Development of stable and rapidly acting adjuvanted vaccines for biodefense

产品说明：（申请人提供）随着目前对由蛋白质亚基组成的确定疫苗的重视，持续需要改进疫苗的稳定性和性能。大多数疫苗是在含有铝盐佐剂的水性缓冲液和悬浮液中配制的，疫苗免疫原降解并失去效力（和功效）。温度升高会加快蛋白质降解的速度。因此，液体疫苗必须在冷藏或冷冻条件下储存。从生产点到最终接种者，必须保持一个控制良好的环境冷链。在疫苗很少使用或没有广泛分发的情况下，特别是在疫苗要储存用于生物防御的情况下，温度控制最终不会令人满意。本提案的目标是为吸附铝佐剂的两种生物防御亚单位疫苗开发工艺和特定的热稳定制剂。这将通过使用干燥技术和赋形剂来实现，所述干燥技术和赋形剂防止铝佐剂颗粒在冷冻干燥和随后的储存期间聚集，同时还保持抗原的结构和化学完整性。研究和开发的疫苗亚单位是蓖麻毒素A链疫苗（RTA V76 M/Y80 A，RiVax（tm））和B的高免疫原性突变体（DNI，显性阴性抑制剂）。炭疽保护性抗原（PA）在物理和免疫学特性方面总体上得到很好的表征。本提案的第一个目标是开发和表征疫苗生产中的最终步骤，该步骤包括在稳定辅料存在下冻干氢氧化铝吸附亚单位疫苗，从而保留免疫原的结构和佐剂的功能。该提案的第二个目标是通过采用可添加到铝佐剂亚单位的充分表征的共佐剂来开发更有效的疫苗。预期这将产生干燥的热稳定亚单位疫苗，其可以以加速方案（更少的剂量数）给予，并且其导致保护性免疫的更快的起效。

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.