Improving the lead rF1-V plague vaccine using an SA-4-1BBL/alum adjuvant platform

 描述（由申请人提供）：鼠疫耶尔森氏菌是腺鼠疫和肺鼠疫的病原体，也是一种潜在的生物武器。目前还没有一种疫苗可以保护公众免受潜在的流行病或生物恐怖主义事件的影响。而Y.虽然鼠疫感染可用抗生素治疗，但原发性肺炎感染的有效治疗时间很短（接触鼠疫后少于24小时）。此外，已经报道了自然获得的对抗生素的耐药性，并将Y。鼠疫菌很可能经过改造，对抗生素治疗产生抗药性。因此，开发有效的鼠疫疫苗是一项重要的科学奋进和公共政策目标。目前针对鼠疫的主要疫苗是由明矾佐剂化的重组F1-LcrV融合蛋白（rF 1-V）组成的亚单位疫苗制剂。该疫苗已被证明在啮齿动物模型中有效，但在灵长类动物模型中效力降低，并且在临床试验中抗体产生可变。因此，虽然rF 1-V似乎是鼠疫的优秀候选疫苗，但它需要进一步改进以获得更好的免疫原性。一系列研究表明，Th 1细胞应答在鼠疫防御中起着重要而关键的作用。由于明矾是一种Th 2佐剂，主要产生强大的体液应答，我们假设，主要的rF 1-V疫苗制剂可以受益于佐剂系统，产生平衡的混合体液和Th 1细胞免疫应答。为此，我们建议使用包括明矾和新型佐剂SA-4-1BBL的佐剂平台。SA-4- 1BBL是共刺激配体4-1BBL的重组形式，在产生Th 1免疫应答中具有稳健的功效。先导rF 1-V疫苗的初步数据支持我们的假设，并表明向先导疫苗制剂中添加SA-4-1BBL可产生稳健的rF 1-V特异性Th 1细胞免疫应答。在目标1中，我们将通过建立产生优化的Th 1应答所需的SA-4-1BBL剂量来扩展这些初步研究，所述优化的Th 1应答补充由明矾引起的Th 2应答。在目的2中，我们将直接检验SA-4-1BBL引起的Th 1应答有助于预防鼠疫的假设。这将通过使用免疫细胞耗竭和突变小鼠背景的组合来实现，以确定不同细胞类型和细胞因子对疫苗诱导的鼠疫保护的贡献。这些研究一起将证明使用明矾和SA-4-1BBL的组合佐剂平台可以产生平衡的和保护性的Th 1/Th 2免疫应答。此外，除了改进主要候选鼠疫疫苗及其用于NHP和人类临床试验的开发之外，所提出的佐剂系统还可以用作产生亚单位疫苗和/或改进现有亚单位疫苗针对其他细胞内病原体宿主的功效的平台。

 DESCRIPTION (provided by applicant): Yersinia pestis is the causative agent of bubonic and pneumonic plague and a potential bioweapon. Currently there is not a vaccine available to protect the public from a potential epidemic or bioterrorism event. While Y. pestis infection can be treated with antibiotics, the effective treatment window for primary pneumonic infection is very short (less than 24 hrs after exposure). Furthermore, naturally acquired resistance to antibiotics has been reported, and weaponized Y. pestis could likely be modified to be resistant to antibiotic treatment. Therefore, the development of an efficacious plague vaccine is an important scientific endeavor and public policy goal. The current lead vaccine against plague is a subunit vaccine formulation consisting of a recombinant F1-LcrV fusion protein (rF1-V) adjuvanted with alum. This vaccine has proven effective in rodent models, but has decreased efficacy in primate models and variable antibody production in clinical trials. Therefore, while rF1-V appears to be an excellent vaccine candidate for plague, it needs further improvement for a better immunogenicity profile. A series of studies have demonstrated the important and critical role of Th1 cellular responses in protection against plague. Inasmuch as alum is a Th2 adjuvant that primarily generates a robust humoral response, we hypothesized that the lead rF1-V vaccine formulation can benefit from an adjuvant system that generates a balanced mixed humoral and Th1 cellular immune responses. Towards this end, we propose the use an adjuvant platform that includes alum and the novel adjuvant SA-4-1BBL. SA-4- 1BBL is a recombinant form of costimulatory ligand 4-1BBL with demonstrated robust efficacy in generating Th1 immune responses. Preliminary data with the lead rF1-V vaccine support our hypothesis and show that the addition of SA-4-1BBL to the lead vaccine formulation generates a robust rF1-V-specific Th1 cellular immune response. In Aim 1 we will extend these preliminary studies by establishing the SA-4-1BBL dose required to produce an optimized Th1 response that complements the Th2 response elicited by alum. In Aim 2, we will directly test the hypothesis that the Th1 response elicited by SA-4-1BBL contributes to protection against plague. This will be accomplished by using a combination of immune cell depletion and mutant mouse backgrounds to define the contribution of different cell types and cytokines to vaccine-induced protection against plague. Together these studies will demonstrate that a combinatorial adjuvant platform using alum and SA-4-1BBL can produce a balanced and protective Th1/Th2 immune response. Furthermore, in addition to improving the lead candidate plague vaccine and its development for NHP and human clinical trials, the proposed adjuvant system may also be used as a platform to generate subunit vaccines and or improve the efficacy of the existing ones against a host of other intracellular pathogens.