Mucosal Immunization with Attenuated Salmonella enterica Serovar Typhi Expressing Protective Antigen of Anthrax Toxin (PA83) Primes Monkeys for Accelerated Serum Antibody Responses to Parenteral PA83 Vaccine
Mucosal Immunization with Attenuated Salmonella enterica Serovar Typhi Expressing Protective Antigen of Anthrax Toxin (PA83) Primes Monkeys for Accelerated Serum Antibody Responses to Parenteral PA83 Vaccine
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DOI：
10.1086/596066
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发表时间：
2009-02-01
影响因子：
6.4
通讯作者：
Levine, Myron M.
中科院分区：
文献类型：
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作者：
Galen, James E.;Chinchilla, Magaly;Levine, Myron M.
肠沙门氏菌伤寒疫苗株 CVD 908-htrA 经过基因工程改造，可稳定表达与输出蛋白 ClyA 融合的炭疽毒素保护性抗原 (PA83) (ClyA-PA83)。在第 0 天和第 14 天通过粘膜（即鼻内）免疫的 12 只恒河猴和 20 只食蟹猴中评估了表达 ClyA-PA83 的 CVD 908-htrA 的引发潜力。在第 42 天和第 225 天给恒河猴注射了含有纯化 PA83 加明矾的胃肠外加强剂；食蟹猴仅在初次接种后 3 个月内接受了一次 PA 或许可的炭疽疫苗（BioThrax；Emergent Biosolutions）加强接种。接受加强剂后 7 天，用表达 ClyA-PA83 的伤寒沙门氏菌免疫的猴子产生高水平的血清毒素中和活性 (TNA) 抗体（50% 有效剂量 [ED50]，> 1.3 x 10(3)），而未免疫的对照缺乏血清 TNA（ED50，0）。在非人类灵长类动物中，这种基于异源粘膜引发和肠外亚单位疫苗加强剂的炭疽疫苗策略的成功为临床试验铺平了道路。
Salmonella enterica serovar Typhi vaccine strain CVD 908-htrA was genetically engineered for stable plasmid-based expression of protective antigen of anthrax toxin (PA83) fused with the export protein ClyA (ClyA-PA83). The priming potential of CVD 908-htrA expressing ClyA-PA83 was assessed in 12 rhesus and 20 cynomolgus macaques that were immunized mucosally (i.e., intranasally) on days 0 and 14. A parenteral booster with purified PA83 plus alum was given to rhesus macaques on days 42 and 225; cynomolgus monkeys received a booster with either PA or licensed anthrax vaccine (BioThrax; Emergent Biosolutions) only one time, 3 months after priming. Monkeys primed with S. Typhi expressing ClyA-PA83 developed high levels of serum toxin-neutralization activity (TNA) antibodies (50% effective dose [ED50], > 1.3 x 10(3)), 7 days after receipt of the booster, whereas unprimed controls lacked serum TNA(ED50, 0). In nonhuman primates, the success of this anthrax vaccine strategy based on heterologous mucosal priming followed by a parenteral subunit vaccine booster paves the way for clinical trials.