SUMMARY 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 multidrug-resistant Y. pestis strains occur in recent years. The plague bacillus has been used as a biological weapon recorded in human history and is one of the more likely biological threats to be used by terrorists. 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 is insufficient to guarantee long-term defense against plague in humans. In order to overcome the drawbacks of subunit vaccines composed of LcrV and F1 antigens, we propose to use Y. pseudotuberculosis (Yptb) OMVs as an acellular vaccine against plague: (1) Construct Yptb strains which robustly produce highly immunogenic self-adjuvanting OMVs carrying an array of Y. pestis protective antigens; (2) Evaluate protective immunity of OMVs in rodents (mouse and rat). (3) Carefully decipher mechanisms of immune protection induced by the Yersinia OMVs to provide fundamentals for rational plague vaccine development. Finally, the success of this project will provide highly effective and safe plague vaccines for humans.

NARRATIVE We propose to develop Yersinia OMVs enclosing both protective antigens from Y. pestis as an effective acellular vaccine against plague.