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

使用 SA-4-1BBL/明矾佐剂平台改进先导 rF1-V 鼠疫疫苗

• 批准号: 8995186
• 负责人: Matthew B Lawrenz
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-15 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8995186
• 关键词: Adjuvant; Adjuvanticity; Agonist; Alhydrogel; Antibiotic Resistance; Antibiotic Therapy; Antibiotics; Antibody Formation; Antigen Targeting; Antigens; Attenuated Live Virus Vaccine; Automobile Driving; Bacteria; Bacterial Vaccines; Bioterrorism; Bubonic Plague; CD8B1 gene; Cells; Chimeric Proteins; Clinical Trials; Complement; Data; Development; Dose; Epidemic; Equilibrium; Event; Extracellular Domain; FDA approved; Formulation; Future; Generations; Goals; Health; Human; Immune; Immune response; Immune system; Immunologic Adjuvants; Inactivated Vaccines; Individual; Infection; Infectious Agent; Interferon Type II; Lead; Ligands; Malignant Neoplasms; Modeling; Mus; Mutant Strains Mice; Plague; Plague Vaccine; Pneumonic Plague; Primates; Production; Public Policy; Recombinant Proteins; Recombinants; Reporting; Rodent Model; Role; Safety; Series; Signal Transduction; Streptavidin; Subunit Vaccines; System; T cell response; T-Lymphocyte; TNF gene; Testing; Th1 Cells; Time; Treatment Efficacy; Vaccination; Vaccines; Work; Yersinia pestis; aluminum sulfate; base; cell mediated immune response; cell type; combinatorial; cytokine; defined contribution; effective therapy; immunogenicity; improved; long term memory; mouse model; nonhuman primate; novel; novel vaccines; pathogen; pre-clinical; preclinical study; prophylactic; protective efficacy; receptor; response; vaccine candidate; vaccine development; vaccine-induced immunity

 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.

 描述（由适用提供）：耶尔森氏菌是泡泡和肺炎瘟疫的真正药物和潜在的生物武器。目前，尚无疫苗来保护公众免受潜在的流行病或生物恐怖事件的侵害。虽然可以用抗生素治疗Y. Pestis感染，但原发性肺炎感染的有效治疗窗口非常短（暴露后不到24小时）。此外，已经报道了自然获得的对抗生素的抗性，并且可以将武器化的Y. pestis修改为对抗生素治疗具有耐药性。因此，开发有效的瘟疫疫苗是一项重要的科学努力和公共政策目标。当前针对瘟疫的铅疫苗是由用校友调节的重组F1-LCRV融合蛋白（RF1-V）组成的亚基疫苗配方。该疫苗已证明在啮齿动物模型中有效，但在临床试验中的主要模型和可变抗体产生中的功效提高了。因此，尽管RF1-V似乎是鼠疫的出色疫苗候选者，但它需要进一步改进才能获得更好的免疫原性。一系列研究表明，Th1细胞反应在保护瘟疫中的重要和关键作用。 AS AS AS AS AS AS TH2调整了主要的体液反应，我们假设铅RF1-V疫苗公式可以受益于可调节的系统，该系统会产生均衡的混合体液和Th1细胞免疫呼吸。为此，我们提出了一个可调节平台，其中包括明矾和小说调整SA-4-1BBL。 SA-4- 1BBL是一种重组形式的共刺激配体4-1BBL，在产生Th1免疫调查中表现出强大的效率。铅RF1-V疫苗的初步数据支持我们的假设，并表明向铅疫苗配方中添加SA-4-1BBL会产生强大的RF1-V特异性TH1细胞免疫响应。在AIM 1中，我们将通过建立产生优化的TH1响应所需的SA-4-1BBL剂量来扩展这些初步研究，该响应符合明矾敏感的TH2响应。在AIM 2中，我们将直接检验以下假设：SA-4-1BBL敏感的Th1响应有助于保护瘟疫。这将通过结合使用免疫小鼠部署和突变小鼠背景来定义不同细胞类型和细胞因子对疫苗诱导的瘟疫的保护的贡献。这些研究将共同​​表明，使用明矾和SA-4-1BBL的可调节平台可以产生平衡且受保护的TH1/TH2免疫响应。此外，除了改善候选鼠疫疫苗及其在NHP和人类临床试验中的开发外，该提议的调整系统还可以用作生成亚基疫苗的平台，或者或或或提高现有的其他细胞内病原体的效率。