Institute of Microbiology, D-BIOL, ETH Zürich, Zürich, Switzerland.
PLoS One. 2012;7(9):e45433. doi: 10.1371/journal.pone.0045433. Epub 2012 Sep 24.
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.
减毒活疫苗在预防传染病方面具有重要价值。它们在充分的定植介导适应性免疫和最小化疫苗株自身感染风险之间达成了微妙的平衡。免疫缺陷会使疫苗株感染的风险增加。目前仍不清楚是否可以通过使疫苗在免疫缺陷个体中减毒而不影响其在正常宿主中的性能来提高疫苗的安全性。我们使用鼠伤寒沙门氏菌腹泻的小鼠模型和减毒活鼠伤寒沙门氏菌（ssaV）株来验证这一假说。该菌株在野生型小鼠中引发了保护性免疫，但在缺乏 NADPH 氧化酶和诱导型一氧化氮合酶的免疫缺陷 cybb(-/-)nos2(-/-)动物中会引起致命的全身感染。在 cybb(-/-)nos2(-/-)小鼠中，我们分析了携带一个额外突变的 35 个 ssaV 株的衰减情况。一个菌株 Z234（ssaV SL1344_3093）在 cybb(-/-)nos2(-/-)小鼠中衰减超过 1000 倍，在 tnfr1(-/-)动物中衰减约 100 倍。然而，在 wt 小鼠中，Z234 在宿主定植和引发保护性、O 抗原特异性黏膜分泌型 IgA（sIgA）反应方面与 ssaV 一样有效。这些数据表明，可以设计专门在免疫功能低下宿主中减毒的减毒活疫苗。这可能有助于提高疫苗的安全性。
