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。

• 批准号: 8391269
• 负责人: ROBERT E. JOHNSTON
• 金额: $ 53.29万
• 依托单位: GLOBAL VACCINES, INC.
• 依托单位国家: 美国
• 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/8391269
• 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

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.

描述（由申请人提供）：许多曾经被广泛普及的疾病通过使用疫苗而被控制或已消除。但是，新佐剂越来越需要增强候选疫苗与其他重要病原体（如疟疾，艾滋病毒和结核病）。这种新的佐剂可能有助于用亚基或杀死的抗原替代活衰减的疫苗，这些抗原更安全，更易于与其他抗原结合，并且具有较短的发育和实施周期。新的辅助策略利用了先天免疫信号的激活，从而导致对疫苗抗原的适应性免疫反应。委内瑞拉马脑炎（VEE）复制子颗粒（VRP）是一个新颖的佐剂。这些颗粒执行单个复制弹，没有进一步的繁殖，并且已被证明是人类疫苗向量的安全性。使用非粘膜接种途径，VRP表现出重要的粘膜和全身辅助活性，例如H5N1和脊髓灰质炎疫苗，疟疾可溶性蛋白和诺如病毒VLPS。在四种不同的小鼠菌株以及非人类灵长类动物中观察到这种辅助作用。在猕猴中，佐剂放大了对季节性流感现成的疫苗的反应，二十倍以上，并显着增加了免受挑战的保护。通过肠胃外免疫对粘膜免疫的稳健诱导是该辅助药的一种新颖而有价值的特征，并且优于霍乱毒素（一种模型粘膜佐剂）所获得的粘膜免疫。迄今为止，强烈的粘膜免疫的发展需要抗原递送到粘膜部位或使用活衰减的疫苗。尽管这些有希望的数据，但对含有VRP-Adjuvant的疫苗的监管批准将需要更好地理解其作用机理。对VRP-辅助效应的这种机械研究也将通过提高我们对树突状细胞（DCS）和先天免疫信号通路对α病毒的作用的理解，从而使病毒免疫力领域受益。此外，这些研究将通过鉴定可以针对的途径来使未来的疫苗设计受益，以便在疫苗接种后获得更强的免疫力。我们发表的和初步的数据表明，VRP感染了树突状细胞（DCS）的特定子集，从而诱导了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如何与VRP的辅助作用有关。我们期望阐明DCS的VRP先天免疫反应如何有助于建立针对病毒和可溶性抗原的适应性免疫反应。对VRP作用机制的理解也可能解决安全问题并改善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基于DC转移疗法期间增强DC激活的宝贵工具。