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: 8605172
• 负责人: ZHENGRONG CUI
• 金额: $ 23.11万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8605172
• 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（由申请人提供）：疫苗已经成为人类与传染病的一部分，已有两个世纪以上。疫苗或抗原通常需要佐剂诱导强烈的免疫反应，从而使其成为疫苗的关键成分。铝盐（例如氢氧化铝）广泛用于各种人类疫苗中。在最近批准AS04之前，几十年来，含铝的佐剂是美国唯一获得批准的疫苗辅助剂。甚至AS04都包含氢氧化铝。尽管它们表现出了有利的安全性，但铝盐只能弱或中度增强抗原特异性抗体反应，并且通常被认为无法增强细胞免疫反应。因此，仍然需要寻找安全，更有效的疫苗佐剂。我们的长期目标是开发一种安全疫苗佐剂，该辅助剂比传统的铝佐剂更有效。最近，我们发现，通过修改氢氧化铝悬浮液的物理特性之一，可以显着增强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的潜力是一种新型的疫苗佐剂。但是，为了充分理解这种新颖的氢氧化铝辅助辅助物在未来的人类疫苗开发中的可行性，至关重要的需要进一步表征其辅助活动并评估其在动物模型中的安全性，并且本应用旨在满足这种关键需求。具体而言，我们将（i）特征由吸附在新型氢氧化铝辅助佐剂上的蛋白质抗原引起的免疫反应。在本研究中，炭疽芽孢杆菌保护性抗原蛋白将用作功能模型抗原，以表征特定的B细胞和T细胞反应。 （ii）阐明我们新型氢氧化铝辅助辅助辅助辅助活性的机制； （iii）评估含氢氧化铝辅助辅助的安全性/毒性。我们拟议的研究最具创新性的方面是增强传统氢氧化铝辅助剂的效力，并通过创新的物理修饰克服其局限性。我们从该项目中产生的预期结果是彻底表征吸附在含氢氧化铝辅助辅助的抗原引起的抗原引起的免疫反应，并在啮齿动物模型中初步评估其安全性。此外，我们希望理解为什么传统氢氧化铝的佐剂活性可以通过修改其物理特性之一来受到调节。总的来说，这些结果将为这种新型氢氧化铝辅助剂的未来开发提供一个合理的科学基础，使其成为一种安全，更有效的人类疫苗辅助剂，可用于开发新的疫苗以及重建现有的疫苗。