A Novel TLR5 Agonist-Based Adjuvant for Poliovirus Vaccine

一种基于 TLR5 激动剂的新型脊髓灰质炎病毒疫苗佐剂

• 批准号: 9305008
• 负责人: Vadim Mett
• 金额: $ 29.32万
• 依托单位: BUFFALO BIOLABS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9305008
• 关键词: Address; Adjuvant; Adsorption; Agonist; Antigens; Antiviral Agents; Applications Grants; Businesses; Clinical; Clinical Trials; Collaborations; Custom; Development; Disease; Dose; Elements; Employee Strikes; Engineering; FDA approved; Flagellin; Formulation; Foundations; Goals; Human; Human Papilloma Virus Vaccine; Human poliovirus; Immunity; Immunization; Immunize; Immunologic Adjuvants; Immunotherapeutic agent; Inbred BALB C Mice; Incidence; Industrialization; Inflammasome; Innate Immune Response; Intestines; Letters; Medical; Modification; Mouse Strains; Mus; NF-kappa B; Natural Immunity; Nature; Pharmacology; Phase; Poliomyelitis; Poliovirus Vaccines; Property; Proteins; Radiation; Recombinant Vaccines; Research Personnel; Residual state; Safety; Salmonella; Signal Transduction; Small Business Innovation Research Grant; Splenocyte; Supportive care; System; T-Lymphocyte Epitopes; TLR4 gene; TLR5 gene; TLR9 gene; Technology; Testing; Tissues; Toll-like receptors; Toxicology; Vaccinated; Vaccination; Vaccine Antigen; Vaccines; Variant; Viral Antigens; Virus; Virus Activation; Virus Diseases; World Health Organization; aluminum sulfate; base; cancer therapy; cell motility; clinical development; commercialization; cost; cost effective; design; immunogenicity; improved; influenzavirus; innovation; low and middle-income countries; neutralizing antibody; novel; rapid growth; receptor; success; synergism; vaccine development

PROJECT SUMMARY/ABSTRACT Antiviral vaccines remain the largest segment of the rapidly growing global vaccine market. Despite near-complete eradication of poliovirus through vaccination efforts, continued need for inactivated polio vaccine (IPV) is projected to reach 450 million doses per year worldwide. Among major obstacles to widespread use of the current IPV formulation are its high cost and insufficient potency to induce robust intestinal immunity. Therefore, development of an effective, safe and affordable adjuvant for IPV that would allow reduction of the costly IPV antigen content represents a highly significant unmet need. This Phase I SBIR proposal aims to address this challenge through optimization of a novel adjuvant system combining the immunostimulatory power of the toll-like receptor 5 (TLR5) agonist, entolimod (previously CBLB502), with the well- known adjuvant properties of Alum. Entolimod is being developed for tissue protective (anti- radiation and supportive care in cancer treatment) and anticancer immunotherapeutic applications by Cleveland BioLabs, Inc. (CBLI) and has an established safety profile. Given the demonstrated adjuvant properties of the natural TLR5 agonist (and entolimod parent) flagellin, investigators of this proposal in partnership with CBLI developed an innovative [entolimod+Alum]-based adjuvant system (termed SA702) with advantages in terms of efficacy (combined effect of two adjuvants), versatility (modular platform easily customized for many different antigen types); and decreased futile (adjuvant-directed) immunogenicity. Preliminary studies confirmed that immunization of mice with IPV (10% human dose) co-adsorbed on SA702 led to induction of increased levels of anti-poliovirus neutralizing antibodies compared to immunization with IPV alone or [IPV+Alum]. Here, we propose further optimization of entolimod as a co-adjuvant through targeting of its residual immunogenicity and its ancillary inflammasome-directed signaling activity (Aim 1) followed by characterization and optimization of the stability, efficacy and safety of SA702-IPV formulations containing the identified optimal entolimod variant (Aim 2). In addition, we will determine the impact of entolimod's residual immunogenicity on adjuvant activity of SA702 via mapping and elimination of mouse T cell epitopes. Together, the deliverables of these aims will define and validate an optimal design for the SA702 platform and a new SA702-IPV formulation and set the stage for Phase II SBIR application and commercialization.

项目总结/摘要 抗病毒疫苗仍然是快速增长的全球疫苗市场的最大部分。 尽管通过疫苗接种工作几乎完全根除了脊髓灰质炎病毒，但仍需要 灭活脊髓灰质炎疫苗（IPV）预计将达到每年4.5亿剂。 广泛使用目前IPV制剂的主要障碍之一是其高成本， 不足以诱导强大的肠道免疫力。因此，发展一个有效的， 安全且可负担得起的IPV佐剂，其将允许降低昂贵的IPV抗原含量 这是一个非常重要的未满足的需求。第一阶段SBIR提案旨在解决这一问题 通过优化结合免疫刺激剂的新型佐剂系统来挑战 Toll样受体5（TLR 5）激动剂恩托莫德（先前为CBLB 502）与孔- 已知明矾的佐剂特性。Entolimod正在开发用于组织保护（抗- 癌症治疗中的放射和支持性护理）和抗癌免疫疗法 Cleveland BioLabs，Inc.（CBLI），并具有既定的安全性特征。鉴于 证实了天然TLR 5激动剂（和恩托莫德母体）鞭毛蛋白的佐剂性质， 该提案的研究人员与CBLI合作开发了一种创新的 基于[恩托莫德+明矾]的佐剂系统（称为SA 702），在疗效方面具有优势 （两种助剂的组合效果）、多功能性（模块化平台可轻松定制， 不同的抗原类型）;和降低的无效（免疫原性导向的）免疫原性。初步 研究证实，用共吸附在 与对照组相比，SA 702诱导抗脊髓灰质炎病毒中和抗体水平升高。 用单独的IPV或[IPV+明矾]免疫。在此，我们提出进一步优化恩托莫德 通过靶向其残余免疫原性及其辅助免疫原性， 炎性小体导向的信号传导活性（Aim 1），随后进行表征和优化 SA 702-IPV制剂的稳定性、有效性和安全性， 恩托莫德变体（Aim 2）。此外，我们将确定恩托莫德残留的影响， 小鼠T细胞定位和消除对SA 702免疫原性影响 表位这些目标的可交付成果将共同定义并验证以下方面的最佳设计： SA 702平台和新的SA 702-IPV配方，并为第二阶段SBIR奠定基础 应用和商业化。