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The use of the pregnant sheep model in vaccine safety studies against brucellosis

怀孕绵羊模型在布鲁氏菌病疫苗安全性研究中的应用

基本信息

批准号：
8913881
负责人：
Angela M Arenas
金额：
$ 19.16万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-18 至 2017-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913881
关键词：
Abortion Rates Alginates Animals Antigens Attenuated Attenuated Live Virus Vaccine Bacteria Brucella Brucella Vaccine Brucella abortus Brucella melitensis Brucellosis Carbon Caring Cells Clinical Trials Complement Consumption Country DNA DNA Vaccines Data Development Disease Ensure Environment Evaluation Excretory function Exhibits FDA approved Failure Future Genetic Goals Goat Growth Health Human Immune Immune response Immune system Inactivated Vaccines Infection Investigation Laboratory Animals Licensure Life Locales Methods Modeling Mus Mutation Nature Organism Placenta Predisposition Production Property Recording of previous events Regulation Research Residual state Resolution Risk Ruminants Safety Science Sheep Source Specimen Staging Subunit Vaccines Symptoms Testing Time Tissues Vaccines Virulence Virulent abortion base commercialization crosslink design human disease immature animal improved innovation knockout gene mouse model mutant nonhuman primate novel particle preference pregnant prevent research study safety study safety testing success tissue tropism transmission process trophoblast vaccination strategy vaccine candidate vaccine development vaccine evaluation vaccine safety

项目摘要

DESCRIPTION (provided by applicant): The goal of our proposed research is the development of vaccines against Brucella infection that are safe and efficacious. Our general approach has focused on the use of live attenuated vaccines (LAV). The use of live attenuated organisms are generally considered to be the vaccine of choice for intracellular bacteria such as Brucella spp. This strategy take advantage of the natural properties of the organism, including cell invasion and tissue tropism while presenting a full complement of immunogens, and is supported by a history of success. However, currently available vaccines are unsafe for use in humans. We have sought to identify improved live, attenuated vaccine candidates that are safe for use in humans. Routine testing of potential Brucella vaccines utilizes the mouse model to evaluate virulence and immune protection. However, mice fail to exhibit the outward signs of "Brucella" infection. As a result the next step in evaluation of vaccine candidates has been in the target species. For human vaccine development this might suggest the use of nonhuman primates at this stage of evaluation. However, evaluation of vaccines may be performed in a small ruminant model such as sheep or goats to eliminate candidates that produce symptoms associated with disease including abortion, providing an ultimate evaluation of safety. Although placental tissue tropism remains a well-documented phenomenon in ruminants, Brucella has not been considered to be a significant cause of human abortion. However, recent evidence revealed a strong correlation between exposure and elevated rates of abortion in endemic regions. Furthermore, there is strong evidence supporting growth of Brucella melitensis in human trophoblasts. Taken together, these data provide strong support for continued development of our LAV based on the obvious need for improved protection strategies to reduce the potential for human disease. Experiments in sheep are expected to provide the support for experimentation to test these candidates in nonhuman primates with the ultimate goal of developing a Brucella vaccine that is safe and efficacious for human use. The efforts outlined have taken advantage of our recently developed platform (encapsulation) to prolong immune system stimulation without prolonging the survival of the vaccine strain. Using this innovative approach we have progressed through multiple levels of investigation to demonstrate efficacy and safety of the LAV providing strong justification to bring development to fruition. The competitive advantages and innovations of approach presented include: (1) evaluation of highly attenuated, safe, gene knockouts in well-established, stable genetic background; (2) safety evaluation under the most stringent conditions possible, (3) support for development of a nonhuman primate model; (4) potential to reduce biocontainment level and support for manufacturing (GMP) and future progress for clinical trials, production and distribution.

描述（由申请人提供）：我们拟议研究的目标是开发安全有效的布鲁氏菌感染疫苗。我们的一般方法侧重于使用减毒活疫苗（LAV）。使用减毒活生物体通常被认为是细胞内细菌（如布鲁氏菌）的首选疫苗。这种策略利用了生物体的自然特性，包括细胞侵袭性和组织趋向性，同时呈现出完整的免疫原，并有成功的历史支持。然而，目前可用的疫苗用于人类是不安全的。我们已寻求确定可安全用于人类的改良减毒活疫苗候选疫苗。潜在布鲁氏菌疫苗的常规测试利用小鼠模型来评估毒力和免疫保护。然而，小鼠没有表现出“布鲁氏菌”感染的外在迹象。因此，评估候选疫苗的下一步是在