Yersinia pestis, the etiologic agent of plague, has been responsible for high mortality in several epidemics throughout human history. Plague has been classified as a re-emerging disease by the World Health Organization since there are several thousand reported cases of the disease worldwide annually and Y. pestis strains resistant to multiple drugs have been detected in recent years. The plague bacillus began to be used as a biological weapon at least 800 years ago and is today one of the more likely biological threats. Currently, no licensed plague vaccines are available in Western world. Isolation of virulent F1-negative Y. pestis strains from natural sources and the existence of lcrV polymorphisms in Yersinia may result in Y. pestis variants that escape protective immunity induced by LcrV and F1 antigens. Therefore, vaccines solely based upon LcrV and F1 antigens may be insufficient to guarantee long-term defense against plague in humans. In order to overcome the drawbacks of vaccines composed of LcrV and F1 antigens, we propose to use Y. pestis OMVs as an acellular vaccine against plague: (1) Construct Y. pestis strains which robustly produce self-adjuvanted and highly immunogenic OMVs; (2) Evaluate protective immunities of OMVs in murine model. Finally, the success of this project will provide a rational strategy for designing highly effective and safe plague vaccines for human use.