Evaluation of protection afforded by Brucella abortus and Brucella melitensis unmarked deletion mutants exhibiting different rates of clearance in BALB/c mice
Evaluation of protection afforded by Brucella abortus and Brucella melitensis unmarked deletion mutants exhibiting different rates of clearance in BALB/c mice
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DOI：
10.1128/iai.01787-05
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发表时间：
2006-07-01
影响因子：
3.1
通讯作者：
Ficht, T. A.
中科院分区：
文献类型：
--
作者：
Kahl-McDonagh, M. M.;Ficht, T. A.
新型布鲁氏菌疫苗的研究重点是活疫苗株的开发，事实证明这种疫苗比灭活疫苗或亚单位疫苗更有效。为了开发改进的疫苗，对带有特征标记的突变体库进行了筛选，以识别减毒的生存突变体。从这些筛选中选择的突变体表现出以清除率为特征的不同程度的衰减，从感染24小时后巨噬细胞无法生长到在小鼠模型中无法持续超过8周。理想的候选疫苗应该对宿主安全，同时激发保护性免疫力。在目前的工作中，我们在流产布鲁氏菌和羊种布鲁氏菌中构建了三个候选基因 manBA、virB2 和 asp24 的未标记缺失突变体。 Delta asp24 突变体在体内持续较长时间，在疫苗接种后 12、16 和 20 周后，其抗同源攻击感染的能力优于当前的疫苗株和在小鼠模型中测试的其他缺失株。与 Delta manBA 和 Delta virB2 突变体相比，Delta asp24 突变体还表现出针对小鼠异源攻击的卓越保护作用。从这项研究来看，所有疫苗组之间的感染保护和细胞因子反应之间的直接关联并不明显，因此，需要进一步考虑保护性免疫的相关性。疫苗株的持久性与感染保护之间的明显相关性得到了证实。
Research for novel Brucella vaccines has focused upon the development of live vaccine strains, which have proven more efficacious than killed or subunit vaccines. In an effort to develop improved vaccines, signature-tagged mutant banks were screened to identify mutants attenuated for survival. Mutants selected from these screens exhibited various degrees of attenuation characterized by the rate of clearance, ranging from a failure to grow in macrophages after 24 h of infection to a failure to persist in the mouse model beyond 8 weeks. Ideal vaccine candidates should be safe to the host, while evoking protective immunity. In the present work, we constructed unmarked deletion mutants of three gene candidates, manBA, virB2, and asp24, in both Brucella abortus and Brucella melitensis. The Delta asp24 mutants, which persist for extended periods in vivo, are superior to current vaccine strains and to other deletion strains tested in the mouse model against homologous challenge infection after 12, 16, and 20 weeks postvaccination. The Delta asp24 mutants also display superior protection compared to Delta manBA and Delta virB2 mutants against heterologous challenge in mice. From this study, a direct association between protection against infection and cytokine response was not apparent between all vaccine groups and, therefore, correlates of protective immunity will need to be considered further. A distinct correlation between persistence of the vaccine strain and protection against infection was corroborated.