Preclinical Development of Non-Invasive Anthrax Vaccine

描述(申请人提供)：2001年的炭疽病袭击表明，炭疽病被用作对平民的恐怖武器的威胁是真实存在的。炭疽孢子雾化暴露的成功暴露后治疗需要几乎立即开始抗生素治疗，并要求受害者接受长期的抗生素治疗方案，依从性水平并不总是被证明是现实的。一种安全、有效、非侵入性、易于管理、几乎立即激发针对疾病的先天免疫反应、没有严格的冷链要求的疫苗，为在普通人群中预防炭疽病提供了巨大的优势。我们建议进行临床前疫苗的开发，这种疫苗具有非侵入性的鼻腔给药途径，开发针对毒素和炭疽杆菌的快速免疫保护反应，快速刺激先天免疫，减少对冷藏的要求。这种疫苗已证明能有效地保护兔子免受LD250强毒力Ames炭疽孢子的气雾剂攻击。这项申请的中期目标有四个方面。目的1)最终确定疫苗配方，以推进开发过程。目的2)进行适合GLP毒理学和动物功效研究的材料的工艺开发、放大和资格鉴定，从而实现合同制生产。目的3)用AIMS 1和AIMS 2制成的疫苗制剂对多种物种进行GLP鼻内毒理学试验。目的4)用GLP气雾剂攻击炭疽芽胞免疫兔和灵长类动物，确认疫苗的效力。这些目标的实现将导致定义一种鼻腔注射疫苗，该疫苗有效地通过抗体和细胞介导的免疫反应刺激对肺部炭疽病的保护。它将有一个明确的制造过程，用于确定产品是否符合预期和已知的安全质量的分析。这种疫苗预计需要单剂疫苗才能获得保护，并减少对冷藏的需求。预计它还将刺激先天免疫过程，足以在免疫后不久防止炭疽热暴露。根据这项拨款收集的数据将涵盖疫苗的效力、制造、化验、稳定性和安全性，并将使我们能够提交研究性新药(IND)申请并进入人体第一阶段临床试验。

DESCRIPTION (provided by applicant): The anthrax attacks of 2001 illustrated that the threat of anthrax being used as a weapon of terror on civilians is real. Successful post-exposure treatment of aerosolized anthrax spore exposure requires antibiotic therapy to begin almost immediately and for victims to submit to lengthy antibiotic treatment regimens at compliance levels that have not always proven realistic. A safe, efficacious vaccine that is noninvasive, easy to administer, stimulates innate immune responses against disease almost immediately and that does not have rigid cold-chain requirements offers tremendous advantages for preventing anthrax in the general population. We propose conducting pre-clinical development of a vaccine that is novel by virtue of a non-invasive intranasal delivery route, the development of rapid immune protective responses directed at both the toxin and the B. anthracis bacillus, rapid stimulation of innate immunity and a reduced requirement for cold storage. This vaccine has demonstrated efficacy in protecting rabbits against an aerosol challenge with LD250 spores of virulent Ames anthrax spores. The interim objectives of this application are four-fold. Aim 1) Finalize the vaccine formulation to take forward into development processes. Aim 2) Perform process development, scale up, and qualification leading to contract manufacturing of material suitable for GLP toxicology and animal efficacy studies. Aim 3) Conduct GLP intranasal toxicology in multiple species using the vaccine formulation resulting from Aims 1 and 2. Aim 4) Affirm the efficacy of the vaccine via GLP aerosol challenge of immunized rabbits and primates with virulent anthrax spores. The attainment of these objectives will result in the definition of an intranasally delivered vaccine that is effective at stimulating protection against pulmonary anthrax by both antibody- and cellular-mediated immune responses. It will have a defined manufacturing process, assays for determining that the product is as intended and known safety qualities. This vaccine is expected to require a single dose to elicit protection and to have reduced need for cold storage. It is also expected to stimulate innate immune processes sufficient to protect against an anthrax exposure soon after immunization. The data collected under this grant will cover vaccine efficacy, manufacturing, assaying, stability, and safety, and will position us to submit an Investigational New Drug (IND) application and move into Phase I clinical trials in humans.