Development of Efficacious and Stable Nasal Vaccine Formulations

有效且稳定的鼻疫苗制剂的开发

• 批准号: 7802325
• 负责人: Herman F Staats
• 金额: $ 73.31万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802325
• 关键词: Adjuvant; Adverse effects; Amino Acids; Antigens; Development; Dose; Drug Formulations; Goals; Human; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Length; Ligands; Medicine; Modeling; Mucosal Immunity; Mus; Nature; Needles; Nose; Oryctolagus cuniculus; Peptides; Powder dose form; Refrigeration; Reporting; Serum; Structure; Surface; Temperature; Testing; Toll-like receptors; Vaccine Antigen; Vaccines; Viral Antigens; West Nile virus; aluminum sulfate; cost; design; mast cell; novel; protein aminoacid sequence; response; small molecule

DESCRIPTION (provided by applicant): Currently, the only adjuvant available for world-wide human use is alum, a poor adjuvant with limited capacity to induce mucosal immunity. Additional adjuvants such as Toll-like receptor (TLR) ligands are being investigated, but these adjuvants are limiting with respect to efficacy and cost. Recently, we described a novel class of potent mucosal adjuvants with broad applicability against a wide range of vaccine antigens (Nature Medicine April 20, 2008). We reported that needle free, nasal administration of vaccine formulations containing small molecule mast cell (MC) activating compounds, evoked high levels of antigen-specific IgG in the serum and IgA along mucosal surfaces in mice. These responses were protective in lethal challenge models, and moreover, did not incur any harmful side effects. Many of these MC activating compounds are small peptide sequences (mast cell activating peptides, MCAP) ~ 14 amino acids in length, which can be readily and economically prepared with high purity. MCAP combined with TLR ligands MPL or CpG provided adjuvant activity that was superior to any adjuvant used alone. We have also determined that dry powder formulations of vaccine antigens maintain potency after room temperature storage and are highly efficacious after nasal immunization, suggesting that they will not require refrigeration during transport while maintaining the ability to induce protective immunity. Therefore the goal of this project is to develop a highly efficacious and safe dry powder vaccine formulation for nasal immunization against West Nile Virus. The Specific Aims are therefore: 1. Utilize reiterative peptide design to determine the optimal structure of MC activating peptides (MCAP) for maximal adjuvant activity with West Nile Virus antigens in mice. 2. Determine if MC activating peptides combined with TLR ligand adjuvants provides additive or synergistic adjuvant activity able to reduce the antigen dose required for induction of protective WNV immunity. 3. Develop and test WNV dry powder nasal vaccine formulations in rabbits, which share structural features with human nasal passages.

描述（由申请人提供）：目前，世界范围内唯一可用于人类使用的佐剂是明矾，一种诱导粘膜免疫能力有限的差佐剂。其他佐剂，如toll样受体（TLR）配体正在研究中，但这些佐剂在功效和成本方面受到限制。最近，我们描述了一类新型有效的粘膜佐剂，对多种疫苗抗原具有广泛的适用性（自然医学2008年4月20日）。我们报道了含小分子肥大细胞（MC）激活化合物的疫苗制剂的无针鼻注射，在小鼠的血清中诱发了高水平的抗原特异性IgG和沿粘膜表面的IgA。这些反应在致命挑战模型中具有保护作用，而且不会产生任何有害的副作用。这些MC激活化合物大多是长度约为14个氨基酸的小肽序列（肥大细胞激活肽，MCAP），制备方便、经济、纯度高。MCAP与TLR配体MPL或CpG联合提供的佐剂活性优于任何单独使用的佐剂。我们还确定，疫苗抗原的干粉制剂在室温保存后仍能保持效力，并在鼻免疫后非常有效，这表明它们在运输过程中不需要冷藏，同时保持诱导保护性免疫的能力。因此，本项目的目标是研制一种高效、安全的西尼罗病毒鼻免疫干粉疫苗制剂。因此，具体目标是：1。利用重复多肽设计法确定具有最大西尼罗病毒佐剂活性的MCAP的最佳结构。2. 确定MC激活肽与TLR配体佐剂联合是否提供添加剂或协同佐剂活性，能够减少诱导保护性西尼罗河病毒免疫所需的抗原剂量。3. 在兔身上开发和测试与人类鼻腔通道具有相同结构特征的西尼罗河病毒干粉鼻疫苗制剂。