Development of stable and rapidly acting adjuvanted vaccines for biodefense

开发稳定且快速起效的生物防御佐剂疫苗

• 批准号: 7645401
• 负责人: ROBERT N. BREY
• 金额: $ 130.58万
• 依托单位: SOLIGENIX, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-24 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7645401
• 关键词: Adjuvant; Aerosols; Aluminum; Aluminum Hydroxide; Animal Model; Anthrax disease; Antibody Formation; Antigens; Bacillus anthracis; Biochemical; Buffers; Chemicals; Clinical Research; Clinical Trials; Cold Chains; Cyclic GMP; Development; Dominant-Negative Mutation; Dose; Drug Formulations; Environment; Epitopes; Excipients; FDA approved; Freeze Drying; Freezing; Goals; Immune response; Immunity; Intramuscular Injections; Knowledge; Life; Liquid substance; Macaca mulatta; Methodology; Mus; Oryctolagus cuniculus; Performance; Principal Investigator; Process; Property; Prophylactic treatment; Protein Subunits; Proteins; Protocols documentation; QS21; Reproduction spores; Ricin; Ricin A Chain; Salts; Saponin; Saponins; Series; Sodium Chloride; Structure; Subunit Vaccines; Suspension substance; Suspensions; Technology; Temperature; Testing; Time; Toxicology; Treatment Protocols; United States National Institutes of Health; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Vial device; Virulent; Water; aqueous; biodefense; comparative; immunogenicity; improved; inhibitor/antagonist; mutant; news; next generation; nonhuman primate; particle; physical property; potency testing; pre-clinical; prevent; protein degradation; prototype; reconstitution; response; stability testing; vaccine candidate; vaccine evaluation

DESCRIPTION: (provided by the applicant) With the current emphasis on defined vaccines composed of protein subunits, there is a persistent need to improve the stability and performance of vaccines. Most vaccines are formulated in aqueous buffers and suspensions with aluminum salts adjuvants, vaccine immunogens degrade and lose potency (and efficacy). Elevated temperature increases the rate of protein degradation. As a result, liquid vaccines must be stored under refrigerated or frozen conditions. A well-controlled environmental cold chain must be maintained from the point of manufacture to the ultimate vaccinee. Temperature control will ultimately not be satisfactory in situations where vaccines are rarely used or not widely distributed especially where the vaccines are to be stockpiled for use for biodefense. The goal of this proposal is to develop processes and specific thermally stable formulations for two biodefense subunit vaccines adsorbed to aluminum adjuvants. This will be accomplished by using a drying technology and excipients that prevent the aggregation of aluminum adjuvant particles during freeze-drying and subsequent storage, while also preserving the structural and chemical integrity of the antigen. The vaccine subunits for study and development, a Ricin A chain vaccine (RTA V76M/Y80A, RiVax(tm)) and a hyperimmunogenic mutant (DNI, dominant negative inhibitor) of B. anthracis protective antigen (PA), are overall well characterized in physical and immunological properties. The first goal of this proposal is to develop and characterize the terminal step in manufacture of the vaccines, which would comprise lyophilization aluminum hydroxide-adsorbed subunit vaccines in the presence of stabilizing excipients, permitting retention of structure of the immunogens and functionality of the adjuvant. The second goal of this proposal is to develop vaccines that are more effective by employing well-characterized co-adjuvants that can be added to aluminum adjuvants subunits. This is expected to result in dried thermostable subunit vaccines that can be given in an accelerated regimen (fewer numbers of doses) and which result in more rapid onset of protective immunity.

描述：(由申请人提供)随着目前对由蛋白质亚单位组成的限定疫苗的重视，一直需要改进疫苗的稳定性和性能。大多数疫苗是在含铝盐佐剂的水溶液和悬浮液中配制的，疫苗免疫原会降解并失去效力(和效力)。温度升高会增加蛋白质的降解速度。因此，液体疫苗必须在冷藏或冷冻条件下储存。必须保持从生产到最终接种疫苗的良好控制的环境冷链。在疫苗很少使用或没有广泛分发的情况下，温度控制最终将不能令人满意，特别是在疫苗将被储存用于生物防御的情况下。这项提议的目标是开发两种吸附在铝佐剂上的生物防御亚单位疫苗的工艺和特定的热稳定配方。这将通过使用干燥技术和辅料来实现，这些辅料在冷冻干燥和随后的储存过程中防止铝佐剂颗粒聚集，同时还保留了抗原的结构和化学完整性。研究和开发的疫苗亚基是蓖麻毒素A链疫苗(RTA V76M/Y80A，RiVax(Tm))和炭疽杆菌保护性抗原(PA)的高免疫原性突变体(DNI，显性负抑制物)，总体上具有良好的物理和免疫学特性。这项建议的第一个目标是开发和描述疫苗生产的最后步骤，其中将包括在稳定辅料存在的情况下冷冻干燥氢氧化铝吸附亚单位疫苗，允许保留免疫原的结构和佐剂的功能。这项提议的第二个目标是通过使用特性良好的辅助剂来开发更有效的疫苗，这些辅助剂可以添加到铝佐剂亚单位中。预计这将导致干燥的耐热亚单位疫苗，可以以加速方案(较少的剂量)给予，并导致更快地启动保护性免疫。