Effectiveness and safety of mutant Escherichia coli heat-labile enterotoxin (LT H44A) as an adjuvant for nasal influenza vaccine
Effectiveness and safety of mutant Escherichia coli heat-labile enterotoxin (LT H44A) as an adjuvant for nasal influenza vaccine
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DOI：
10.1016/s0264-410x(00)00414-x
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发表时间：
2001-02-28
期刊：
影响因子：
5.5
通讯作者：
Tamura, S
中科院分区：
文献类型：
--
作者：
Hagiwar, Y;Tsuji, T;Tamura, S
研究了大肠杆菌不耐热肠毒素LT H44 A（A亚基A1片段N端44位His被Arg取代）作为鼻用流感疫苗佐剂的有效性和安全性。(1)当0.2 μ g LT H44 A与0.2 μ g A/PR/8/34流感病毒一起（PR 8，H1N1）疫苗鼻内给予BALB/c小鼠（两次，间隔4周），抗PR 8血凝素（HA）伊加和IgG抗体（Ab）在足以提供针对小体积PR 8病毒悬浮液感染的完全保护的水平诱导应答，用致命剂量的悬浮液部分保护免受感染。此处使用的突变LT和疫苗的剂量（0.2 μ g/20 g剂量小鼠）对应于每人的估计剂量。即0.1 mg/10 kg体重。(2)使用这些疫苗接种条件，未诱导额外的总IgE Ab应答。(3)当使用Y1肾上腺细胞在体外（1/483 EC 50）或通过回肠环试验分析毒性时，证实突变体的毒性低于天然LT。(4)将100微克的突变体鼻内或腹膜内注射到豚鼠（Heartley品系，0.3-0.4 kg）中，给药后7天没有引起体重变化，尽管腹膜内注射100微克的天然LT在2天内导致所有豚鼠因腹泻而死亡。鼻内给药100 μ g突变体在给药后3天几乎没有导致鼻粘膜的病理变化。这些结果表明，LT H44 A可以在E.大肠杆菌培养物（约5 mg/L），可作为人流感疫苗鼻用佐剂之一。(C)2001爱思唯尔科技有限公司版权所有。
The effectiveness and safety of mutant Escherichia coli heat-labile enterotoxin, LT H44A (His to Arg substitution at position 44 from the N-terminus of the Al fragment of the A subunit) as an adjuvant for nasal influenza vaccine were examined. (1) When 0.2 mug of LT H44A, together with 0.2 mug of influenza A/PR/8/34 virus (PR8, H1N1) vaccine, was administered intranasally into BALB/c mice (twice, 4 weeks apart), anti-PR8 hemagglutinin (HA) IgA and IgG antibody (Ab) responses were induced at levels that were sufficient to provide either complete protection against infection with a small volume of PR8 virus suspension or partial protection against infection with a lethal dose of the suspension. The dose of the mutant LT and vaccine used here (0.2 mug/20 g doses mouse) corresponded to the estimated dose per person. i.e. 0.1 mg/10 kg body weight. (2) Using these vaccination conditions, no additional total IgE Ab responses were induced. (3) The mutant was confirmed to be less toxic than the native LT when the toxicity was analyzed either using Y1 adrenal cells in vitro (1/483 EC50) or by an ileal loop test. (4) One hundred micrograms of the mutant, administered intranasally or intraperitoneally into guinea-pigs (Heartley strain, 0.3-0.4 kg), caused no body-weight changes 7 days after administration, although 100 mug of the native LT administered intraperitoneally caused death in all guinea-pigs due to diarrhea within 2 days. The intranasal administration of 100 mug of the mutant resulted in almost no pathological changes in the nasal mucosa 3 days after administration. These results suggest that LT H44A, which can be produced in high yields in an E. coli culture (about 5 mg/l), could be used as one of the effective and safe adjuvants for nasal influenza vaccine in humans. (C) 2001 Elsevier Science Ltd. All rights reserved.