Novel adjuvants for biodefense vaccines

描述(申请人提供)：理想的针对生物战/生物恐怖主义潜在毒剂的疫苗应该是安全的，易于投放，提供长期保护，只需要一剂或几剂，并对不同的毒剂提供保护性免疫。此外，由于粘膜和呼吸道表面是许多雾化生物制剂与人类宿主接触的第一个产生点，因此需要检查粘膜免疫在保护中的作用。非肠外注射疫苗(即通过粘膜或经皮途径)已被证明在免疫动物和人类的全身和粘膜间隔中都能有效地诱导体液和细胞抗原特异性免疫反应。与肠外免疫相比，这种“无针”免疫提供了许多潜在的优势，一些组织正在评估用于生物防御疫苗的疫苗。这些非肠外途径诱导的免疫反应依赖于合适的佐剂的共同作用，这些佐剂可以启动和支持从先天免疫到获得性免疫的转变。在这项应用中，我们建议研究三种新型佐剂(LTR192G)，CpG ODN，CTA1-DD，它们能够诱导针对炭疽杆菌(RPA)、鼠疫杆菌(F1-V)、肉毒毒素(HC)和葡萄球菌肠毒素B(SEBv)相关疫苗抗原的高滴度、长时间的保护性抗体反应。这些研究的发现应该广泛适用于来自这些和其他生物制剂的其他抗原。这些研究的主要目标是对这些新型佐剂进行优化和临床前测试，这些佐剂中的每一种都曾在其他经粘膜或经皮递送的传染病疫苗中显示出希望。预计这些佐剂中的一种或多种将被考虑作为未来临床试验计划的I-II-III阶段测试的候选药物。 这项应用的另一个目的是确定非肠外增强是否可以在已被肠外刺激的动物中诱导保护性次级免疫反应，以及该反应是否可以被重定向以包括粘膜免疫成分。挑战研究将使我们能够将免疫反应与保护效果联系起来，并确定粘膜免疫反应对保护的贡献。最后，我们将确定由来自四种不同病原体的相关抗原组成的联合疫苗的有效性，具体目标是确定疫苗组件之间的协同或干扰，以及佐剂和递送途径在克服干扰方面的作用。

DESCRIPTION (provided by applicant): An ideal vaccine against potential agents of biological warfare/bioterrorism should be safe, easy to deliver, provide long-lasting protection, require only one or a few doses, and provide protective immunity against different agents. Moreover, since mucosal and respiratory surfaces represent the first productive points of contact with the human host for many aerosolized biological agents, the role of mucosal immunity in protection needs to be examined. Nonparenteral delivery of vaccines (i.e., by the mucosal or transcutaneous route) has been shown to be effective at inducing both humoral and cellular antigen-specific immune responses in both the systemic and mucosal compartments of immunized animals and humans. Such "needle free" immunizations offer many potential advantages over parenteral immunization and are being evaluated by a number of groups for use in biodefense vaccines. Induction of immune responses by these nonparenteral routes is dependent upon the co-administration of appropriate adjuvants that can initiate and support the transition from innate to adaptive immunity. In this application we are proposing to investigate three novel adjuvants (LTR192G), CpG ODN, CTA1-DD) for their ability to induce high titer, long lived, protective antibody responses against relevant vaccine antigens from B. anthracis (rPA), Y. pestis (F1-V), botulinum toxin (Hc), and staphylococcal enterotoxin B (SEBv). The findings from these studies should be broadly applicable to other antigens from these and other biological agents. The primary objective of these studies is the optimization and preclinical testing of these novel adjuvants, each of which has previously shown promise in other infectious disease vaccines delivered mucosally or transcutaneously. It is expected that one or more of these adjuvants will be considered as candidates for future Phase I-II-III testing in clinical trial programs. Another objective of this application is to determine if nonparenteral boosting can induce a protective secondary immune response in animals that have been parenterally primed and if that response can be redirected to include a mucosal immune component. Challenge studies will allow us to correlate immune responses with protective efficacy and determine the contribution of mucosal immune responses to protection. Finally, we will determine the effectiveness of a combined vaccine consisting of relevant antigens from the four different pathogens with the specific objective of determining synergy or interference between the vaccine components and the role of adjuvants and route of delivery in overcoming interference.