Identifying the Most Effective Adjuvant(s) for Leading Group A Streptococcal Vaccine Antigens in Preclinical Mouse and Nonhuman Primate Models

在临床前小鼠和非人灵长类动物模型中确定 A 组链球菌疫苗抗原最有效的佐剂

• 批准号: 10577066
• 负责人: Victor Nizet
• 金额: $ 70.58万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-05 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577066
• 关键词: 3-Dimensional; Acute; Adjuvant; Adjuvant Study; Adult; Animal Model; Antigens; Autoimmune; Carbohydrates; Cessation of life; Child; Clinical; Collaborations; Communities; Conjugate Vaccines; Disease; Disease model; Emulsions; Formulation; Goals; Health Priorities; Heart; Human; Immune; Immune response; Immunity; Immunization; Infection; Investigation; Link; Liposomes; Mission; Modeling; Mus; N-terminal; Pharyngeal structure; Pharyngitis; Phase; Plasminogen; Play; Primary Infection; Productivity; Program Development; Proteins; Public Health; Pyoderma; Queensland; Resources; Rheumatic Fever; Rheumatic Heart Disease; Role; Safety; Scientist; Series; Skin; Streptococcal Vaccines; Streptococcus pyogenes; Subunit Vaccines; Switzerland; Technology Transfer; Tennessee; Tissues; Tonsillitis; Transgenic Organisms; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Research; Vaccines; Work; aluminum sulfate; animal efficacy; brain tissue; care burden; cross reactivity; data modeling; efficacy study; experience; experimental group; global health; head-to-head comparison; immunogenic; intraperitoneal; manufacture; mortality; mouse model; multiple myeloma M Protein; nonhuman primate; pathogen; pathogenic bacteria; pre-clinical; preclinical development; preclinical study; prevent; protective efficacy; reduce symptoms; response; technology training; vaccine candidate; vaccine development; vaccine efficacy; vaccine formulation; vaccine safety; 3-Dimensional; Acute; Adjuvant; Adjuvant Study; Adult; Animal Model; Antigens; Autoimmune; Carbohydrates; Cessation of life; Child; Clinical; Collaborations; Communities; Conjugate Vaccines; Disease; Disease model; Emulsions; Formulation; Goals; Health Priorities; Heart; Human; Immune; Immune response; Immunity; Immunization; Infection; Investigation; Link; Liposomes; Mission; Modeling; Mus; N-terminal; Pharyngeal structure; Pharyngitis; Phase; Plasminogen; Play; Primary Infection; Productivity; Program Development; Proteins; Public Health; Pyoderma; Queensland; Resources; Rheumatic Fever; Rheumatic Heart Disease; Role; Safety; Scientist; Series; Skin; Streptococcal Vaccines; Streptococcus pyogenes; Subunit Vaccines; Switzerland; Technology Transfer; Tennessee; Tissues; Tonsillitis; Transgenic Organisms; Universities; Vaccinated; Vaccination; Vaccine Antigen; Vaccine Research; Vaccines; Work; aluminum sulfate; animal efficacy; brain tissue; care burden; cross reactivity; data modeling; efficacy study; experience; experimental group; global health; head-to-head comparison; immunogenic; intraperitoneal; manufacture; mortality; mouse model; multiple myeloma M Protein; nonhuman primate; pathogen; pathogenic bacteria; pre-clinical; preclinical development; preclinical study; prevent; protective efficacy; reduce symptoms; response; technology training; vaccine candidate; vaccine development; vaccine efficacy; vaccine formulation; vaccine safety

SUMMARY The leading human bacterial pathogen group A Streptococcus (GAS) causes over 700,000,000 cases of superficial disease such as pharyngitis and pyoderma each year but can also lead to serious invasive infections and autoimmune sequelae, which combine to make GAS one of top 10 causes of infection-associated deaths worldwide. The highest mortality burden of GAS disease is caused by rheumatic heart disease (RHD), which results from repeated bouts of acute rheumatic fever (ARF). It is difficult to overstate the urgent public health need for a safe and efficacious GAS vaccine for human use. A significant number of experimental GAS vaccines are backlogged in preclinical development, with questions around safety, global GAS strain coverage, potential for efficacy in humans (i.e. lack of animal efficacy model data that accurately reflects disease). We have recently demonstrated that choice of adjuvant plays a pivotal role in imparting protective efficacy for an experimental multi-component GAS subunit vaccine in both a murine invasive disease model and the non-human primate (NHP) model that closely recapitulates GAS pharyngitis, the primary target for vaccine protection. Moreover, these studies suggest that promoting immunity skewed towards Th1 may elicits optimal protection beyond that afforded by the standard Alum adjuvant formulation. Herein, our highly experienced team of scientists with an extensive track record of productive collaboration will expand this important line of investigation to deliver proof- of-concept of the impact of adjuvant on the efficacy of three leading experimental GAS vaccines: (1) a 30-valent N-terminal M protein vaccine (StreptAnova) from the University of Tennessee that has reached phase 1 human trials; (2) Vaxcyte VAX-AI from Vaxcyte, Inc. in collaboration with UC San Diego, a conjugate vaccine with modified group A carbohydrate conjugate, and GAS proteins SLO, SpyAD, SCPA; and (3) Combo#5 from the University of Queensland incorporating 5 conserved immunogenic GAS antigens: SLO, SCPA, SpyCEP, ADI, TF. The vaccines will be formulated with Alum or selected emulsion and liposome-based adjuvants, using four distinct mouse models (skin, intranasal, intraperitoneal and invasive disease). Protective efficacy, immune response, correlates of protection, and vaccine safety (cross reactivity to human heart tissue) will be assessed. Finally, protection afforded by three selected vaccine-adjuvant combinations will be assessed in the non-human primate model of GAS pharyngitis, which most closely mimics GAS primary infection of humans, and clinical scoring and vaccine safety parameters determined. To advance the entire GAS vaccine field, our head-to-head comparison of M protein and non-M protein GAS vaccines, in both select mouse models and the NHP pharyngitis model, will have broad implications. across the field. We will identify the most efficacious antigen and adjuvant formulations using the animal models we have developed. Adjuvants that we identify will be available for use with other GAS vaccines via the Vaccine Formulation Institute (Switzerland), a not-for-profit organization who help guide advancement of effective formulations toward human trials and commercial use.

概括 领先的人类细菌病原体A组A链球菌（气）导致超过700万例 每年的浅表疾病，例如咽炎和脓毒性疾病，但也可能导致严重的侵入性感染 和自身免疫后遗症，结合使气体成为感染相关死亡的十大原因之一 全世界。气疾病的死亡率最高是由风湿性心脏病（RHD）引起的，该疾病是由此引起的 急性风湿热（ARF）反复出现的结果。很难夸大紧急公共卫生 需要安全有效的气体疫苗用于人类使用。大量的实验气体疫苗 在临床前开发中以对安全性，全球气体应变覆盖范围，潜在的问题进行了积压 对于人类的功效（即缺乏准确反映疾病的动物功效模型数据）。我们最近有 证明辅助的选择在赋予实验性保护功效方面起着关键作用 在鼠侵入性疾病模型和非人类灵长类动物中，多组分气体亚基疫苗既 （NHP）密切概括气体咽炎的模型，咽炎是疫苗保护的主要目标。而且， 这些研究表明，促进免疫力偏向Th1可能会引起最佳保护 由标准明矾辅助配方提供。在此，我们经验丰富的科学家团队拥有 生产协作的广泛记录将扩大这一重要的调查路线，以提供证明 - 佐剂对三种领先实验气体疫苗功效的影响的概念：（1）30个价值 田纳西大学的N末端M蛋白疫苗（Streptanova）已达到人类1期 试验； （2）Vaxcyte，Inc。的Vaxcyte vax-ai与加州大学圣地亚哥加州大学共轭疫苗合作 修改的A组碳水化合物结合物和SCPA Spyad的气体蛋白SLO； （3）组合＃5 昆士兰大学纳入5种保守的免疫原性抗原：SLO，SCPA，Spycep，Adi， TF。疫苗将使用明矾或选定的乳液和脂质体佐剂配制，使用四个 不同的小鼠模型（皮肤，鼻内，腹膜内和侵入性疾病）。保护功效，免疫 将评估反应，保护的相关性和疫苗安全性（对人心脏组织的交叉反应性）。 最后，将在非人类中评估三种选定的疫苗 - 辅助组合提供的保护 气咽炎的灵长类动物模型，最紧密地模仿了人类气体原发性感染和临床 确定评分和疫苗安全参数。为了推进整个气体疫苗场，我们的正面 在某些小鼠模型和NHP咽炎中，M蛋白和非M蛋白质气体疫苗的比较 模型将具有广泛的影响。在整个领域。我们将确定最有效的抗原和佐剂 使用我们开发的动物模型的配方。我们确定的佐剂将可以使用 通过疫苗配方研究所（瑞士）与其他天然气疫苗一起使用，这是一个非营利组织 有助于指导有效制定的人类试验和商业用途的进步。