Preclinical Development of Non-Invasive Anthrax Vaccine

描述（由申请人提供）：2001年的炭疽袭击表明，炭疽被用作平民恐怖武器的威胁是真实存在的。雾化炭疽孢子暴露后的成功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，其依从性水平并不总是被证明是现实的。一种安全、有效的疫苗，无侵入性，易于管理，几乎可以立即刺激对抗疾病的先天免疫反应，并且没有严格的冷链要求，为预防普通人群中的炭疽提供了巨大的优势。我们建议开展一种新型疫苗的临床前开发，该疫苗具有以下特点：非侵入性鼻内递送途径、针对毒素和炭疽芽孢杆菌的快速免疫保护反应、快速刺激先天免疫和减少冷藏需求。该疫苗已证明能有效保护家兔免受致命艾姆斯炭疽孢子LD250孢子的气溶胶攻击。此应用程序的临时目标有四个方面。目标1)最终确定疫苗配方，以便进入开发过程。目标2)进行工艺开发，扩大规模，并确认适合GLP毒理学和动物功效研究的材料的合同制造。目标3)使用目标1和目标2产生的疫苗制剂对多种物种进行GLP鼻内毒理学研究。目的4)通过GLP气溶胶对免疫的家兔和灵长类动物进行强毒炭疽孢子攻击，确认疫苗的有效性。这些目标的实现将导致鼻内接种疫苗的定义，该疫苗通过抗体和细胞介导的免疫反应有效地刺激对肺炭疽的保护。它将有一个明确的生产过程，测定产品是否符合预期和已知的安全质量。这种疫苗预计只需要一次剂量就能产生保护作用，并减少冷藏的需要。它还有望刺激先天免疫过程，足以在免疫接种后不久防止炭疽暴露。在这笔拨款下收集的数据将涵盖疫苗的功效、制造、分析、稳定性和安全性，并将使我们能够提交新药研究（IND）申请，并进入人体I期临床试验。

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.