A glycolipid adjuvant to promote dose sparing, accelerate immunization schedules and extend durability of high-level protection with an attenuated, live sporozoite malaria vaccine

一种糖脂佐剂，可促进剂量节约、加快免疫计划并延长减毒活子孢子疟疾疫苗高水平保护的持久性

• 批准号: 10659246
• 负责人: Sumana Chakravarty
• 金额: $ 96.82万
• 依托单位: SANARIA, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659246
• 关键词: Acceleration; Adjuvant; Affinity; Antigens; Attenuated; Attenuated Vaccines; Binding; Biodistribution; Biological Assay; Biological Markers; CCL20 gene; CD8-Positive T-Lymphocytes; Cells; Cellular Immunity; Chemicals; Chemoprophylaxis; Child; Chloroquine; Clinic; Clinical; Clinical Protocols; Clinical Trials; Coculture Techniques; Combined Vaccines; Contracts; Cryopreservation; Cyclic GMP; Development; Dose; Formulation; Glycolipids; Goals; Human; Immune response; Immune system; Immunity; Immunization; Immunization Programs; Immunization Schedule; Immunize; Immunologic Markers; In Vitro; Inbred Mouse; Inbreeding; Infection; Legal patent; Licensing; Ligands; Liver; Logistics; Lymphocyte; Macaca mulatta; Macaca nemestrina; Malaria; Malaria Vaccines; Malaria prevention; Mass Vaccinations; Methodology; Methods; Modeling; Mus; Outcome; Parasites; Pilot Projects; Plasmodium falciparum; Plasmodium falciparum vaccine; Positioning Attribute; Preparation; Primates; Prophylactic treatment; Quality Control; Radiation; Regimen; Route; Safety; Seasons; Speed; Sporozoites; Sterility; T cell response; T-Lymphocyte; Testing; Toxic effect; Toxicology; Vaccinated; Vaccination; Vaccines; Venous; Woman; analog; biomarker discovery; cellular targeting; child bearing; clinical implementation; clinical lot; comparative; cost effective; design; efficacy evaluation; efficacy outcomes; efficacy study; immunogenicity; improved; in vivo; malaria infection; manufacture; mouse model; nonhuman primate; novel; permissiveness; pre-Investigational New Drug meeting; pre-clinical; preclinical evaluation; preclinical study; protective efficacy; reconstitution; research clinical testing; vaccine efficacy

We propose to further enhance Plasmodium falciparum (Pf) Sporozoite (SPZ)-based vaccines against malaria that are the only immunogens proven to induce >90% short term (3 weeks) and long term (at least 14 months) protection against controlled human malaria infection with Plasmodium falciparum (Pf) in humans. Using a unique glycolipid adjuvant 7DW8-5, the goal is to prolong the duration of vaccine efficacy (VE) and to increase efficacy in endemic settings. In the mouse model using P. yoelii (Py) sporozoites (SPZ) we achieved > 80% protection at 16 weeks with 2 dose and 4 dose accelerated regimens of irr PySPZ plus 7DW8-5 adjuvant administered by direct venous inoculation (DVI) representing a 2-fold enhancement over irr PySPZ without adjuvant. The adjuvant could be mixed with irr PySPZ. High level (>80%) protection of mice persisted at 16 weeks with irr PySPZ by DVI, in the presence of 7DW8-5, but not by non-DVI routes. Manufacturing of 7DW8-5 under cGMPs was completed and in a pilot study with P. knowlesi (Pk) SPZ, irr PkSPZ we achieved 50% VE and no improvement with the adjuvant, likely attributable to sub-optimal comparative dose or dosing regimens, or the short-term infectious challenge design. Due to the excellent demonstrable safety record of the combined SPZ-adjuvant vaccine in NHPs, and comparable bioactivity on co- culture human iNKT cells in vitro, we propose further optimization of dosing regimens for durable immunity in pig-tailed macaques, the natural host for Pk, along with protection studies to assess adjuvant effects on chemically attenuated (PySPZ-chemoprophylaxis vaccine CVac) and genetically attenuated (PySPZ-LARC) in mice. Using humanized HISA2/ hCD1d mice possessing functional human CD8+ T cells and human iNKT cells (cellular targets of 7DW8-5) we will investigate whether a PfSPZ-7DW8-5 combination immunogen can enhance the human CD8+ T-cell response to PfSPZ. Adjuvant-associated biomarker discovery studies are also planned in mice. Towards clinical use of the PfSPZ-7DW8-5 combination vaccine, we will establish stability criteria and formulation methodologies for 7DW8-5, and further comparability testing of GMP-grade 7DW8-5 for bioactivity in vitro as a lot release attribute and humanized HISA2/ hCD1d mice in vivo, compile a pre-IND package in preparation for pre-clinical and clinical evaluation of the safety and efficacy of 7DW8-5-PfSPZ combinations, and manufacture GMP 7DW8-5 for clinical use. Because studies outlined in this project will be conducted with clinical grade, well characterized 7DW8-5, a positive outcome in our studies will place us in a position to rapidly design and conduct formal pre-clinical toxicology and/or biodistribution studies in compliance with FDA mandates for a speedier path to the clinic. Completion of this project will mark the first development of an adjuvant for a live eukaryotic parasite vaccine.

我们建议进一步增强恶性疟原虫（PF）孢子岩（SPZ）的疫苗 反对疟疾是唯一被证明诱导短期> 90％（3周）和长时间的免疫原子 术语（至少14个月）对受控人类疟疾感染的保护 人类中的恶性（PF）。使用唯一的糖脂佐剂7DW8-5，目标是延长 疫苗功效（VE）的持续时间并在地方性环境中提高功效。在鼠标模型中 使用P. yoelii（Py）孢子岩（SPZ），我们在16周时以2剂和4剂获得了80％的保护 IRR PYSPZ的剂量加速方案加上7DW8-5辅助剂，由直接静脉施用 接种（DVI）代表没有辅助的IRR PYSPZ增强2倍。佐剂 可以与Irr pyspz混合。高水平（> 80％）对小鼠的保护在16周时持续存在 DVI的PYSPZ，在7dw8-5存在的情况下，而不是非DVI路线。制造7dw8-5 在CGMP下完成，在与P. Knowlesi（PK）SPZ的试点研究中，我们达到了IRR PKSPZ 50％VE且无改善的佐剂，可能归因于优化的比较剂量或 给药方案或短期感染挑战设计。由于出色的证明 NHP中SPZ-Adjuvant疫苗联合的安全记​​录，以及对共同活性的可比性 培养人类Inkt细胞的体外，我们提出了对耐用的剂量方案的进一步优化 猪尾猕猴的免疫力，PK的天然宿主以及保护研究以评估 佐剂对化学衰减（PYSPZ-脱脂基因疫苗CVAC）和遗传上的影响 小鼠中的衰减（pyspz-larc）。使用具有功能性的人源化HISA2/ HCD1D小鼠 人CD8+ T细胞和人Inkt细胞（7dw8-5的细胞靶标）我们将研究A是否是否 PFSPZ-7DW8-5组合免疫原可以增强人类CD8+ T细胞对PFSPZ的反应。 在小鼠中还计划了与辅助相关的生物标志物发现研究。临床用途 PFSPZ-7DW8-5组合疫苗，我们将建立稳定标准和配方 7DW8-5的方法论，以及GMP级7DW8-5的进一步可比性测试 体外释放属性和人性化的hisa2/ hcd1d小鼠在体内，编译预先打包的包装 为7DW8-5-PFSPZ的安全性和功效的临床前和临床评估做准备 组合和生产GMP 7DW8-5用于临床使用。因为该项目概述了研究 将以临床等级进行，表征7DW8-5，这是我们研究的积极结果 将使我们处于快速设计和进行正式临床前毒理学和/或 生物分布研究符合FDA的要求，以便通往诊所的速度更快。完成 该项目将标志着现场真核寄生虫疫苗的辅助剂的首次发展。