An innovative approach to improve the activity of an aluminum-containing adjuvant

描述(申请人提供)：两个多世纪以来，疫苗一直是人类抗击传染病的一部分。疫苗或抗原通常需要佐剂才能诱导强烈的免疫反应，使其成为疫苗的关键组成部分。铝盐，如氢氧化铝，被广泛用于各种人类疫苗。在最近批准AS04之前，几十年来，含铝佐剂一直是美国唯一被批准用于人类使用的疫苗佐剂。即使是AS04也含有氢氧化铝。尽管铝盐被证明具有良好的安全性，但它们只能微弱或适度地增强抗原特异性抗体反应，通常被认为不能增强细胞免疫反应。因此，仍有必要寻找安全和更有效的疫苗佐剂。我们的长期目标是开发一种比传统铝佐剂更有效的安全疫苗佐剂。最近我们发现，通过对氢氧化铝悬浮液的一种物理性质进行改性，可以显著提高传统氢氧化铝的佐剂活性。这些令人兴奋的发现表明，这种新型氢氧化铝配方作为一种新型疫苗佐剂具有潜力。然而，为了充分认识在未来的人类疫苗开发中使用这种新型氢氧化铝佐剂的可行性，迫切需要进一步表征其佐剂活性，并在动物模型中评估其安全性，本申请旨在解决这一关键需求。具体地说，我们将(I)表征吸附在我们新型氢氧化铝佐剂上的蛋白质抗原所诱导的免疫反应。在这项研究中，炭疽杆菌保护性抗原蛋白将被用作功能模型抗原，以表征诱导的特异性B细胞和T细胞反应；(Ii)阐明我们的新型氢氧化铝佐剂有效佐剂活性的机制；以及(Iii)评估我们的氢氧化铝佐剂的安全性/毒性。我们提出的研究最具创新性的方面是通过创新的物理修饰来增强传统氢氧化铝佐剂的效力，并克服其局限性。该项目的预期结果是彻底表征吸附在我们新的氢氧化铝佐剂上的抗原所诱导的免疫反应，并在啮齿动物模型中初步评估其安全性。此外，我们希望了解为什么传统氢氧化铝的佐剂活性可以通过改变其一种物理性质来进行有利的调节。总而言之，这些成果将为未来将这种新型氢氧化铝佐剂开发成安全和更有效的人类疫苗佐剂提供坚实的科学基础，这种佐剂可用于开发新疫苗和重新配制现有疫苗。

DESCRIPTION (provided by applicant): Vaccine has been part of human fight against infectious diseases for more than two centuries. An adjuvant is often required for a vaccine or antigen to induce a strong immune response, making it a crucial component in vaccines. Aluminum salts, such as aluminum hydroxide, are widely used in various human vaccines. Before the recent approval of AS04, for decades, aluminum-containing adjuvants were the only approved vaccine adjuvant for human use in the United States. Even AS04 contains aluminum hydroxide. Despite their demonstrated favorable safety profile, aluminum salts can only weakly or moderately potentiate antigen-specific antibody responses, and is generally considered incapable of enhancing cellular immune responses. Therefore, there continues to be a need to search for safe and more potent vaccine adjuvants. Our long-term goal is to develop a safe vaccine adjuvant that is more potent than the traditional aluminum adjuvants. Recently we discovered that the adjuvant activity of the traditional aluminum hydroxide can be significantly enhanced by modifying one of the physical properties of the aluminum hydroxide suspension. These exciting findings point to the potential of this novel aluminum hydroxide formulation as a novel vaccine adjuvant. However, to fully appreciate the feasibility using this novel aluminum hydroxide-containing adjuvant in future human vaccine development, there is a critical need to further characterize its adjuvant activity and to assess its safety in animal models, and the present application is designed to address this critical need. Specifically, we will (i) characterie the immune responses induced by a protein antigen adsorbed on our novel aluminum hydroxide-containg adjuvant. Bacillus anthracis protective antigen protein will be used as a functional model antigen in this study to characterize the specific B cell and T cell responses induced; (ii) elucidate the mechanisms underlying the potent adjuvant activity of our novel aluminum hydroxide-containing adjuvant; and (iii) assess the safety/toxicity of our aluminum hydroxide-containing adjuvant. The most innovative aspect of our proposed research is to enhance the potency of the traditional aluminum hydroxide adjuvant and to overcome its limitations by an innovative physical modification. Our expected outcomes from this project are to thoroughly characterize the immune responses induced by antigens adsorbed on our new aluminum hydroxide-containing adjuvant and to preliminarily assess its safety profile in a rodent model. Moreover, we expect to understand why the adjuvant activity of traditional aluminum hydroxide can be favorably modulated by modifying one of its physical properties. Collectively, these outcomes will provide a sound scientific foundation for future development of this novel aluminum hydroxide-containing adjuvant into a safe and more potent human vaccine adjuvant, which can be used in developing new vaccines as well as re-formulating existing vaccines.