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

基本信息

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
项目类别：
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

项目摘要

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）：两个多世纪以来，疫苗一直是人类对抗传染病的一部分。疫苗或抗原通常需要佐剂来诱导强烈的免疫反应，这使其成为疫苗的重要组成部分。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，含铝佐剂是美国唯一批准用于人类使用的疫苗佐剂。甚至AS04也含有氢氧化铝。尽管铝盐已被证明具有良好的安全性，但它只能弱或中度增强抗原特异性抗体反应，并且通常被认为不能增强细胞免疫反应。因此，仍然需要寻找安全且更有效的疫苗佐剂。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，通过改变氢氧化铝悬浮液的物理性质之一，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，为了充分了解这种新型含氢氧化铝佐剂在未来人类疫苗开发中的可行性，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问题关键需求。具体来说，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反应。本研究将使用炭疽芽孢杆菌保护性抗原蛋白作为功能模型抗原来表征所诱导的特异性 B 细胞和 T 细胞反应； (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； (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增强传统氢氧化铝佐剂的效力，并通过创新的物理改性克服其局限性。我们该项目的预期结果是彻底表征吸附在我们的新型含氢氧化铝佐剂上的抗原诱导的免疫反应，并初步评估其在啮齿动物模型中的安全性。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物理性质之一来有利地调节。总的来说，这些结果将为这种新型含氢氧化铝佐剂未来开发成安全且更有效的人类疫苗佐剂提供坚实的科学基础，该佐剂可用于开发新疫苗以及重新配制现有疫苗。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nasal aluminum (oxy)hydroxide enables adsorbed antigens to induce specific systemic and mucosal immune responses.

鼻用（羟基）氢氧化铝能够使吸附的抗原诱导特异性的全身和粘膜免疫反应。

DOI：
发表时间：
2017-11-02
期刊：
影响因子：
4.8
作者：
Xu, Haiyue;Ruwona, Tinashe B;Thakkar, Sachin G;Chen, Yanping;Zeng, Mingtao;Cui, Zhengrong
通讯作者：
Cui, Zhengrong

The immunogenicity of thin-film freeze-dried, aluminum salt-adjuvanted vaccine when exposed to different temperatures.

薄膜冻干铝盐佐剂疫苗在不同温度下的免疫原性。

DOI：
发表时间：
2017-04-03
期刊：
影响因子：
4.8
作者：
Thakkar, Sachin G;Ruwona, Tinashe B;Williams 3rd, Robert O;Cui, Zhengrong
通讯作者：
Cui, Zhengrong

Intranasal immunization with aluminum salt-adjuvanted dry powder vaccine.

铝盐佐剂干粉疫苗鼻内免疫。

DOI：
发表时间：
2018-12-28
期刊：
影响因子：
0
作者：
Thakkar, Sachin G;Warnken, Zachary N;Alzhrani, Riyad F;Valdes, Solange A;Aldayel, Abdulaziz M;Xu, Haiyue;Williams 3rd, Robert O;Cui, Zhengrong
通讯作者：
Cui, Zhengrong

A method of lyophilizing vaccines containing aluminum salts into a dry powder without causing particle aggregation or decreasing the immunogenicity following reconstitution.

一种将含有铝盐的疫苗冻干成干粉的方法，在重构后不会引起颗粒聚集或降低免疫原性。