Developing a Multivalent Subunit Particle Vaccine Against Tuberculosis

开发抗结核病多价亚单位颗粒疫苗

• 批准号: 10441958
• 负责人: Jonathan F Lovell
• 金额: $ 48.09万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441958
• 关键词: Adjuvant; Aerosols; Animal Model; Antigen-Presenting Cells; Antigens; BCG Live; Bacille Calmette-Guerin vaccination; Benchmarking; Binding; Biochemical; Biological; Biological Assay; C3HeB/FeJ Mouse; COVID-19 vaccine; Cavia; Cells; Cobalt; Data; Development; Dose; Formulation; Freeze Drying; Generations; Gold; Immune; Immune response; Immunization; In Vitro; Inbred BALB C Mice; Individual; Intramuscular; Intranasal Administration; Label; Liposomes; Lung; Molecular; Mucosal Immune Responses; Mucous Membrane; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; NIH Program Announcements; Nanotechnology; Nature; Oryctolagus cuniculus; Outcome; Peptides; Performance; Phase; Phospholipids; Porphyrins; Proteins; QS21; Recombinants; Route; Saponins; Serum; Surface; Surface Antigens; System; T cell response; Testing; Time; Toxic effect; Tuberculosis; Tuberculosis Vaccines; Upper respiratory tract; Vaccination; Vaccine Adjuvant; Vaccine Antigen; Vaccines; antigen-specific T cells; base; comparative efficacy; density; design; draining lymph node; guinea pig model; immunogenicity; improved; in vivo; innovation; mouse model; nanoliposome; nanoparticle; next generation; novel vaccines; particle; research clinical testing; response; thermostability; uptake; vaccine development; vaccine discovery

PROJECT SUMMARY An effective vaccine is likely required to reduce the global burden of tuberculosis (TB). Development of one has been difficult, in part due to the ability for Mycobacterium tuberculosis (Mtb) to reside for long periods within host antigen (Ag) presenting cells (APCs), where it expresses a multitude of Ags, many of which have been targeted for vaccine development. Recombinant Ags have been the focus of numerous vaccines, however outcomes to clinical testing have been less than ideal. This R61/R33 proposal in response to program announcement RFA-AI-21-007: “Innovation for Tuberculosis Vaccine Discovery” will leverage a next- generation, vaccine adjuvant system that induces seamless particle-formation of recombinant Ags to assess a multivalent Mtb vaccine. A new immunization paradigm will be advanced, based on combining (via simple mixing) well-characterized soluble protein Mtb Ags with a vaccine adjuvant that induces spontaneous nanoliposome-Ag particleization. Liposomes that contain small amounts of cobalt porphyrin-phospholipid (CoPoP) bind to his-tagged Ags via spontaneous insertion of the his-tag into the bilayer. This approach gives rise to rapid particleization that is stable in biological media. Recombinant Ags are simply admixed with CoPoP liposomes at the time of vaccination (without further purification) to be fully converted for display on the surface of ~100 nm particles. CoPoP recently completed phase I and entered phase II clinical testing as a key component of a COVID-19 vaccine (NCT04783311). CoPoP also induces potent cellular responses using short MHC-I restricted peptide immunogens at nanogram peptide dosing in mice; multiple orders of magnitude lower dosing compared to Ag doses with conventional vaccine adjuvants. Preliminary data demonstrates that multivalent particles decorated with the established Mtb Ags Ag85A, CFP10, ESAT-6, HSP-X, and Mpt64 induce protective cellular immune responses in mice. The underlying hypothesis is that multivalent, particle- based Mtb Ags will induce a potently protective immune responses more effective than Bacillus Calmette– Guérin (BCG) in multiple small animal models of TB infection. The R61 phase of the proposal will use mouse models of TB infection to: (1) Develop well-characterized, multivalent Mtb Ag particles; (2) Assess how particle parameters impact functional immunogenicity; and (3) Compare the efficacy of intranasal and intramuscular particle administration. Ambitious and quantitative R61-R33 transitional milestones are proposed based on A) generating well-characterized particles with storage stability with B) multivalent Ags providing superior protection relative to the best single Ag particles with C) superiority to conventional BCG immunization in mice. The R33 phase of the project will involve (4) assessing the vaccine in the guinea pig model, and (5) developing and assessing the efficacy and toxicity of a lyophilized thermostable version of the vaccine.

项目概要 可能需要一种有效的疫苗来减轻全球结核病的负担。 一直很困难，部分原因是结核分枝杆菌 (Mtb) 能够长期驻留 在宿主抗原 (Ag) 呈递细胞 (APC) 内，它表达多种 Ag，其中许多具有 重组抗原已成为许多疫苗的焦点， 然而，针对该计划的 R61/R33 提案的临床测试结果并不理想。 公告 RFA-AI-21-007：“结核病疫苗发现的创新”将利用下一个- 产生，疫苗佐剂系统，诱导重组抗原的无缝颗粒形成，以评估 将基于组合（通过简单的方式）推进一种新的免疫模式。 混合）已充分表征的可溶性蛋白 Mtb Ag 与诱导自发性感染的疫苗佐剂 纳米脂质体-银颗粒化含有少量钴卟啉-磷脂。 (CoPoP) 通过将 his 标签自发插入双层来与带有 his 标签的 Ag 结合。 重组 Ag 与 CoPoP 混合即可快速颗粒化，在生物介质中保持稳定。 疫苗接种时的脂质体（无需进一步纯化）将完全转化以展示在表面上 ~100 nm 颗粒的 CoPoP 最近完成了 I 期并进入 II 期临床测试作为关键。 CoPoP 是 COVID-19 疫苗 (NCT04783311) 的组成部分，也可利用短时间诱导有效的细胞反应。 MHC-I 限制肽免疫原在纳克肽剂量下降低多个数量级； 与传统疫苗佐剂的 Ag 剂量相比，初步数据表明： 用已建立的 Mtb Ags Ag85A、CFP10、ESAT-6、HSP-X 和 Mpt64 修饰的多价颗粒 诱导小鼠的保护性细胞免疫反应 潜在的假设是多价、颗粒- 基于 Mtb Ags 将诱导比卡介苗更有效的强效保护性免疫反应 – Guérin (BCG) 在多种结核感染小动物模型中的 R61 阶段将使用小鼠。 结核病感染模型：(1) 开发特征明确的多价 Mtb Ag 颗粒；(2) 评估颗粒如何形成； 参数影响功能免疫原性；(3) 比较鼻内和肌内注射的功效； 基于 A) 提出了雄心勃勃且定量的 R61-R33 过渡里程碑。 B) 多价银可生成具有良好储存稳定性的特征良好的颗粒，提供卓越的性能 相对于最好的单一银颗粒的保护作用，C) 优于小鼠中的传统 BCG 免疫。 该项目的 R33 阶段将涉及 (4) 在豚鼠模型中评估疫苗，以及 (5) 开发疫苗 并评估冻干热稳定疫苗的功效和毒性。