Improved Live Attenuated Brucella Vaccines to Reduce Human Diseases

 描述（由申请方提供）：拟定研究的目标是开发安全有效的布鲁氏菌感染疫苗。我们的一般方法集中在减毒活疫苗的使用上。虽然从热灭活的生物体、粗提物或重组亚单位开发的疫苗已证明效力很小，但布鲁氏菌LAV已被证明在与检测和屠宰结合使用时非常有效。然而，当应用于欠发达国家时，这些计划可能会导致动物生产力和家庭生计的重大损失，因此执法不严。目前可用的布鲁氏菌疫苗直接用于妊娠动物或人类是不安全的。此外，将其用于动物对公共卫生构成次级风险，特别是在牲畜是主要营养来源的不发达国家。出于这些原因，我们试图确定改进的LAV，这些LAV在妊娠的所有阶段都可以安全地用于动物，因此对人类的风险降低。在非人灵长类动物中进行的实验已经证实了一定的安全性，为开发人类安全使用的布鲁氏菌疫苗的平行目标提供了持续的支持。在山羊中成功证明安全性也有望为降低生物防护水平提供支持，从而可以检查山羊中的有效性。该疫苗的总体设计结合了LAV的最佳特征，即安全、在动物中无副作用且有效，并具有通过微囊化提供增强的免疫刺激的递送系统。这些研究的成功结果将用于生产一种疫苗，该疫苗可提供显著的预防流产保护，并提高动物生产力，同时限制人类感染，包括环境污染。然而，减毒活疫苗的缺点包括毒力返强的问题。出于这个原因，我们提出了一个二次突变的评估，可能会有效地“锁定”到减毒状态的生物体，同时提供一个诊断测试，能够区分疫苗从感染的动物。由于与农业动物产品密切相关或食用农业动物产品导致的全球持续人类感染（每年500，000例新病例），因此非常需要改进布鲁氏菌疫苗。最近世界范围内野生和野生猪种群的急剧增加也成为人类感染的水库，以及农业物种。由于缺乏有关免疫保护机制和布鲁氏菌潜在用途的知识，这一问题更加严重。作为生化武器

 DESCRIPTION (provided by applicant): The goal of the proposed research is the development of vaccines against Brucella infection that are safe and efficacious. Our general approach is focused on the use of live attenuated vaccines, LAVs. While vaccines developed from heat-killed organisms, crude extracts or recombinant subunits have demonstrated little efficacy, Brucella LAVs have proven highly effective when used in conjunction with test and slaughter. However, when applied to under-developed countries such programs can result in significant losses in animal productivity and family livelihood and as such enforcement is lax. Currently available Brucella vaccines are unsafe for use either directly in gestating animals or humans. Furthermore, their use in animals poses a secondary risk to public health especially in underdeveloped countries where livestock are a primary source of nourishment. For these reasons, we have sought to identify improved LAVs that are safe for use in animals at all stages of gestation, and, therefore, pose a reduced risk to humans. Ongoing experiments in nonhuman primates have confirmed a level of safety that provides continued support for a parallel goal of developing a Brucella vaccine that is safe for human use. Successful demonstration of safety in goats is also expected to provide support for reduced biocontainment level allowing examination of efficacy in goats. The overall design of the vaccine combines the optimal features of a LAV that is safe, free of side effects in animals and efficacious with a delivery system that provides enhanced immune stimulation through microencapsulation. The successful outcome of these studies will be used to produce a vaccine that provides significant protection against abortion and to enhance animal productivity while also restricting human infection including environmental contamination. However, drawbacks of live attenuated vaccines include the concern of reversion to virulence. For this reason, we have proposed an evaluation of secondary mutations that may be expected to effectively "lock" the organism into an attenuated state while providing a diagnostic test capable of distinguishing vaccines from infected animals. The need for improved Brucella vaccines is highly warranted due to continue human infection worldwide (500,000 new cases annually) resulting from close association with or consumption of agricultural animal products. Recent dramatic increases worldwide in wild and feral swine populations also act as reservoirs of human infection, as well as agricultural species. This concern is exacerbated by a lack of knowledge concerning mechanisms of immune protection and the potential use of Brucella spp. as bioweapons.