Nasal Vaccines: Mode of Action, Composition & Delivery

描述（由申请人提供）：鼻用疫苗可能是有效、经济、无针的免疫方法，能够诱导全身和粘膜免疫。鼻腔免疫可以安全有效地预防新出现的传染病和选择病原体。虽然鼻免疫策略的发展已经取得了进展，但需要更好地了解鼻腔接种疫苗的佐剂的递送部位和作用方式。目前尚不清楚鼻疫苗佐剂是否通过激活粘膜上皮或上皮下腔室的免疫细胞而表现出佐剂活性。此外，虽然小鼠鼻腔免疫诱导的全身免疫反应与肠外免疫诱导的全身免疫反应相当，但兔或非人灵长类动物的鼻腔免疫在诱导抗原特异性血清IgG方面不如肠外免疫有效。我们推测，兔和非人灵长类动物鼻腔免疫缺乏有效性是由于对非啮齿动物上呼吸道免疫诱导组织的了解不足，以及对疫苗经鼻递送后的解剖分布和控制其停留时间的方法的了解有限。最后，鼻腔疫苗和佐剂必须既有效又安全。因此，需要进一步的临床前毒性研究来评估有效的鼻用疫苗制剂的安全性。我们的长期目标是开发安全有效的用于人类的鼻用疫苗。我们的具体目标是：具体目标一：确定鼻腔疫苗佐剂IL-1的作用模式？TLR4配体RC-529 AF。这将在一系列实验中得到解决，以研究粘膜佐剂是否激活(a)粘膜基质细胞或(b)上皮下树突状细胞或淋巴细胞。特定目的二：确定小鼠、大鼠和家兔以水或干粉形式鼻腔给药时疫苗的解剖部位和清除时间，并确定给药和清除是否与在全身或粘膜室诱导抗原特异性免疫相关。

DESCRIPTION (provided by applicant): Nasally administered vaccines have the potential to be effective, economical, needle-free methods of immunization able to induce both systemic and mucosal immunity. Nasal immunization may allow for safe and effective vaccination against emerging infectious diseases and select agent pathogens. Although progress has been made in the development of nasal immunization strategies, a better understanding of the site(s) of delivery and mode(s) of action of adjuvants for nasally-administered vaccines is needed. It is not clear if nasal vaccine adjuvants exhibit adjuvant activity by activating the mucosal epithelium or immune cells in the subepithelial compartment. Additionally, while nasal immunization of mice induces systemic immune responses comparable in magnitude to those induced by parenteral immunization, nasal immunization of rabbits or non-human primates is not as effective as parenteral immunization for the induction of antigen- specific serum IgG. We postulate that the lack of efficacy of nasal immunization in rabbits and non-human primates is due to poor understanding of the immune inductive tissues of the upper respiratory tract in non- rodents and limited knowledge of the anatomical distribution of vaccines after nasal delivery and methods of controlling their residence time. Finally, nasal vaccines and adjuvants must be both effective and safe. Therefore, additional preclinical toxicity studies are needed to evaluate the safety of effective nasal vaccine formulations. Our long term goal is to develop safe and effective nasally administered vaccines for use in humans. Our specific aims are: Specific Aim One: Determine the mode of action of nasal vaccine adjuvants IL-1? and TLR4 ligand RC-529 AF. This will be addressed in a series of experiments to investigate if mucosal adjuvants activate (a) the mucosal stromal cells or (b) subepithelium dendritic cells or lymphocytes. Specific Aim Two: Identify the anatomical site of delivery and time of clearance of vaccines when delivered nasally as aqueous or dry-powder formulations in mice, rats and rabbits and determine if delivery and clearance correlates with the induction of antigen-specific immunity in the systemic or mucosal compartment.