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

提高含铝佐剂活性的创新方法

• 批准号: 8493404
• 负责人: ZHENGRONG CUI
• 金额: $ 19.33万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493404
• 关键词: Acute; Address; Adjuvant; Adjuvanticity; Affect; Aluminum; Aluminum Hydroxide; Animal Model; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Cells; Communicable Diseases; Data; Development; Dose; Drug Formulations; Evaluation; Foundations; Future; Goals; Human; Immune; Immune response; Injection of therapeutic agent; Laboratories; Lead; Literature; Mission; Modeling; Modification; Outcome; Particle Size; Particulate; Prevention; Production; Proteins; Public Health; Relative (related person); Research; Rodent Model; Safety; Salts; Site; Sodium Chloride; Solubility; Suspension substance; Suspensions; T cell response; Testing; Toxic effect; United States; Vaccine Adjuvant; Vaccines; Water; Work; anthrax protective factor; base; cytokine; design; fight against; improved; infectious disease treatment; innovation; interest; mouse model; nanometer; nanoparticle; nanoparticulate; novel; novel vaccines; particle; physical property; public health relevance; sound; vaccine development

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.

描述（申请人提供）：疫苗是人类对抗传染病的一部分，已有两个多世纪。疫苗或抗原通常需要佐剂来诱导强烈的免疫应答，使其成为疫苗中的关键组分。铝盐，如氢氧化铝，广泛用于各种人类疫苗中。在AS 04最近获得批准之前，数十年来，含铝佐剂是美国唯一批准的人用疫苗佐剂。甚至AS 04也含有氢氧化铝。尽管铝盐具有良好的安全性，但其只能微弱或适度地增强抗原特异性抗体应答，并且通常被认为不能增强细胞免疫应答。因此，仍然需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安全的疫苗佐剂，比传统的铝佐剂更有效。最近我们发现，通过改变氢氧化铝悬浮液的物理性质之一，可以显著增强传统氢氧化铝的佐剂活性。这些令人兴奋的发现指出了这种新型氢氧化铝制剂作为新型疫苗佐剂的潜力。然而，为了充分理解在未来的人疫苗开发中使用这种新型含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评估其在动物模型中的安全性，本申请旨在解决这一关键需求。具体而言，我们将（i）表征由吸附在我们的新型含氢氧化铝佐剂上的蛋白质抗原诱导的免疫应答。炭疽杆菌保护性抗原蛋白将在本研究中用作功能性模型抗原，以表征诱导的特异性B细胞和T细胞应答;（ii）阐明我们的新型含氢氧化铝佐剂的有效佐剂活性的机制;和（iii）评估我们的含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提高传统氢氧化铝佐剂的效力，并通过创新的物理改性来克服其局限性。本项目的预期结果是彻底表征吸附在含氢氧化铝的新型佐剂上的抗原诱导的免疫应答，并初步评估其在啮齿动物模型中的安全性。此外，我们期望了解为什么传统氢氧化铝的佐剂活性可以通过改变其物理性质之一来进行有利地调节。总的来说，这些结果将为未来将这种新型含氢氧化铝佐剂开发成安全且更有效的人类疫苗佐剂提供良好的科学基础，其可用于开发新疫苗以及重新配制现有疫苗。