Advanced anthrax vaccine made with ISS DNA formulations

描述（由申请人提供）：我们建议使用ISS开发一种改进的炭疽疫苗，该疫苗将是安全的，并在一次或两次免疫接种后提供免疫力。该疫苗将受到重组炭疽保护性抗原（rPA）的损害，该抗原与免疫刺激（ISS）寡核苷酸佐剂一起递送，该佐剂由新型凝聚层制剂增强。我们将比较目前在临床试验中的ISS序列1018与我们更活跃的ISS序列C274，以确定最有效的疫苗配方。与目前使用吸附于明矾的rPA的第二代方法或与目前许可的疫苗AVA相比，在新型凝聚层载体中使用ISS应显著增强针对rPA产生的抗体应答的速度和幅度。该项目的具体目标是： 1.在小鼠、家兔和恒河猴中检测重组炭疽保护性抗原（rPA）联合和不联合ISS凝聚层制剂的免疫原性;将通过PA特异性ELISA评价血清，并使用体外细胞培养试验评价中和炭疽毒素的能力。 2.确定1-2剂优化ISS凝聚层/rPA疫苗在炭疽芽孢杆菌孢子攻毒后保护实验动物体内免受炭疽感染的能力。 A.保护小鼠免受B攻击。炭疽孢子通过鼻内途径给药。 B。用B气溶胶激发后对兔免受吸入性炭疽的保护。炭疽孢子 C.用B攻击恒河猴后对吸入性炭疽的保护。炭疽孢子 3.进行毒理学评价并启动ISS凝聚层/rPA疫苗的GMP生产，假设特定目的1-3的结果为阳性。 由于后期具体目标（目标3C和4）的成本较高，因此每个具体目标的活动将按顺序进行，并在项目进入下一个目标之前确定可行性。 假设在个别特定目标方面取得成功，该提案旨在生产一种可迅速进入临床试验的IND准备好的新炭疽疫苗。

DESCRIPTION (provided by applicant): We propose to use ISS to develop an improved anthrax vaccine that will be safe and will provide immunity after one or two immunizations. This vaccine will be compromised of recombinant anthrax protective antigen (rPA) delivered with an immunostimulatory (ISS) oligonucleotide adjuvant enhanced by a novel coacervate formulation. We will compare the ISS sequence currently in clinical trials, 1018, with our more active ISS sequence, C274 to identify the most potent vaccine formulation. The use of ISS in the novel coacervate carrier should provide dramatic enhancement of both the speed and magnitude of the antibody response developed against rPA compared to current second generation approaches using rPA adsorbed to alum or compared to the currently licensed vaccine, AVA. The specific aims for this project are: 1. To test the immunogenicity of recombinant anthrax protective antigen (rPA) with and without combination with ISS coacervate formulations in mice, rabbits, and rhesus macaques; sera will be evaluated by PA-specific ELISAs and for the capacity to neutralize the anthrax toxins using in vitro cell culture assays. 2. To establish the ability of 1-2 doses of the optimized ISS coacervate/rPA vaccine to protect experimental animals against anthrax in vivo following challenge with Bacillus anthracis spores. A. Protection of mice against challenge with B. anthracis spores administered by the intranasal route. B. Protection of rabbits against inhalation anthrax following aerosol challenge with B. anthracis spores. C. Protection of rhesus macaques against inhalation anthrax following challenge with B. anthracis spores. 3. To perform toxicological evaluation and to initiate GMP production of the ISS coacervate/rPA vaccine, assuming positive results in Specific Aims 1-3. Because of the high cost of the later Specific Aims (Aims 3C and 4), activities for each Specific Aim will be performed sequentially, and feasibility will be established before the project moves onto the next Aim. Assuming success in the individual Specific Aims, this proposal is intended to produce an IND-ready new anthrax vaccine that could rapidly move into clinical testing.