GMP production and GLP safety of bidirectionally targeted SARS-CoV-2 booster vaccine

Tendel的CoTend-s3 B SARS-CoV-2加强疫苗靶向T滤泡辅助细胞（Tfh）， 非常广泛和持久的抗体反应，这是弹性疫苗所必需的， 长期保护。候选疫苗包含“s3”靶向部分， 诱导有效的T滤泡辅助（Tfh）细胞应答。这种新型的，一流的佐剂是融合到受体 SARS-CoV-2的Omicron变体（BA.4/BA.5）的结合结构域（RBD）。结合的分子 同时靶向RBD特异性B细胞和T细胞，特别是局部Tfh细胞，从而加速和 扩展B细胞发育。临床前非人灵长类动物（NHP）研究已经证明， 高中和抗体滴度，当通过低剂量腺病毒递送时稳定>10个月 35型（Ad 35）递送载体。相比之下，对缺乏s3的对照疫苗的中和抗体反应 部分（即，单独含有免疫原的CoTend-B）在6小时内减少到低于保护水平 这与FDA批准的mRNA疫苗在人体中观察到的结果相似。 在与学术合作伙伴史蒂夫Deeks（加州大学旧金山分校）和卡拉周（加州大学洛杉矶分校），Tendel完成了 有利的pre-IND相互作用，并设计了首次人体试验。在这款R44 我们提出了几项任务，这些任务将提供所需的研究产品和毒理学数据， 以及其他支持性机制数据，以支持CoTend-B和 CoTend-s3 B作为2024年初开始的加强疫苗。我们将完成GMP级的生产， 疫苗的数量足以进行GLP安全性研究和计划的I期试验。我们将测试 通过下一代测序（NGS）进行外源因子检测的技术可行性。最后，我们将使用 瓶装疫苗，以完成猕猴的GLP安全性研究，同时收集高维 库数据以证明通过s3佐剂平台的上级B细胞募集。 这项工作的可交付成果是经过充分表征的GMP级疫苗库存（CoTend-B和CoTend-s3 B） 以及允许IND申请成功和临床试验开始的相应安全性数据。 目标1。根据GMP生产瓶装CoTend-B和CoTend-s3 B疫苗产品。 目标二。完成放行检测，包括通过NGS方法进行的外源因子检测。 目标3。对瓶装产品进行GLP毒理学和免疫原性试验。 这项R44申请中提出的工作将使新的药物在人类中进行首次测试的必要步骤成为可能。 促进抗原特异性B细胞发育的方法。如果成功，s3平台的风险消除将 提供了一种变革性的新工具，可以使人类B细胞发育沿着 目前的疫苗很少使用。

Tendel’s CoTend-s3B SARS-CoV-2 booster vaccine targets T follicular helper (Tfh) cells to generate extraordinarily broad and long-lived antibody responses, which are required for resilient vaccines that maintain protection over long periods. The vaccine candidate incorporates the “s3” targeting moiety, which induces a potent T follicular helper (Tfh) cell response. This novel, first-in-class adjuvant is fused to the receptor binding domain (RBD) from the Omicron variant of SARS-CoV-2 (BA.4/BA.5). The combined molecule simultaneously targets RBD-specific B cells and T cells, and especially local Tfh cells, thus accelerating and expanding B-cell development. Preclinical non-human primate (NHP) studies have demonstrated extraordinarily high neutralizing antibody titers that were stable for >10 months when delivered via a low dose of adenovirus type 35 (Ad35) delivery vector. In contrast, neutralizing antibody responses to control vaccine lacking the s3 moiety (i.e., CoTend-B containing immunogen alone), were diminished to below the level of protection within 6 months, similar to results seen in humans with FDA-approved mRNA vaccines. In cooperation with academic partners Steve Deeks (UCSF) and Kara Chew (UCLA), Tendel completed favorable pre-IND interactions for this s3-adjuvanted vaccine and designed a first-in-human trial. In this R44 application we propose several tasks that will provide the needed investigational products and toxicology data, as well as additional supportive mechanistic data, to support comparative phase-1 testing of CoTend-B and CoTend-s3B as booster vaccines beginning in early 2024. We will complete GMP-grade production of both vaccines in amounts sufficient for both GLP safety studies and the planned phase-1 trial. We will test the technical feasibility of adventitious-agent testing by next-generation sequencing (NGS). Finally, we will use the vialed vaccine to complete GLP safety studies in macaques while simultaneously gathering high-dimensional repertoire data to demonstrate superior B-cell recruitment by the s3 adjuvant platform. The deliverables of this work are fully characterized, GMP-grade vaccine stocks (CoTend-B and CoTend-s3B) and corresponding safety data that will permit a successful IND application and commencement of clinical trials. Aim 1. Produce vialed CoTend-B and CoTend-s3B vaccine products according to GMP. Aim 2. Complete release testing, including adventitious-agent testing by an NGS approach. Aim 3. Perform GLP toxicology and immunogenicity testing of the vialed product. The work proposed in this R44 application will enable necessary steps towards the first test in humans of a new approach to promoting development of antigen-specific B cells. If successful, de-risking of the s3 platform will provide a transformative new tool that can enable and drive human B-cell development along paths that are infrequently reached by current vaccines.