Novel adjuvants for biodefense vaccines

描述（由申请人提供）：针对潜在的生物战/生物恐怖主义剂的理想疫苗应该是安全的，易于交付，提供持久的保护，只需要一次或几次剂量，并对不同的剂提供保护性免疫。此外，由于粘膜和呼吸表面是许多雾化生物制剂与人体宿主的第一个接触点，因此需要研究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的全身和粘膜区室中诱导体液和细胞抗原特异性免疫反应是有效的。这种“无针”免疫比肠外免疫有许多潜在的优势，一些研究小组正在对其在生物防御疫苗中的应用进行评估。通过这些非肠外途径诱导免疫应答依赖于适当佐剂的共同施用，这些佐剂可以启动和支持从先天免疫到适应性免疫的过渡。在本申请中，我们建议研究三种新型佐剂（LTR192G）、CpG ODN、CTA1-DD)诱导高滴度、长寿命、针对炭疽芽孢杆菌（rPA）、鼠疫芽孢杆菌（F1-V）、肉毒杆菌毒素（Hc）和葡萄球菌肠毒素B （SEBv）相关疫苗抗原的保护性抗体反应的能力。这些研究的结果应该广泛适用于这些和其他生物制剂的其他抗原。这些研究的主要目的是对这些新型佐剂进行优化和临床前测试，每一种佐剂都曾在其他传染病疫苗中显示出粘膜或经皮递送的前景。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项目中I-II-III期测试的候选药物。

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.