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

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.

摘要 人类主要致病菌A组链球菌(GAS)导致7亿多例 每年都会出现咽炎和脓皮病等浅表疾病，但也可能导致严重的侵袭性感染 和自身免疫后遗症，这使得GAS成为感染相关死亡的前十大原因之一 全世界。气病死亡负担最高的是风湿性心脏病(RHD)， 由反复发作的急性风湿热(ARF)所致。很难夸大公共卫生的紧迫性 需要一种安全有效的人类使用的气体疫苗。相当数量的实验性气体疫苗 在临床前开发中积压，存在关于安全性、全球毒株覆盖率、潜在 对于人类的疗效(即缺乏准确反映疾病的动物功效模型数据)。我们最近做了 证明佐剂的选择在赋予实验动物保护效果方面起着关键作用。 多组分GAS亚单位疫苗在小鼠侵袭性疾病模型和非人灵长类动物中的应用 (NHP)模型，它紧密地概括了疫苗保护的主要目标--气性咽炎。此外， 这些研究表明，促进偏向Th1的免疫可能会产生更好的保护作用 由标准明矾佐剂配方提供。在此，我们经验丰富的科学家团队拥有 广泛的卓有成效的协作记录将扩大这一重要的调查范围，以提供证据- 佐剂对三种主要的实验性GAS疫苗效力影响的概念：(1)30价 田纳西大学的N-末端M蛋白疫苗(StreptAnova)已达到人类第一阶段 试验；(2)Vaxcell，Inc.与加州大学圣地亚哥分校合作的Vaxcell VAX-AI，一种结合疫苗 修饰的A组碳水化合物结合物和GAS蛋白SLO、SpyAD、SCPA；和(3)来自 昆士兰大学整合了5种保守的免疫原性气体抗原：SLO，SCPA，SpyCEP，ADI， Tf.这些疫苗将使用明胶或选定的乳剂和脂质体佐剂配制，使用四种 不同的小鼠模型(皮肤、鼻腔、腹膜和侵袭性疾病)。保护功效，免疫 将评估疫苗的反应、保护的相关性和疫苗安全性(对人体心脏组织的交叉反应性)。 最后，三种选定的疫苗-佐剂组合提供的保护将在非人类中进行评估。 最接近人类GAS原发感染的气性咽炎灵长类动物模型，以及临床 确定评分和疫苗安全参数。为了推进整个天然气疫苗领域，我们面对面地 M蛋白和非M蛋白GAS疫苗在两种小鼠模型和NHP咽炎模型中的比较 模型，将具有广泛的影响。穿过田野。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供使用 与其他气体疫苗通过疫苗配方研究所(瑞士)，一个非营利性组织，谁 帮助引导有效配方向人体试验和商业用途的发展。