Enhancing potency of the MERS vaccine by a novel ASP-1+alum adjuvant combination

通过新型 ASP-1 明矾佐剂组合增强 MERS 疫苗的效力

基本信息

批准号：
9322299
负责人：
SHIBO JIANG
金额：
$ 78.45万
依托单位：
NEW YORK BLOOD CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9322299
关键词：
Adjuvant Adjuvant Study Adjuvanticity Adsorption Adult Aluminum Animals Antibodies Antibody Response Antigens B-Lymphocytes Binding Biological Assay CD8-Positive T-Lymphocytes Cells Chimeric Proteins Communicable Diseases Coronaviridae Coronavirus Coronavirus spike protein Dendritic Cells Dendritic cell activation Development Disease Outbreaks Dose Effectiveness Elderly Emerging Communicable Diseases Ensure Environment Formulation Genes Genetic Transcription Human Immune Immune response Immunization In Vitro Individual Inflammasome Injection of therapeutic agent Intestinal Volvulus Middle East Respiratory Syndrome Coronavirus Modeling Mus Nematoda Onchocerca volvulus Pathway interactions Periodicity Peripheral Blood Mononuclear Cell Population Property Proteins Recurrence Regimen Role Safety Site Subunit Vaccines T-Lymphocyte TLR2 gene TLR4 gene Testing Time Vaccination Vaccine Antigen Vaccines Viral Viral Vaccines aged aluminum sulfate aqueous base cell mediated immune response cell type chemokine combat cost cytokine immunogenicity improved in vivo influenzavirus lymph nodes mortality neutralizing antibody next generation nonhuman primate novel pandemic disease pathogen public health relevance receptor receptor binding response synergism trivalent influenza vaccine vaccine candidate vaccine efficacy vaccine safety

项目摘要

DESCRIPTION (provided by applicant): The recurrent outbreak of deadly infectious diseases worldwide heightens the urgency to develop new and improved vaccines to combat their spread. Unfortunately, many of the current vaccines, or those in development, induce suboptimal immune responses and require large antigen doses, multiple immunizations, or periodic boosting to provide long-term protection. It is known that adjuvant combinations can increase the efficacy and safety of vaccines, promote dose sparing, and, possibly, contribute to more rapid and durable immune protection against pathogensin particular those that target multiple receptors and pathways. Studies to date, however, have focused on individual adjuvants; needed now is a deeper understanding of the mechanisms by which combination adjuvants produce their effects. At this time, aluminum-containing adjuvants (alum) are the most popular because of their strong and long-lasting immunostimulatory effects and long-standing safety record; they are also low-cost. But these adjuvants promote primarily Th2-biased humoral immune responses, not the strong Th1 and/or CD8+ cell-mediated immune responses needed for vaccines targeting intracellular pathogens. To meet this need, we propose to test a new adjuvant combinationa novel protein adjuvant (ASP-1) and the traditional adjuvant alumand study the mechanisms by which it induces its effects when formulated with the receptor-binding domain (RBD) in the spike (S) protein of Middle East respiratory syndrome (MERS) coronavirus (MERS-CoV), a viral pathogen with a high mortality rate and high pandemic potential. The ASP-1 adjuvant, a naturally occurring secreted protein of Onchocerca volvulus shown to have intrinsic immunostimulatory properties on innate cells, can promote a balanced antibody response and Th1-biased cellular responses to several soluble vaccine candidate antigens, as well as commercial inactivated viral vaccines. It also promotes dose sparing when combined with a commercial trivalent influenza vaccine, and confers protection in young and aged adult mice after one immunization against homologous or heterologous influenza virus challenge. As important, antibodies produced to it during vaccinations do not limit its utility or adjuvanticity n any setting tested. We will study the effect of the physical association between ASP- 1 and alum on their adjuvanticity (adsorption to alum is possibly essential here) by comparing the immunogenicity in vivo when formulated with MERS-RBD. Upon identification of the most effective ASP- 1/alum/RBD formulation, we will determine the mechanism of action of this novel adjuvant combination, both in vitro and in vivo, to determine the precise interactions among the various innate and adaptive cell types, chemokines, and cytokines that they stimulate in the injection site and in the draining lymph nodes responsible for potentiating the enhanced immunogenicity elicited by the ASP-1 and alum-adjuvanted MERS-RBD vaccine. Looking forward, we hope to develop a highly effective adjuvant combination safe for use in humans, one that will boost distinctive immune responses against various pathogens with a minimal amount of the vaccine immunogen.

描述（由适用提供）：全世界致命感染疾病的反复爆发增强了开发新的和改进的疫苗以应对其传播的紧迫性。不幸的是，许多当前的疫苗或正在开发的疫苗会诱导次优免疫调查，需要大型抗原剂量，多种免疫抑制或定期提升以提供长期保护。众所周知，调整组合可以提高疫苗的效率和安全性，促进剂量保留，并可能有助于对病原体的更快，耐用的免疫保护，尤其是针对多个接收器和途径的病原体。然而，迄今为止的研究集中在单个调节器上。现在需要的是对结合调节器产生其效果的机制的更深入的理解。目前，含铝的调节器（明矾）是最受欢迎的，因为它们具有强烈而持久的免疫刺激效果和长期的安全记录。它们也是低成本。但是这些调节器促进了原发性Th2偏置的体液免疫调查，而不是针对靶向细胞内病原体所需的疫苗所需的强大TH1和/或CD8+细胞介导的免疫剂。为了满足这一需求，我们建议测试一种新的佐剂组合一种新型蛋白质佐剂（ASP-1）和传统的辅助校友，并研究与中东呼吸综合征（Mers-Mers）的尖峰（S）蛋白质（S）蛋白质（S）coronavirus（Mers-Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）（Mers-cog）诱导其效果的机制（Mers-cog）大流行可能性。 ASP-1可调节，一种天然存在的OnChocerca volvulus的分泌蛋白，可在先天细胞上具有内在的免疫刺激性，可以促进对几种固体疫苗候选物的平衡抗体反应和Th1偏置细胞反应，以及商业失活的病毒疫苗。当一种免疫抑制后，与商业三价影响疫苗结合使用时，它还可以促进剂量的稀疏性，并在对同源或异源影响病毒挑战后进行保护。同样重要的是，在疫苗期间产生的抗体不会限制其效用或可调性。我们将通过比较与MERS-RBD配方时比较体内的免疫原性，研究ASP-1和明矾之间的物理关联对它们的辅助物的影响（在这里吸附是必不可少的）。通过鉴定出最有效的ASP-1/校友/RBD公式，我们将确定这种新型可调节组合的作用机理，无论是体外和体内的，都可以确定各种先天和适应性细胞类型，趋化因子，趋化因子和细胞因子的精确相互作用，从而在淋巴结中刺激淋巴结效果，以增强淋巴结效果，以增强淋巴结的可能性，从而增强淋巴结的可能性，并在淋巴结中提高淋巴结的可能性。校友的MERS-RBD疫苗。展望未来，我们希望开发一种安全用于人类的高效辅助组合，这种辅助组合将增强对各种病原体的独特免疫原子反应，并以最少的疫苗免疫原反应。