Evaluation of a Next Generation SchistoShield Vaccine

下一代 SchistoShield 疫苗的评估

基本信息

批准号：
10761529
负责人：
Sean Alex Gray
金额：
$ 30万
依托单位：
PAI LIFE SCIENCES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-12 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10761529
关键词：
Address Adjuvant Adsorption Africa Anabolism Animal Model Antibodies Antigens Antinuclear Antibodies Asia Benchmarking Binding Biochemical Brazil COVID-19 COVID-19 vaccine Catalysis Cells Clinical Trials Country Disease Dose Drug resistance Emergency Situation Ensure Evaluation Exhibits Fermentation Foundations Funding Genetic Transcription Grant Human Hydrophobicity Immune response Immunize Immunoglobulin G India Infection Lead Life Lipids Moderna COVID-19 vaccine Monoclonal Antibodies Mus Papio Parasites Parasitic Diseases Persons Pharmaceutical Preparations Phase Phase Ib Trial Praziquantel Production Proteins Protocols documentation RNA RNA delivery RNA replication RNA vaccine Recombinant Proteins Reporting Risk Safety Schistosoma mansoni Schistosomatidae Schistosomiasis Signal Transduction Small Business Innovation Research Grant Solubility South America TLR4 gene Technology Testing Tissues Vaccines Variant clinical candidate comparative cost design disease transmission drug candidate egg global health human disease improved in vivo invention nanoparticle next generation novel novel vaccines phase II trial protein p80 protein purification vaccine candidate

项目摘要

ABSTRACT Schistosomiasis is a major parasitic disease which could impact one billion people with 252 million currently infected and 779 million at risk to acquire the infection in 74 countries. Current control strategies have relied on repeated treatments with the drug praziquantel alone – however, this strategy has proven inadequate due to minimal reduction of disease transmission, reinfection, and the inherent threat of drug resistance. Over the course of 20 years, we have developed a potent schistosomiasis vaccine, termed SchistoShield®, targeting a functionally important antigen, Sm-p80, formulated in the TLR4-targeted adjuvant, GLA-SE. SchistoShield® has been exhaustively tested in numerous animal models and has consistently exhibited protection at all parasite life stages. We are near completion of a Phase 1 safety and dose-ranging human clinical trial with SchistoShield® in the US – with no serious safety signals reported – and will begin Phase 1B trials in Q3 of 2023 with a Phase 2 trial currently funded as well by the Bill and Melinda Gates Foundation. Despite the promise of SchistoShield®, it is important to ready a next-generation follow-on candidate that builds a pipeline and serves as an alternative should we encounter problems down the road in terms of e.g. scalability, cost, or field efficacy. To address these concerns, we are proposing to evaluate two new variations on the current SchistoShield® vaccine: the first being a redesigned Sm-p80 protein antigen, while the second being a novel RNA delivery platform version of the Sm- p80 antigen. For the redesign, we removed the hydrophobic and other irrelevant (outside of the catalytic triad domain) regions of the ~85 kDa Sm-p80 antigen resulting in a smaller, and more antigenically focused, ~44 kDa antigen which we have termed Catalysis-Targeted Constructs (CaTaCo™). CaTaCo™ is similar to Sm-p80 in that domains required for enzymatic activity are maintained while soluble production yields are improved. Compared to Sm- p80, CaTaCo™ exhibits minimal aggregation and less degradation -- a potential problem with the current antigen that was flagged by the FDA for potential improvement. In mice, CaTaCo™ elicits comparatively high titers in mice, binds to anti-Sm-p80 monoclonal antibodies (mAbs), and is detected by sera from mice and baboons immunized with SchistoShield®. With the increased use of RNA vaccines, we will also produce and evaluate both CaTaCo™ and Sm-p80 as RNA vaccines using a proprietary technology invented by our partners at HDT Bio. HDT recently used this technology for their COVID-19 vaccine HDT-301, which is similar to the COVID-19 vaccines from Moderna and Pfizer/BioNTech. The HDT-301 platform consists of a self-replicating RNA (repRNA) adsorbed and stabilized on a Lipid InOrganic Nanoparticle (LION™) carrier. This vaccine received emergency use approval in India – the only self-amplifying platform to be approved in humans. Introduction of the repRNA into cells results in ongoing biosynthesis of antigen-encoding RNA resulting in markedly higher protein concentrations in vivo leading to enhanced humoral and cellular immune responses and - perhaps most importantly - a dose sparing effect. The HDT-301 vaccine has been evaluated in both Phase 1 and Phase 2 human clinical trials trial in Brazil and the US and has been shown to be safe while eliciting high anti-COVID-19 titers. In this SBIR, we propose to produce both CaTaCo™ and Sm-p80 as repRNA/LION™ vaccines as well as the CaTaCo™ antigen, immunize them into mice, and challenge with S. mansoni directly comparing each to the existing SchistoShield® vaccine. Successful completion of this grant will address two key questions: 1) is an RNA vaccine for SchistoShield® feasible or superior to the existing vaccine, and 2) whether the redesigned CaTaCo™ antigen is an improvement for the next generation SchistoShield®.

抽象的血吸虫病是一种主要寄生虫病，可能影响 10 亿人，目前有 2.52 亿人 74 个国家的 7.79 亿人有感染风险，目前的控制策略依赖于这一点。单独使用吡喹酮药物进行重复治疗——然而，这一策略已被证明是不够的，因为最大限度地减少疾病传播、再感染和耐药性的固有威胁。经过 20 年的努力，我们开发了一种强效血吸虫病疫苗，称为 SchistoShield®，针对功能重要的抗原 Sm-p80，配制在 TLR4 靶向佐剂 GLA-SE 中。在众多动物模型中进行了详尽的测试，并且始终显示出对所有寄生虫生命的保护作用我们即将完成 SchistoShield® 的第一阶段安全性和剂量范围人体临床试验。美国——没有报告严重的安全信号——并将于 2023 年第三季度开始 1B 期试验，并进行 2 期试验尽管 SchistoShield® 做出了承诺，但目前该试验也由比尔和梅琳达·盖茨基金会资助。重要的是要准备好下一代后续候选人来建立管道并作为替代方案我们是否应该在可扩展性、成本或现场效率等方面遇到问题来解决这些问题。出于担忧，我们建议评估当前 SchistoShield® 疫苗的两种新变种：第一种是重新设计的 Sm-p80 蛋白抗原，而第二个是 Sm-p80 的新型 RNA 递送平台版本 p80 抗原。为了重新设计，我们删除了疏水性和其他不相关（催化三联体结构域之外）的区域约 85 kDa Sm-p80 抗原产生更小且更具抗原性的约 44 kDa 抗原，我们将其称为催化靶向结构 (CaTaCo™)，在该领域与 Sm-p80 类似。与 Sm- 相比，酶活性所需的酶活性得以维持，同时可溶性产量得到提高。 p80、CaTaCo™ 表现出最小的聚集和较少的降解——这是当前抗原的潜在问题 FDA 指出，CaTaCo™ 在小鼠体内可产生相对较高的效价。小鼠，与抗 Sm-p80 单克隆抗体 (mAb) 结合，并可通过小鼠和狒狒的血清检测到使用 SchistoShield® 进行免疫接种。随着 RNA 疫苗使用的增加，我们还将生产和评估 CaTaCo™ 和 Sm-p80 我们的 HDT Bio 合作伙伴最近使用了这种采用专有技术的 RNA 疫苗。他们的 COVID-19 疫苗 HDT-301 的技术，类似于 Moderna 和的 COVID-19 疫苗 Pfizer/BioNTech 的 HDT-301 平台由吸附并稳定在其上的自我复制 RNA (repRNA) 组成。脂质无机纳米颗粒 (LION™) 载体该疫苗在印度获得了紧急使用批准。唯一在人类中获得批准的自我扩增平台。编码抗原的 RNA 的生物合成导致体内蛋白质浓度显着升高增强体液和细胞免疫反应，以及——也许最重要的是——剂量节省效应。 HDT-301疫苗已在巴西和美国进行了1期和2期人体临床试验评估美国并已被证明是安全的，同时可引发高抗 COVID-19 滴度。在此 SBIR 中，我们建议生产。 CaTaCo™ 和 Sm-p80 作为repRNA/LION™ 疫苗以及 CaTaCo™ 抗原，将它们免疫小鼠，并用曼氏沙门氏菌进行攻击，直接将每种疫苗与现有的 SchistoShield® 疫苗进行比较。完成这项拨款将解决两个关键问题：1) SchistoShield® 的 RNA 疫苗是否可行或优于现有疫苗，2) 重新设计的CaTaCo™抗原是否是对现有疫苗的改进下一代 SchistoShield®。