Nasal Vaccines: Mode of Action, Composition & Delivery

鼻内接种疫苗有可能成为有效、经济、无针的方法 能够诱导全身和粘膜免疫的免疫。鼻腔免疫可以使安全 以及针对新兴传染病和选定病原体的有效疫苗接种。虽然 在鼻免疫策略的开发方面已经取得了进展，更好地了解了 需要用于鼻内给药疫苗的佐剂的递送位点和作用方式。不 明确鼻用疫苗佐剂是否通过激活粘膜上皮或免疫细胞而表现出佐剂活性 在上皮下此外，虽然小鼠的鼻免疫诱导全身免疫， 免疫应答的幅度与胃肠外免疫、鼻内免疫 兔或非人灵长类动物不像胃肠外免疫那样有效地诱导抗原- 特异性血清IgG。我们推测，鼻免疫在兔和非人中缺乏有效性， 灵长类动物的免疫缺陷是由于对非免疫系统中上呼吸道的免疫诱导组织缺乏了解， 啮齿类动物和有限的知识的解剖分布疫苗后，鼻腔输送和方法， 控制其停留时间。最后，鼻用疫苗和佐剂必须既有效又安全。 因此，需要进行额外的临床前毒性研究来评估有效鼻用疫苗的安全性 制剂。我们的长期目标是开发安全有效的鼻腔给药疫苗， 人类我们的具体目标是： 具体目的一：确定鼻用疫苗佐剂IL-1a和TLR 4配体RC-529的作用方式 AF.这将在一系列实验中解决，以研究粘膜佐剂是否激活（a）粘膜佐剂。 粘膜基质细胞或（B）上皮下树突细胞或淋巴细胞。 具体目标二：确定接种的解剖部位和疫苗清除的时间， 在小鼠、大鼠和兔中作为水性或干粉制剂经鼻递送，并确定递送是否 并且清除与全身或粘膜中抗原特异性免疫的诱导相关 车厢

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-1a 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.