Dual Antigen Nanoparticle Vaccine System For Bacillus Infectious Disease

描述（由申请人提供）：开发合理设计的疫苗是一项重要的需求，纳米技术具有巨大的改变潜力。纳米粒子的发展已经被纳入批准的小分子疗法中。配体靶向纳米颗粒具有组织选择性递送能力，这正是开发更好的疫苗的关键要求之一。然而，尽管大多数抗原是高度亲水性的，绝大多数用于疫苗开发的纳米颗粒系统（NP）最适合于高效装载疏水有效载荷。一个同样重要的问题是缺乏生物可降解的纳米颗粒疫苗系统。我们计划生成并测试一个可生物降解的NP疫苗平台来解决这两个问题。我们将研究将亲水性抗原有效结合的可行性，并将其与高级佐剂一起以诱导保护性免疫反应的方式递送到抗原提呈细胞。这种NP平台的设计完全基于蛋白质和肽材料的构建，以一种允许通用的、定制的加载方式来适应大多数抗原或抗原组合，以及结合佐剂来定制免疫反应，例如高电荷的CpG寡核苷酸。NP设计完全是简单的肽，有助于确保强大的可制造性和生物降解性。其中一种结构材料将改编自细菌保护胶囊的高阴离子部分，用作亲水抗原的多功能锚点，同时也充当抗原本身（需要免疫反应的抗原）。最初，将使用来自炭疽芽孢杆菌的一对抗原来测试该平台的可行性，这是开发更好疫苗的一个激烈努力的领域。因此，成功的可行性也有望允许开发第一个产品，以填补大量的需求。此外，同样的疫苗应该有助于再次接种其他主要的芽孢杆菌感染问题，如多重耐药葡萄球菌。此外，该系统应易于适应携带其他抗原和/或抗原的组合。为了确定所提出的多功能NP疫苗系统在I期研究计划中的可行性，我们首先将构建配对抗原结构，并组装和表征NP系统的胶体特性。然后，我们将研究其对两种抗原产生免疫反应的能力，并提供对炭疽毒素攻击的保护，如果成功，研究吸入暴露于细菌孢子的保护。如果成功，将需要进行II期研究，以解决生产、临床前药理学和毒理学的问题，从而推进临床研究。公共卫生相关性：开发合理设计的疫苗是一项重要需求，因为纳米技术具有巨大的转化潜力，特别是APC靶向纳米颗粒，它可以携带多种抗原，并结合可定制免疫反应的佐剂。然而，绝大多数纳米颗粒疫苗系统是疏水的，因此不适合大多数抗原，因为它们通常是亲水的。一个同样重要的问题是缺乏生物可降解的纳米颗粒疫苗系统。计划中的研究是生成和测试一个可生物降解的NP疫苗平台，解决这两个问题。该平台将使用来自炭疽芽孢杆菌的一对抗原进行开发和可行性测试，这是目前需要更好的疫苗的领域，预计也将应用于其他主要的芽孢杆菌感染问题，如多重耐药葡萄球菌。如果成功，将需要进行II期研究，以解决生产、临床前药理学和毒理学的问题，从而推进临床研究。

DESCRIPTION (provided by applicant): Development of rationally designed vaccines is an important need that nanotechnology has tremendous potential to transform. Already nanoparticle developments are incorporated into approved small molecule therapeutics. Advances are making rapid progress toward ligand targeted nanoparticles exhibiting tissue selective delivery, which is precisely one of the key requirements for better vaccines. However, despite most antigens being highly hydrophilic, the vast majority of nanoparticle systems (NP) being developed for vaccines are best suited for efficient loading of hydrophobic payloads. An equally important problem is a lack of nanoparticle systems for vaccines that are biodegradable. We plan to generate and test a biodegradable NP vaccine platform to address both of these problems. We will investigate feasibility to incorporate hydrophilic antigens efficiently and to deliver them in concert with advanced adjuvants to Antigen Presenting Cells in a manner that can induce a protective immune response. This NP platform design is based on construction entirely with protein and peptide materials in a manner to permit versatile, tailored loading to accommodate most antigens, or combinations of antigens, as well as incorporation adjuvants to tailor the immune response, such as the highly charged CpG oligonucleotides. The NP design is entirely with simple peptides, helping to insure robust manufacturability and biodegradability. One of the structural materials will be adapted from a highly anionic portion of a bacteria protective capsule and used as a versatile anchor for hydrophilic antigens, while also acting as an antigen itself (and one for which an immune response is needed). Initially this platform will be tested for feasibility using a pair of antigens from Bacillus anthracis, which is an area of intense effort to develop a better vaccine. Therefore, successful feasibility also is expected allow development of a first product to fill a large need. Moreover, the same vaccine should be useful to vaccinate again other major Bacillus infection problems, such as multiple drug resistant staph. Also, the system should be easily adapted to carry other antigens and/or combinations of antigens. To determine feasibility of the proposed versatile NP vaccine system in this Phase I research plan, we first will construct the paired antigen constructs and assemble and characterize the colloidal properties of the NP system. We then will investigate its ability to generate immune responses to both antigens and provide protection from challenge with Anthrax toxin and, if successful, investigate protection from inhalation exposure to bacterial spores. With success, Phase II studies will be needed to address manufacturing, and preclinical pharmacology and toxicology to enable advancement to clinical investigation. PUBLIC HEALTH RELEVANCE: Development of rationally designed vaccines is an important need that nanotechnology has tremendous potential to transform, in particular with APC targeted nanoparticles that can carry multiple antigens and incorporate adjuvants that tailor the immune response. However, the vast majority of nanoparticle vaccine systems are hydrophobic and thus not ideal for most antigens since they are typically hydrophilic. An equally important problem is a lack of nanoparticle systems for vaccines that are biodegradable. The planned studies are to generate and test a biodegradable NP vaccine platform addressing both of these problems. This platform will be developed and tested for feasibility using a pair of antigens from Bacillus anthracis, which is an area of current need for a better vaccine and is expected to also have application for other major Bacillus infection problems, such as multiple drug resistant staph. With success, Phase II studies will be needed to address manufacturing, and preclinical pharmacology and toxicology to enable advancement to clinical investigation.