Stable Micronized Vaccines Against Smallpox and Japanese Encephalitis

描述（由申请人提供）：天花是世纪上半叶世界范围内发病和死亡的最重要原因之一。天花是一种潜在的生物恐怖主义制剂，已被指定为A类优先病原体。尽管1980年宣布消灭天花，但天花库存的存在和生物恐怖主义的威胁要求通过接种疫苗保持对天花的免疫力。近年来，蚊子传播的感染正在以惊人的速度在世界范围内重新出现或出现。日本脑炎是一种潜在的生物恐怖主义制剂，已被指定为C类优先病原体。目前还没有针对乙脑的许可抗病毒药物，只有针对天花的实验性治疗方法。因此，疫苗接种和病媒控制是唯一有效的预防工具，而疫苗接种是最具成本效益的战略。因此，有效保护人们需要立即采取针对这些病原体的对策。因此，最好在当地储存对策，以确保最大效率地对抗病原体并迅速阻止其传播。如果当地的卫生专业人员和紧急救援人员能够方便地在当地提供疫苗供应，避免需要冷藏以确保储存期间的稳定性，那么就可以实现最佳方案。在过去的几年里，我们的两个合作小组之一，Acambis的托马斯·莫纳斯博士小组已经开发出一种新的天花疫苗（改良安卡拉牛痘（MVA）和日本脑炎（ChimeriVax-JE活的减毒嵌合疫苗）。两种产品均在美国食品药品监督管理局（FDA）批准的IND下进行临床开发。两者都是减毒活疫苗，因此对热降解敏感;因此，疫苗必须冷藏保存。在过去的几年里，我们两个合作小组中的第二个，通用稳定技术（LIST），在维克托布朗斯坦博士的指导下，开发了令人兴奋的新技术，用于稳定细菌和其他活产品。这些技术消除了传统冷冻干燥的破坏性影响，并允许制备在环境温度下稳定的活产品，从而消除了对冷链的需求。该资助提案的目的是将LIST开发的新型稳定化技术应用于环境温度稳定的微粉化MVA天花疫苗和ChimeriVax乙脑疫苗的生产。这种配制的疫苗潜在地可以使用透皮、口服、鼻或吸入递送途径递送而不需要重构。在第一年，我们的目标是在干燥和随后在环境温度下储存后保持高活力和效力的疫苗。Acambis和LIST将合作培养疫苗，探索各种环境温度稳定方法，确认保存疫苗的稳定性和效力，并使用小鼠模型测试保存疫苗的免疫原性和有效性。

DESCRIPTION (provided by applicant): Smallpox was one of the most important causes of morbidity and mortality worldwide through the first half of the 20th Century. Smallpox is a potential agent of bioterrorism; it has been designated as Category A Priority Pathogen. Despite the declaration of smallpox eradication in 1980, the existence of variola stockpiles and the threat of bioterrorism demand that immunity to smallpox through vaccination be maintained. In recent years, mosquito-borne infections are reemerging or emerging worldwide at an alarming rate. Japanese Encephalitis is a potential agent of bioterrorism; it has been designated as Category C Priority Pathogen. There are no licensed antiviral drugs against JE and only experimental treatments exist for smallpox. Therefore, vaccination and vector control are the only effective preventive tools, with vaccination being the most cost-effective strategy. Because of this effective protection of people requires immediate application of the countermeasures against these pathogens. Therefore, local storage of the countermeasures is preferable to ensure the greatest efficiency in combating the pathogens and to rapidly stop their spread. The best scenario could be achieved if local health professionals and emergency personal had convenient locally available supplies of vaccines that obviate the need for cold to ensure stability during storage. In the past few years, one of our two collaborating groups, the Group of Dr. Thomas Monath at Acambis has developed a new vaccine against Smallpox (Modified Vaccinia Ankara (MVA) and Japanese Encephalitis (ChimeriVax-JE live, attenuated chimeric vaccine). Both products are in clinical development under Food and Drug Administration (FDA) approved INDs. Both are live, attenuated vaccines and as such are susceptible to thermal degradation; hence, the vaccines must be kept refrigerated. During the past few years, the second of our two collaborating groups, Universal Stabilization Technologies (LIST), under the direction of Dr. Victor Bronshtein, has developed exciting new technologies for stabilizing bacteria and other live products. These technologies eliminate the damaging effects of conventional freeze-drying and allow the preparation of a live product that is stable at ambient temperature, eliminating the need for a cold chain. The objective of this grant proposal is to apply the novel technologies for stabilization developed at LIST to the manufacture of micronized ambient temperature stable MVA smallpox vaccine and ChimeriVax JE vaccine. Such formulated vaccines potentially could be delivered without need for reconstitution using transdermal, oral, nasal or inhalation delivery routes. During the first year our target will be vaccines that maintain high viability and potency after drying and subsequent storage at ambient temperatures. Working in collaboration, the Acambis and LIST will culture the vaccines, explore various ambient temperature stabilization approaches, confirm the stability and potency of the preserved vaccine, and test the immunogenicity and efficacy of the preserved vaccine using the mouse model.