Live attenuated S. Typhimurium vaccine with improved safety in immuno-compromised mice.
Live attenuated S. Typhimurium vaccine with improved safety in immuno-compromised mice.
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DOI：
10.1371/journal.pone.0045433
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hardt WD
中科院分区：
文献类型：
--
作者：
Periaswamy B;Maier L;Vishwakarma V;Slack E;Kremer M;Andrews-Polymenis HL;McClelland M;Grant AJ;Suar M;Hardt WD
减毒活疫苗对预防传染病具有重要价值。它们代表了足够的定殖介导的适应性免疫和最小化疫苗株本身感染风险之间的微妙妥协。免疫缺陷可导致疫苗株感染。目前尚不清楚是否可以通过在免疫缺陷个体中减弱疫苗而不损害疫苗在正常宿主中的性能的突变来提高疫苗的安全性。我们已经解决了这一假设，使用沙门氏菌腹泻的小鼠模型和减毒活鼠伤寒沙门氏菌菌株（ssaV）。用该菌株接种疫苗在野生型小鼠中引起保护性免疫，但在缺乏NADPH氧化酶和诱导型NO合酶的免疫缺陷型cybb −/− nos 2 −/−动物中引起致命的全身感染。在cybb −/− nos 2 −/−小鼠中，我们分析了35个ssaV毒株的减毒情况，每个毒株携带一个额外的突变。其中一株Z234（ssaV SL1344_3093）在cybb −/− nos 2 −/−小鼠中减毒>1000倍，在tnfr 1 −/−动物中减毒> 100倍。然而，在野生型小鼠中，Z234在宿主定植和引发保护性的O-抗原特异性粘膜分泌伊加（sIgA）应答方面与ssaV一样有效。这些数据表明，有可能设计出在免疫受损宿主中特异性减毒的活减毒疫苗。这可能有助于提高疫苗的安全性。
Live attenuated vaccines are of great value for preventing infectious diseases. They represent a delicate compromise between sufficient colonization-mediated adaptive immunity and minimizing the risk for infection by the vaccine strain itself. Immune defects can predispose to vaccine strain infections. It has remained unclear whether vaccine safety could be improved via mutations attenuating a vaccine in immune-deficient individuals without compromising the vaccine's performance in the normal host. We have addressed this hypothesis using a mouse model for Salmonella diarrhea and a live attenuated Salmonella Typhimurium strain (ssaV). Vaccination with this strain elicited protective immunity in wild type mice, but a fatal systemic infection in immune-deficient cybb −/− nos2 −/− animals lacking NADPH oxidase and inducible NO synthase. In cybb −/− nos2 −/− mice, we analyzed the attenuation of 35 ssaV strains carrying one additional mutation each. One strain, Z234 (ssaV SL1344_3093), was >1000-fold attenuated in cybb −/− nos2 −/− mice and ≈100 fold attenuated in tnfr1 −/− animals. However, in wt mice, Z234 was as efficient as ssaV with respect to host colonization and the elicitation of a protective, O-antigen specific mucosal secretory IgA (sIgA) response. These data suggest that it is possible to engineer live attenuated vaccines which are specifically attenuated in immuno-compromised hosts. This might help to improve vaccine safety.
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通讯作者：
Hardt WD