Role of innate immune responses in the activity of an Alphavirus based adjuvant.

先天免疫反应在甲病毒佐剂活性中的作用。

基本信息

批准号：
8197764
负责人：
ROBERT E. JOHNSTON
金额：
$ 56.69万
依托单位：
GLOBAL VACCINES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2014-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197764
关键词：
Address Adjuvant Affect Alphavirus Antibody Formation Antigen Targeting Antigens Attenuated Attenuated Live Virus Vaccine CD8B1 gene Cells Cellular Immunity Cholera Toxin Chronic Clinical Research Communicable Diseases Data Dendritic Cells Dendritic cell activation Development Disease Effectiveness Engineering Ensure Future Genes Genome HIV Human Immune Immune response Immune system Immunity Immunization Immunologic Receptors In Vitro Inactivated Vaccines Infection Influenza A Virus, H5N1 Subtype Injection of therapeutic agent Knowledge Laboratories Life Life Cycle Stages Light Link Macaca Malaria Malaria Vaccines Malignant Neoplasms Mediating Modeling Mouse Strains Mucosal Immune Responses Mucosal Immunity Mus Norovirus Oral Orphan Pathway interactions Poliomyelitis Production Proteins Publishing RNA Replicon Research Role Route Safety Signal Pathway Signal Transduction Site Solutions Source Structural Protein Subunit Vaccines T cell response T-Cell Activation T-Lymphocyte Testing Vaccination Vaccine Antigen Vaccine Design Vaccines Venezuelan Equine Encephalitis Virus Venezuelan Equine Encephalomyelitis Viral Virus Work base cytokine design improved in vitro Model in vivo influenza virus vaccine killings lymph nodes mucosal site nonhuman primate novel particle pathogen preclinical study public health relevance response seasonal influenza tool vaccine candidate vaccine development vector vaccine

项目摘要

DESCRIPTION (provided by applicant): Many diseases that were once widespread are now controlled or have been eradicated through the use of vaccines. However, there is an increasing need for new adjuvants to potentiate candidate vaccines against other important pathogens such as Malaria, HIV and TB. Such new adjuvants may help replace live attenuated vaccines with subunit or killed antigens, which are safer, easier to combine with other antigens, and have shorter development and implementation cycles. New adjuvant strategies exploit the activation of innate immune signals which results in a vigorous adaptive immune response to vaccine antigens. One novel adjuvant is Venezuelan equine encephalitis (VEE) replicon particles (VRP). These particles perform a single replication round with no further propagation and have proven safety as vaccine vectors in humans. Using non- mucosal routes of inoculation, VRP demonstrated strong mucosal and systemic adjuvant activity for important vaccine antigens such as H5N1 and Polio vaccines, Malaria soluble proteins and Norovirus VLPs. This adjuvant effect was observed in four different mouse strains as well as in non-human primates. In macaques the adjuvant amplified the response to an off-the-shelf vaccine for seasonal influenza by over twenty-fold and significantly increased protection from challenge. The robust induction of mucosal immunity by parenteral immunization is a novel and valuable feature of this adjuvant, and is superior to that achieved by cholera toxin, a model mucosal adjuvant. To date, development of strong mucosal immunity has required either antigen delivery into the mucosal site or use of live attenuated vaccines. Despite these promising data, the regulatory approval of vaccines containing VRP-adjuvant will require about a better understanding of its mechanism of action. Such mechanistic studies of the VRP-adjuvant effect will also benefit the field of viral immunity by improving our understanding of the role of dendritic cells (DCs) and innate immune signaling pathways in response to alphaviruses. In addition, these studies will benefit future vaccine design by identification of pathways that can be targeted in order to achieve stronger immunity after vaccination. Our published and preliminary data indicate that VRP infect specific subsets of dendritic cells (DCs), inducing the activation of an innate immune response. During the next four years we will focus our research to investigate how VRP infection of DCs and the activation of the innate immune response are linked to the adjuvant effect of VRP. We expect to shed light on how VRP-triggered innate immune responses by DCs help to establish an adaptive immune response against viruses and soluble antigens. An understanding of the VRP mechanism of action might also address safety concerns and improve the design of preclinical and clinical studies. Last but not least, VRP may be a valuable tool for augmentation of DC-activation during DC-transfer based therapies in vaccines against cancer and chronic infectious diseases. PUBLIC HEALTH RELEVANCE: Our proposal is aimed at understanding the mechanism of action of a novel potentiator of the immune system, a necessary step for his use approval. This potentiator could result in safer, more effective, and more easily-developed vaccines. We expect that our results will increase the knowledge of how our immune system responds to viruses and vaccines.

描述（由申请人提供）：许多曾经广泛传播的疾病现在已通过疫苗的使用得到控制或根除。然而，越来越需要新的佐剂来增强候选疫苗针对其他重要病原体（如疟疾、艾滋病毒和结核病）的能力。此类新佐剂可能有助于取代亚单位或灭活抗原的减毒活疫苗，这些疫苗更安全，更容易与其他抗原结合，并且开发和实施周期更短。新的佐剂策略利用先天免疫信号的激活，导致对疫苗抗原的强烈适应性免疫反应。一种新型佐剂是委内瑞拉马脑炎 (VEE) 复制子颗粒 (VRP)。这些颗粒进行单轮复制，不会进一步传播，并且已证明作为人类疫苗载体的安全性。使用非粘膜接种途径，VRP 对重要的疫苗抗原（例如 H5N1 和脊髓灰质炎疫苗、疟疾可溶性蛋白和诺如病毒 VLP）表现出强大的粘膜和全身佐剂活性。在四种不同的小鼠品系以及非人类灵长类动物中观察到了这种佐剂效应。在猕猴中，佐剂将现成的季节性流感疫苗的反应增强了二十倍以上，并显着增强了对攻击的保护。通过肠胃外免疫强烈诱导粘膜免疫是该佐剂的一个新颖且有价值的特征，并且优于霍乱毒素（一种粘膜佐剂模型）所实现的效果。迄今为止，强粘膜免疫的发展需要将抗原递送至粘膜部位或使用减毒活疫苗。尽管有这些令人鼓舞的数据，含有 VRP 佐剂的疫苗的监管批准仍需要更好地了解其作用机制。这种 VRP 佐剂效应的机制研究也将有利于病毒免疫领域，提高我们对树突状细胞 (DC) 和先天免疫信号通路对甲病毒反应的作用的理解。此外，这些研究将通过确定可靶向的途径来有利于未来的疫苗设计，以便在接种疫苗后获得更强的免疫力。我们发表的初步数据表明，VRP 感染特定的树突状细胞 (DC) 亚群，诱导先天免疫反应的激活。在接下来的四年中，我们将重点研究 DC 的 VRP 感染和先天免疫反应的激活与 VRP 的佐剂作用之间的关系。我们希望阐明 VRP 触发 DC 的先天免疫反应如何帮助建立针对病毒和可溶性抗原的适应性免疫反应。了解 VRP 的作用机制还可以解决安全问题并改进临床前和临床研究的设计。最后但并非最不重要的一点是，VRP可能是在针对癌症和慢性传染病的疫苗中基于DC转移的疗法期间增强DC激活的有价值的工具。公共卫生相关性：我们的建议旨在了解新型免疫系统增强剂的作用机制，这是其使用批准的必要步骤。这种增效剂可以带来更安全、更有效、更容易开发的疫苗。我们期望我们的结果将增加我们的免疫系统如何响应病毒和疫苗的知识。