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。目前还没有疫苗可以保护公众免受潜在流行病或生物恐怖主义事件的影响。虽然鼠疫耶尔森氏菌感染可以用抗生素治疗，但原发性肺炎感染的有效治疗窗口非常短（接触后不到 24 小时）。此外，据报道，自然获得的抗生素耐药性，武器化的鼠疫耶尔森氏菌很可能经过改造，对抗生素治疗产生耐药性。因此，开发有效的鼠疫疫苗是一项重要的科学努力和公共政策目标。目前针对鼠疫的主要疫苗是一种亚单位疫苗制剂，由以明矾佐剂的重组 F1-LcrV 融合蛋白 (rF1-V) 组成。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的功效下降，并且在临床试验中抗体产生存在差异。因此，虽然 rF1-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。一系列研究证明了 Th1 细胞反应在预防鼠疫方面的重要和关键作用。由于明矾是一种 Th2 佐剂，主要产生强烈的体液反应，因此我们假设领先的 rF1-V 疫苗配方可以受益于产生平衡的混合体液和 Th1 细胞免疫反应的佐剂系统。为此，我们建议使用包含明矾和新型佐剂 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 Th1 免疫应答方面具有强大的功效。主要 rF1-V 疫苗的初步数据支持我们的假设，并表明在主要疫苗配方中添加 SA-4-1BBL 可产生强大的 rF1-V 特异性 Th1 细胞免疫反应。在目标 1 中，我们将通过确定产生优化的 Th1 反应所需的 SA-4-1BBL 剂量来扩展这些初步研究，以补充明矾引起的 Th2 反应。在目标 2 中，我们将直接检验 SA-4-1BBL 引发的 Th1 反应有助于预防鼠疫的假设。这将通过结合免疫细胞耗竭和突变小鼠背景来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来实现。这些研究将共同​​证明，使用明矾和 SA-4-1BBL 的组合佐剂平台可以产生平衡且具有保护性的 Th1/Th2 免疫反应。此外，除了改进主要候选鼠疫疫苗及其针对 NHP 和人体临床试验的开发外，所提出的佐剂系统还可以用作生成亚单位疫苗和/或提高现有疫苗针对许多其他细胞内病原体的功效的平台。