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

双向靶向 SARS-CoV-2 加强疫苗的 GMP 生产和 GLP 安全性

基本信息

批准号：
10766657
负责人：
Ellen Elizabeth Sparger
金额：
$ 100万
依托单位：
TENDEL THERAPIES 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：
2023-07-11 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10766657
关键词：
Acceleration Adenoviruses Adjuvant Antibody Response Antibody titer measurement Antigens B-Cell Development B-Lymphocytes CD3 Antigens COVID-19 booster COVID-19 vaccine California Chimeric Proteins Clinical Clinical Trials Complex Data Development Dose FDA approved Feedback Funding Genetic Genome Goals Good Manufacturing Process Helper-Inducer T-Lymphocyte Human Immunoglobulin Fragments Laboratories Letters Libraries Macaca Monoclonal Antibody HuM291 Persons Phase Production Qualifying RNA vaccine Running SARS-CoV-2 B.1.1.529 Safety Serial Passage T-Lymphocyte Techniques Testing Toxicology Transfection United States National Institutes of Health Vaccines Vial device Viral Virus Work booster vaccine comparative cost deep sequencing delivery vehicle design first-in-human genome sequencing high dimensionality immunogenicity manufacture manufacturing process manufacturing run neutralizing antibody next generation sequencing nonhuman primate novel novel strategies novel vaccines particle phase 1 testing phase I trial plasmid DNA pre-clinical programs receptor binding recruit regenerative resilience response safety study safety testing tool trial design vaccine candidate vector viral detection

项目摘要

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.

Tendel 的 CoTend-s3B SARS-CoV-2 加强疫苗以滤泡辅助 T (Tfh) 细胞为目标，产生非常广泛和持久的抗体反应，这是弹性疫苗所必需的候选疫苗包含“s3”靶向部分，可长期保持保护作用。这种新型的一流佐剂与受体融合，诱导有效的滤泡辅助 T (Tfh) 细胞反应。 SARS-CoV-2 的 Omicron 变体 (BA.4/BA.5) 的结合域 (RBD) 组合分子。同时靶向 RBD 特异性 B 细胞和 T 细胞，特别是局部 Tfh 细胞，从而加速和临床前非人类灵长类动物 (NHP) 研究已经证明了 B 细胞的非凡发展。通过低剂量腺病毒递送时，中和抗体滴度高，稳定时间>10个月相比之下，35 型 (Ad35) 递送载体对缺乏 s3 的对照疫苗产生中和抗体反应。部分（即仅含有免疫原的 CoTend-B）在 6 年内减少至保护水平以下几个月，与 FDA 批准的 mRNA 疫苗在人体中观察到的结果相似。 Tendel 与学术伙伴 Steve Deeks（加州大学旧金山分校）和 Kara Chew（加州大学洛杉矶分校）合作，完成了该 s3 佐剂疫苗具有良好的 IND 前相互作用，并在此 R44 中设计了首次人体试验。应用程序我们提出了几项任务，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 和的第一阶段比较测试 CoTend-s3B 将于 2024 年初开始作为加强疫苗。我们将完成这两种疫苗的 GMP 级生产疫苗数量足以进行 GLP 安全性研究和计划中的第一阶段试验。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在猕猴中完成 GLP 安全性研究，同时收集高维数据库数据证明 s3 佐剂平台具有卓越的 B 细胞募集能力。这项工作的交付成果是经过充分表征的 GMP 级疫苗库存（CoTend-B 和 CoTend-s3B）以及相应的安全数据，以便成功申请 IND 并开始临床试验。目标 1. 根据 GMP 生产瓶装 CoTend-B 和 CoTend-s3B 疫苗产品。目标 2. 完成发布测试，包括通过 NGS 方法进行外来因子测试。目标 3. 对瓶装产品进行 GLP 毒理学和免疫原性测试。 R44 申请中提出的工作将为新的人体首次测试提供必要的步骤促进抗原特异性 B 细胞发育的方法如果成功，将降低 s3 平台的风险。提供一种变革性的新工具，可以实现并推动人类 B 细胞的发展道路目前的疫苗很少能达到这一目标。