Mucosal modified vaccinina Ankara-based plaque vaccines

描述（由申请人提供）：在整个历史上，鼠疫已经摧毁了人类和动物种群。近年来，它在世界许多地方造成严重的流行病，造成人员死亡和严重的经济损失。此外，鼠疫的病原体鼠疫耶尔森氏菌可能是一种毁灭性的生物武器。在一个500万人口的城市故意释放50公斤鼠疫杆菌可能导致多达15万例临床病例和3.6万例死亡。目前，没有针对鼠疫的人用疫苗。需要一种新型疫苗，以防止雾化暴露于鼠疫杆菌。病毒载体是目前开发新型鼠疫疫苗的许多方法之一。改性安卡拉牛痘（MVA）病毒作为下一代生物防御疫苗的病毒载体具有明显的优势。MVA的安全性和诱导粘膜免疫反应已被充分证明适用于多种病原体，MVA正被用作第二代天花疫苗。在相关的痘病毒疫苗载体中，我们证明了几个分子元件显著提高鼠疫杆菌F1荚膜抗原的表达水平并增强免疫反应。我们的长期目标是通过重组MVA优化抗原表达，并开发一种高度安全的粘膜MVA鼠疫疫苗，以防止气溶胶暴露于鼠疫杆菌和天花病毒。具体目的如下。1)构建并评价表达鼠疫菌多种抗原的MVA重组病毒。2)检测重组MVA病毒对鼠疫菌雾化防护的效果。3)评估疫苗对鼠疫杆菌抗原变异的保护作用。4)评价重组MVA/Y的安全性。免疫缺陷小鼠的鼠疫疫苗。将选择重组MVA疫苗组合进行进一步分析，该组合安全地为小鼠提供最完整的保护，使其免受气溶胶暴露于鼠疫杆菌。在第二阶段，将构建一种表达所需抗原的多价MVA疫苗，并在小鼠和非人灵长类动物中进行试验，以防止雾化鼠疫杆菌，并在天花病毒暴露的实验模型中进行保护。

DESCRIPTION (provided by applicant): Plague has devastated human and animal populations throughout history. In recent years, it has caused severe epidemics in many parts of the world, resulting in human deaths and severe economic losses. In addition, Yersinia pestis, the cause of plague, could be a devastating bioweapon. An intentional release of 50 kg of Y. pestis over a city of 5 million people could result in as many as 150,000 clinical cases and 36,000 deaths. Currently, no human vaccines are available for plague. A novel vaccine is needed that can protect against aerosolized exposure to Y. pestis. Viral vectors are among the many approaches currently being pursued to develop novel plague vaccines. Modified vaccinia Ankara (MVA) virus offers distinct advantages as a viral vaccine vector for the next generation of biodefense vaccines. Its safety and induction of mucosal immune responses has been well-documented for a variety of pathogens and MVA is being used as a second generation smallpox vaccine. In a related poxvirus vaccine vector, we demonstrated that several molecular elements significantly enhance the expression levels of Y. pestis F1 capsular antigen and augment the immune response. Our long-term goal is to optimize antigen expression by recombinant MVA and develop a highly safe mucosal MVA-based plague vaccine that protects against aerosol exposure to both Y. pestis and smallpox virus. The specific aims are as follows. 1) Construct and evaluate optimized MVA recombinant viruses that will express several Y. pestis antigens. 2) Test the efficacy of the recombinant MVA viruses for protection from aerosolized Y. pestis. 3) Evaluate vaccine protection against Y. pestfs antigen variants. 4) Evaluate the safety of the recombinant MVA/Y. pestis vaccines in immunodeficient mice. The combination of recombinant MVA vaccines that safely provides the most complete protection of mice from aerosol exposure to Y. pestis will be chosen for further analysis. In phase II, a multivalent MVA vaccine expressing the required antigens will be constructed and tested in mice and in non-human primates for protection against aerosolized Y. pestis and protection in experimental models of smallpox virus exposure.