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

总结 主要的人类细菌病原体A组链球菌（GAS）导致超过7亿例 但也可能导致严重的侵入性感染 和自身免疫性后遗症，这些联合收割机使GAS成为感染相关死亡的十大原因之一 国际吧GAS疾病的最高死亡负担由风湿性心脏病（RHD）引起， 急性风湿热（ARF）反复发作的结果。很难夸大紧迫的公共卫生 需要一种安全有效的GAS疫苗供人类使用。大量的实验性GAS疫苗 在临床前开发方面积压了大量工作，围绕安全性、全球GAS菌株覆盖率、潜在 在人类中的疗效（即缺乏准确反映疾病的动物疗效模型数据）。我们最近 证明佐剂的选择在赋予实验性免疫缺陷病毒的保护功效中起关键作用。 在鼠侵袭性疾病模型和非人灵长类动物中的多组分GAS亚单位疫苗 (NHP)模型，密切概括了GAS咽炎，疫苗保护的主要目标。此外，委员会认为， 这些研究表明，促进向Th 1倾斜的免疫可能会产生最佳保护， 由标准明矾佐剂制剂提供。在此，我们经验丰富的科学家团队， 富有成效的合作的广泛记录将扩大这一重要的调查路线，以提供证据- 佐剂对三种主要实验性GAS疫苗效力的影响的概念：（1）30价GAS疫苗， 来自田纳西大学的N-末端M蛋白疫苗（StreptAnova）已达到1期人类 （2）Vaxcyte VAX-AI，来自Vaxcyte，Inc.与加州大学圣地亚哥分校合作， 修饰的A组碳水化合物缀合物，和GAS蛋白SLO、SpyAD、SCPA;和（3）组合#5， 昆士兰州大学，包含5种保守的免疫原性GAS抗原：SLO、SCPA、SpyCEP、ADI， TF疫苗将使用明矾或选定的乳剂和基于脂质体的佐剂配制，使用四种 不同的小鼠模型（皮肤、鼻内、腹膜内和侵袭性疾病）。免疫保护效力 将评估反应、保护相关性和疫苗安全性（与人心脏组织的交叉反应性）。 最后，将在非人免疫系统中评估三种选定的疫苗-佐剂组合提供的保护。 GAS咽炎的灵长类动物模型，其最接近地模拟人的GAS原发性感染，以及临床 评分和确定疫苗安全性参数。为了推进整个GAS疫苗领域，我们的头对头 M蛋白和非M蛋白GAS疫苗在选择的小鼠模型和NHP咽炎中的比较 模式，将产生广泛的影响。穿过田野我们将确定最有效的抗原和佐剂 使用我们已经开发的动物模型的配方。我们确定的佐剂将可供使用 通过疫苗制剂研究所（瑞士），一个非营利组织， 有助于指导有效制剂向人体试验和商业用途的发展。

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.