent. Although clearly the development of a safe and effective mucosal vaccine against this toxin should be a high priority, essentially no studies to date have assessed mucosal immune responses to this disease. To bridge this gap in our knowledge, we immunized mice weekly for 4 wk with nasal doses of BoNT type A toxoid and a mutant of cholera toxin termed E112K. We found elevated levels of BoNT-specific IgG Abs in plasma and of secretory IgA Abs in external secretions (nasal washes, saliva, and fecal extracts). When mice given nasal BoNT vaccine were challenged with 4 x 10(3) LD50 of BoNT type A (BoNT/A) via the i.p. route, complete protection was seen, while naive mice given the same dosage died within 2 h. To further confirm the efficacy of this nasal BoNT vaccine, an oral LD50 was determined. When mice were given an oral challenge of 5 mug (2 x oral LD50) of progenitor BoNT/A, all immunized mice survived beyond 5 days, while nonimmunized mice did not. The fecal extract samples from nasally vaccinated mice were found to contain neutralizing secretory IgA Abs. Taken together, these results show that nasal BoNT/A vaccine effectively prevents mucosal BoNT intoxication.