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

• 批准号: 9753893
• 负责人: Lanying Du
• 金额: $ 55.55万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 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/9753893
• 关键词: Adjuvant; Adjuvant Study; Adjuvanticity; Adsorption; Adult; Aluminum; Animals; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Binding; CD8-Positive T-Lymphocytes; Cells; Cellular Assay; Chimeric Proteins; Communicable Diseases; 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; Injections; 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 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; pathogenic virus; public health relevance; receptor; receptor binding; response; synergism; trivalent influenza vaccine; vaccine candidate; vaccine efficacy; vaccine safety

 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（由申请人提供）：世界范围内致命传染病的反复爆发加剧了开发新的和改进的疫苗来对抗其传播的紧迫性。不幸的是，许多现有的或正在开发的疫苗会诱导次优的免疫反应，并且需要大的抗原。众所周知，佐剂组合可以提高疫苗的功效和安全性，促进剂量节约，并可能有助于更快速、更持久的免疫保护。然而，迄今为止的研究主要集中在单个佐剂上；目前需要更深入地了解组合佐剂产生作用的机制。明矾）因其强大而持久的免疫刺激作用和长期的安全记录而最受欢迎；但这些佐剂主要促进 Th2 偏向的体液免疫反应，而不是。针对细胞内病原体的疫苗所需的强Th1和/或CD8+细胞介导的免疫反应为了满足这一需求，我们建议测试一种新的佐剂组合——新型蛋白佐剂(ASP-1)和传统佐剂明矾——并进行研究。当与中东呼吸综合征 (MERS) 冠状病毒 (MERS-CoV) 的刺突 (S) 蛋白中的受体结合域 (RBD) 配制时，它诱导其作用的机制，中东呼吸综合征 (MERS) 冠状病毒是一种具有高死亡率的病原体病毒抗体 ASP-1 佐剂是一种天然存在的盘尾丝虫分泌蛋白，对先天细胞具有内在的免疫刺激特性，可以促进对几种可溶性疫苗候选抗原的平衡反应和 Th1 偏向细胞反应，如以及商业灭活病毒疫苗与商业三价流感疫苗联合使用时，还可促进剂量节省，并在针对同源或异源流感进行一次免疫后为年轻和年老的成年小鼠提供保护。同样重要的是，疫苗接种过程中产生的抗体不会限制其在任何测试环境中的效用或佐剂性，我们将研究 ASP-1 和明矾之间的物理关联对其佐剂性的影响（此处明矾的吸附可能至关重要）。 ）通过比较与 MERS-RBD 配制时的体内免疫原性，在确定最有效的 ASP-1/明矾/RBD 制剂后，我们将确定这种新型佐剂组合的作用机制。体外和体内，以确定它们在注射部位和引流淋巴结中刺激的各种先天性和适应性细胞类型、趋化因子和细胞因子之间的精确相互作用，这些细胞因子负责增强 ASP-1 和明矾引起的增强免疫原性展望未来，我们希望开发出一种可安全用于人类的高效佐剂组合，能够用最少量的疫苗免疫原增强针对各种病原体的独特免疫反应。