Evaluation of a Next Generation SchistoShield Vaccine

下一代 SchistoShield 疫苗的评估

• 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
• 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

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®.

摘要 血吸虫病是一种主要的寄生虫病，目前可能影响10亿人， 在74个国家，有7.79亿人受到感染，目前的控制策略依赖于 重复治疗与药物吡喹酮单独-然而，这种策略已被证明是不够的， 最大限度地减少疾病传播、再感染和耐药性的固有威胁。来 经过20年的努力，我们已经开发出一种有效的血吸虫病疫苗，称为SchistoShield®， 功能上重要的抗原Sm-p80，配制在TLR 4靶向佐剂GLA-SE中。SchistoShield®具有 在许多动物模型中进行了详尽的测试，并始终表现出对所有寄生虫的保护作用 阶段我们即将完成一项使用SchistoShield®的第1期安全性和剂量范围的人体临床试验， 美国-没有严重的安全性信号报告-并将于2023年第三季度开始1B期试验， 该试验目前也由比尔和梅林达盖茨基金会资助。尽管血吸虫病盾®的承诺， 重要的是要准备好下一代的后续候选人，建立一个管道，并作为一个替代 如果我们在可扩展性、成本或现场效率方面遇到问题。解决这些 考虑到这些问题，我们建议对目前的SchistoShield®疫苗进行两种新的变异评估：第一种是 重新设计的Sm-p80蛋白抗原，而第二个是Sm-p80蛋白的新型RNA递送平台版本。 p80抗原。 对于重新设计，我们删除了疏水性和其他不相关（催化三联体结构域之外）区域 ~85 kDa Sm-p80抗原的减少导致更小、抗原性更集中的~44 kDa抗原， 我们将其称为催化靶向构建体（CaTaCo™）。CaTaCo™与Sm-p80在以下结构域相似： 保持了酶活性所需的酶活性，同时提高了可溶性产物的产率。相比之下，Sm- 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 被食品药品监督管理局标记为潜在改进的产品在小鼠中，CaTaCo™在小鼠中产生相对高的滴度。 小鼠，与抗Sm-p80单克隆抗体（mAb）结合，并通过小鼠和狒狒的血清检测 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， RNA疫苗使用我们的合作伙伴HDT Bio发明的专有技术。HDT最近用这个 该公司的COVID-19疫苗HDT-301技术，与Moderna的COVID-19疫苗相似， 辉瑞/BioNTech。HDT-301平台由吸附并稳定在载体上的自我复制RNA（repRNA）组成。 脂质无机纳米颗粒（LION™）载体。该疫苗在印度获得紧急使用批准， 这是唯一一个被批准用于人体的自我放大平台。将repRNA引入细胞导致持续的 抗原编码RNA的生物合成导致体内蛋白质浓度显著升高， 增强体液和细胞免疫反应，以及--也许最重要的--剂量节省效应。的 HDT-301疫苗已在巴西的1期和2期人体临床试验中进行了评估， 美国，并已被证明是安全的，同时引发高抗COVID-19滴度。在本SBIR中，我们建议生产 CaTaCo™和Sm-p80作为repRNA/LION™疫苗以及CaTaCo™抗原， 小鼠，用S. mansoni直接将每种疫苗与现有的SchistoShield®疫苗进行比较。成功 完成这项拨款将解决两个关键问题：1）针对SchistoShield®的RNA疫苗是否可行， 上级于现有疫苗，和2）重新设计的CaTaCo™抗原是否是对现有疫苗的改进。 下一代血吸虫病防护盾