Multivalent VAccines for Biodefense

描述(申请人提供)：迫切需要开发用于生物防御的快速有效疫苗。对于病原体和急性毒素来说，以最小的不良反应快速诱导免疫的能力是至关重要的。已鉴定出来自相关病原体和毒素的各种免疫原，但通常需要大量免疫才能诱导保护性反应。开发新的佐剂，既能增强免疫反应，又不会产生不良反应，是非常可取的。我们最近开发了一种独特的试剂，它在单一化合物中结合了炭疽抗毒素和疫苗的功能。这种试剂是基于炭疽毒素受体ANTXR2在二十面体昆虫病毒表面的多价展示。我们发现，重组病毒样颗粒保护大鼠免受炭疽中毒，并且当包被炭疽保护性抗原(PA)时，它们诱导对致命毒素的极强免疫反应。这种免疫反应在一次给药后的四周内保护动物免受致命毒素的攻击，而不需要佐剂。这个应用程序的目的是测试这个展示平台的实用性是否可以扩展到展示迫切需要快速作用疫苗的其他蛋白质。特别是，我们试图测试病毒样颗粒(VLP)平台是否能够适应于对肉毒杆菌神经毒素和蓖麻毒素产生快速和保护性的免疫反应。在目标1中，我们将制备PA-RTA和PA-BONT/A融合蛋白，并组装基于VLP的免疫原。在目标2中，我们将评估这些化合物的体内免疫原性。如果拟议的策略成功，该平台的应用可能会大幅扩大，用于开发针对众多其他病原体的疫苗。(RTA：蓖麻毒素A链；BONT/A：肉毒神经毒素A)。与公共卫生相关：迫切需要开发用于生物防御的快速有效疫苗。我们最近开发了一种独特的试剂，在没有佐剂的情况下，一次注射四周后，就能诱导对炭疽毒素的保护性免疫反应。该试剂基于炭疽毒素受体和炭疽保护性抗原在二十面体昆虫病毒表面的多价展示。这项提案的目的是测试这个展示平台是否可以用来展示迫切需要快速作用疫苗的其他蛋白质。特别是，我们试图测试病毒样颗粒平台是否能够适应于对肉毒杆菌神经毒素和蓖麻毒素产生快速和保护性的免疫反应。如果拟议的策略成功，该平台的应用可能会大幅扩大，用于开发针对众多其他病原体的疫苗。

DESCRIPTION (provided by applicant): There is an urgent need to develop fast-acting vaccines for biodefense. For pathogens and acute toxins, the ability to rapidly induce immunity with a minimum of adverse effects is of paramount importance. A variety of immunogens from relevant pathogens and toxins have been identified, however numerous immunizations are typically required to induce a protective response. The development of novel adjuvants that boost immune responses without adverse effects is highly desirable. We recently developed a unique reagent that combines the functions of an anthrax antitoxin and vaccine in a single compound. This reagent is based on multivalent display of the anthrax toxin receptor, ANTXR2, on the surface of an icosahedral insect virus. We showed that the recombinant virus-like particles protect rats from anthrax intoxication and that they induce an extremely potent immune response against lethal toxin when coated with anthrax protective antigen (PA). This immune response protects animals against lethal toxin challenge within four weeks after a single administration without the need for adjuvant. The goal of this application is to test whether the utility of this presentation platform can be expanded to display other proteins for which fast-acting vaccines are urgently needed. In particular, we seek to test whether the virus-like particle (VLP) platform can be adapted to generate a rapid and protective immune response to botulinum neurotoxin and ricin toxin. In aim 1 we will generate PA-RTA and PA-BoNT/A fusion proteins and assemble the VLP-based immunogens. In aim 2 we will evaluate the immunogenicity of these complexes in vivo. If the proposed strategy is successful, the application of this platform could be expanded dramatically for development of vaccines against numerous other pathogens. (RTA: ricin toxin A chain; BoNT/A: botulinum neurotoxin A). PUBLIC HEALTH RELEVANCE: There is an urgent need to develop fast-acting vaccines for biodefense. We recently developed a unique reagent that induces a protective immune response against anthrax toxin four weeks after a single injection in the absence of an adjuvant. This reagent is based on multivalent display of the anthrax toxin receptor and anthrax protective antigen on the surface of an icosahedral insect virus. The goal of this proposal is to test whether this presentation platform can be used to display other proteins for which fast-acting vaccines are urgently needed. In particular, we seek to test whether the virus-like particle platform can be adapted to generate a rapid and protective immune response to botulinum neurotoxin and ricin toxin. If the proposed strategy is successful, the application of this platform could be expanded dramatically for development of vaccines against numerous other pathogens.