Evaluation of a Next Generation SchistoShield Vaccine

摘要 血吸虫病是一种主要的寄生虫病，目前有2.52亿人，可能影响10亿人。 在74个国家中，有7.79亿人受到感染，面临感染风险。目前的控制策略依赖于 单独使用药物吡喹酮反复治疗--然而，这一策略已被证明不够充分，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。超过了 经过20年的发展，我们已经开发出一种有效的血吸虫病疫苗，名为血吸虫病®，目标是 在TLR4靶向佐剂GLA-SE中配制的具有重要功能的抗原Sm-p80。SchistoShield®拥有 在许多动物模型中进行了详尽的测试，并在所有寄生虫生命中始终显示出保护作用 各阶段。我们即将完成SchistoShield®的一期安全性和剂量范围的人体临床试验 美国-没有报告严重的安全信号-将于2023年第三季度开始第一阶段B试验，第二阶段 该试验目前也得到了比尔和梅林达·盖茨基金会的资助。尽管有SchistoShield®的承诺， 重要的是要准备好建设管道并作为替代方案的下一代后续候选人 如果我们在未来遇到可伸缩性、成本或现场效果等方面的问题。要解决这些问题 关注，我们建议评估当前SchistoShield®疫苗的两个新变种：第一个是 一个是重新设计的Sm-p80蛋白抗原，第二个是Sm-p80蛋白的新的RNA递送平台版本。 P80抗原。 为了重新设计，我们去掉了疏水区域和其他不相关的区域(在催化三联体结构域之外) ~85 kDa Sm-p80抗原产生更小、抗原性更集中的~44 kDa抗原 我们称之为催化靶向构建体(CaTaCo™)。CaTaCo™在这些结构域上与Sm-P80相似 保持了酶活性所需，同时提高了可溶性产物的产量。与Sm相比- P80，CaTaCo™表现出最小的聚集和较少的降解--这是当前抗原的一个潜在问题 这被FDA标记为潜在的改进。在小鼠体内，CaTaCo™可诱导相对较高的滴度 小鼠，与抗Sm-p80单抗(MAbbs)结合，并由小鼠和狒狒的血清检测到 使用SchistoShield®进行免疫。 随着rna疫苗使用的增加，我们还将生产和评估CaTaCo™和Sm-p80为 使用我们在HDT Bio的合作伙伴发明的专利技术的RNA疫苗。HDT最近使用了这个 他们的新冠肺炎疫苗HDT-301的技术，类似于来自莫德纳和 辉瑞/生物科技。HDT-301平台由吸附并稳定在其上的自我复制RNA(EpRNA)组成 一种脂类无机纳米颗粒(LION™)载体。这种疫苗在印度获得了紧急使用批准-- 唯一在人类身上被批准的自我放大平台。将epRNA导入细胞导致正在进行的 编码抗原的RNA的生物合成导致体内蛋白质浓度显著升高，从而导致 增强体液和细胞免疫反应--也许最重要的是--节省剂量的效果。这个 HDT-301疫苗已经在巴西的第一阶段和第二阶段人体临床试验中进行了评估， 并已被证明是安全的，同时引发了高水平的抗新冠肺炎效价。在这份SBIR中，我们建议生产 CaTaCo™和Sm-p80作为RepRNA/Lion™疫苗以及CaTaCo™抗原，都能免疫它们 并用曼氏葡萄球菌直接与现有的SchistoShield®疫苗进行比较。成功 这笔赠款的完成将解决两个关键问题：1)针对SchistoShield®的RNA疫苗是可行的还是 优于现有疫苗，以及2)重新设计的CaTaCo™抗原是否对 新一代SchistoShield®。

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®.