RNA-based multi-antigen vaccine for SARS-CoV-2

基于 RNA 的 SARS-CoV-2 多抗原疫苗

• 批准号: 10259605
• 负责人: Christian W. Mandl
• 金额: $ 27.9万
• 依托单位: TIBA BIOTECH, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259605
• 关键词: 2019-nCoV; Aerosols; Agar Gel Electrophoresis; Animals; Antibodies; Antigens; Autopsy; Benchmarking; Biological Assay; Blood; Brain; COVID-19 pandemic; COVID-19 vaccine; Cells; Cessation of life; Characteristics; Clinical; Codon Nucleotides; Collaborations; Control Groups; Coronavirus; DNA; Dendrimers; Detection; Development; Disease; Dose; E protein; Ensure; Enzyme-Linked Immunosorbent Assay; Evaluation; Family; Fibroblasts; Formulation; Generations; Genes; Hamsters; Harvest; Histopathology; Human; Immune response; In Situ; In Vitro; Inbred BALB C Mice; Infection; Injections; Interferon Type II; Interleukin-2; Interleukin-4; Lead; Life; Lipids; Lung; Measures; Mesocricetus auratus; Messenger RNA; Modality; Modeling; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Nature; Nucleic Acid Vaccines; Peptides; Phase; Production; Proteins; Public Health; Quantitative Reverse Transcriptase PCR; RNA; RNA Degradation; RNA vaccine; Recovery; Replicon; Reporting; Residual state; SARS-CoV-2 antigen; Sampling; Sarna; Secondary Immunization; Serum; Small Business Innovation Research Grant; Spleen; Splenocyte; Sterility; Structural Protein; Structure; System; T cell response; T-Lymphocyte Epitopes; Technology; Testing; Tissues; Titrations; Transcript; Transfection; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Validation; Viral; Virion; Virus; Virus Replication; base; commercialization; coronavirus vaccination; coronavirus vaccine; design; human disease; immunogenic; immunogenicity; innovation; lead candidate; light scattering; lipid nanoparticle; member; nanoparticle; nanoparticle delivery; novel; nucleic acid delivery; pandemic disease; pre-clinical; prototype; response; success; uptake; vaccine candidate; vaccine development; vaccine effectiveness; vector

Project Summary/Abstract (30 lines) The proposal is to develop an RNA-based multi-antigen SARS-CoV-2 vaccine, supporting NIAID’s call to develop a vaccine using emerging antigen design strategies and novel delivery approaches. The SARS-CoV-2 pandemic is actively threatening public health, world economies, and ways of life. Vaccine candidates are in human trials now, but long-term solutions will require an adaptable vaccine system that can be universalized broadly to all members of the coronavirus family. Tiba’s vaccine will be innovative in two respects: 1) The inclusion of all four structural virion proteins will allow a deeper and potentially broader immune response against coronavirus, as multiple conserved T cell epitopes will be presented by the vaccine. In addition, the incorporation of structural proteins besides the Spike (S) protein will allow the formation of immunogenic VLPs in situ. 2) Conventional lipid nanoparticles (LNPs), which are the mainstay of nucleic acid delivery, require a large proportion of “structural” lipid, resulting in a relatively low RNA content. Tiba has developed a modified dendrimer delivery molecule that maximizes RNA mass content, protects RNA from degradation, and enables efficient uptake by cells. This approach will increase immunogenicity and thus effectiveness of the vaccine. The first Phase 1 Aim is to optimize candidate payloads comprising M, N, and E mRNA or saRNA. Conventional mRNAs encoding the M, N, and E proteins will be codon-optimized and lead RNA payloads will then be formulated with Tiba’s modified dendrimer delivery material. With the M, N, and E payloads generated in both saRNA and mRNA formats, effective immunogenic doses for each will be determined by injecting six-week-old BALB/c mice with nanoparticles at different doses. The antigen RNA payloads to proceed for titration into S RNA vaccine candidates will be selected. The minimum effective dose for each M, N, and E mRNA or saRNA will be roughly estimated using a regression model. Aim 2 will test the lead candidate payloads along with S in mice. Combination formulations will be generated wherein different masses of the lead M, N, and E RNAs are titrated into the optimal S mRNA or saRNA formula to identify a formulation mixture that maximizes M, N, and E cellular immune responses while not suppressing the S humoral response. Treatment doses will deliver the same mass of S RNA across all groups, and that optimal mass will be chosen based on the results of dose-finding preliminary studies. Using the results of the study, two mixtures that confer detectable responses against each virion component while not suppressing S antibody and T cell responses will be selected as lead candidates. For Aim 3, the lead candidates will be used in a hamster challenge study. Vaccinations will be performed by i.m. injection in golden Syrian hamsters. Challenges will be performed using the current best practice. The benchmark of success for this study is evidence of immune responses against firstly the S component of the vaccine, and concomitant protection against disease, ideally after a single administration. If successful, further development of lead vaccine candidates and the path to commercialization will be forthcoming in a Phase 2 SBIR Proposal.

项目摘要/摘要（30行） 该提议是开发基于RNA的多抗原Sars-Cov-2疫苗，支持Niaid的开发呼吁 使用新兴抗原设计策略和新型输送方法的疫苗。 SARS-COV-2大流行 正在积极威胁公共卫生，世界经济和生活方式。候选疫苗正在人类试验中 现在，但是长期解决方案将需要一种适应性的疫苗系统，该系统可以广泛地普遍于所有人 冠状病毒家族的成员。 TIBA的疫苗将在两个方面具有创新性：1）包括所有四种 结构性病毒素蛋白将允许对冠状病毒的更深层，更广泛的免疫反应，如 疫苗将提出多个保守的T细胞表位。另外，结构 除峰值（S）蛋白外，蛋白质还可以原位形成免疫原性VLP。 2）常规脂质 纳米颗粒（LNP）是核酸递送的主要支柱，需要很大一部分“结构” 脂质，导致相对较低的RNA含量。 TIBA开发了一个改良的树枝状聚合物递送分子， 最大化RNA质量含量，保护RNA免受降解，并可以有效摄取细胞。这 方法将增加免疫原性，从而增加疫苗的有效性。第一阶段的目标是优化 候选人有效载荷完成M，N和E mRNA或SARNA。编码M，N和E的常规mRNA 蛋白质将进行密码子优化，然后使用TIBA修改后的树枝状聚合物制定铅RNA有效载荷 送货材料。使用SARNA和mRNA格式产生的M，N和E有效载荷，有效 每种免疫原性剂量将通过向纳米颗粒注射六周大的BALB/C小鼠在 不同的剂量。抗原RNA有效载荷以滴定为S RNA疫苗候选者将是 选定。每个M，N和E mRNA或SARNA的最小有效剂量将大致估算 回归模型。 AIM 2将与小鼠中的S一起测试铅候选有效载荷。组合公式 将生成铅m，n和e rNA的不同质量滴定到最佳S mRNA中 或SARNA公式，以识别最大化M，N和E细胞免疫回报的配方奶粉混合物 不抑制体液反应。治疗剂量将在所有人中提供相同的S RNA 组，将根据剂量发现初步研究的结果选择最佳质量。使用 该研究的结果，两种混合物会召集针对每个病毒素成分的可检测反应，而不是 抑制S抗体和T细胞反应将作为铅候选。对于AIM 3，主要候选人 将用于仓鼠挑战研究。 I.M.将进行疫苗接种在黄金叙利亚注入 仓鼠。挑战将使用当前的最佳实践来进行。这项研究成功的基准 首先是针对疫苗的S组成部分进行免疫复杂的证据，并伴随着保护 反对疾病，理想情况下是在一次给药之后。如果成功，请进一步开发铅疫苗 候选人和商业化的途径将在第二阶段的SBIR提案中提出。