Dual Antigen Nanoparticle Vaccine System For Bacillus Infectious Disease

描述(由申请人提供)：开发设计合理的疫苗是纳米技术具有巨大变革潜力的重要需求。纳米颗粒的开发已经被纳入了获得批准的小分子疗法中。在显示组织选择性递送的配体靶向纳米粒子方面取得了快速进展，这正是更好的疫苗的关键要求之一。然而，尽管大多数抗原都是高度亲水的，但为疫苗开发的绝大多数纳米颗粒系统(NP)最适合于有效地装载疏水有效载荷。一个同样重要的问题是缺乏可生物降解的疫苗纳米颗粒系统。我们计划生产和测试一种可生物降解的NP疫苗平台，以解决这两个问题。我们将研究有效地整合亲水性抗原，并将它们与高级佐剂一起输送到抗原提呈细胞，以诱导保护性免疫反应的可行性。这种NP平台的设计完全基于蛋白质和多肽材料的构建，以允许通用的、量身定制的负载来容纳大多数抗原或抗原的组合，以及掺入佐剂来定制免疫反应，例如高电荷的CpG寡核苷酸。NP的设计完全使用简单的多肽，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度阴离子部分，用作亲水性抗原的多功能锚，同时也用作抗原本身(需要免疫反应的抗原)。最初，这一平台将使用炭疽芽孢杆菌的一对抗原进行可行性测试，这是开发更好疫苗的一个激烈努力领域。因此，成功的可行性也有望使第一个产品的开发能够满足大量需求。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，该系统应易于改装以携带其他抗原和/或抗原组合。为了确定所提出的多功能NP疫苗系统在这个第一阶段研究计划中的可行性，我们首先将构建成对的抗原结构，并组装和表征NP系统的胶体特性。然后，我们将研究它对这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，我们将研究对吸入接触细菌孢子的保护。如果取得成功，将需要进行第二阶段的研究，以解决制造、临床前药理学和毒理学问题，以便能够推进到临床研究。与公共卫生相关：开发设计合理的疫苗是纳米技术具有巨大潜力转变的重要需求，特别是具有APC靶向的纳米颗粒，这种纳米颗粒可以携带多种抗原，并包含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性的，因此对大多数抗原来说并不理想，因为它们通常是亲水性的。一个同样重要的问题是缺乏可生物降解的疫苗纳米颗粒系统。计划中的研究将产生并测试一种可生物降解的NP疫苗平台，以解决这两个问题。该平台将使用炭疽芽孢杆菌的一对抗原进行开发和可行性测试，炭疽杆菌是目前需要更好疫苗的一个领域，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。如果取得成功，将需要进行第二阶段的研究，以解决制造、临床前药理学和毒理学问题，以便能够推进到临床研究。

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.