Vaccination strategies to overcome immune deficiencies in neonates

克服新生儿免疫缺陷的疫苗接种策略

• 批准号: 8668895
• 负责人: Martha Ann Alexander-Miller
• 金额: $ 58.49万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-15 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8668895
• 关键词: Accounting; Adjuvant; Adult; Age-Months; Agonist; Animals; Antigens; B-Cell Activation; B-Lymphocytes; Cell Maturation; Cells; Cessation of life; Child; Data; Dendritic Cells; Development; Employee Strikes; Exhibits; Flagellin; Goals; Hepatitis B Virus; Human; Immune; Immune response; Immune system; Immunization; Infant; Infection; Influenza; Intestines; Licensing; Life; Ligands; Lymphocyte; Mediating; Medicine; Modeling; Morbidity - disease rate; Mus; Neonatal; Outcome; Population; Primates; Process; Regulation; Relative (related person); Rodent Model; Signal Transduction; Stimulus; T-Lymphocyte; TLR5 gene; TLR7 gene; TLR8 gene; Testing; Translations; Vaccinated; Vaccination; Vaccines; Viral Load result; Virus; Virus Diseases; arm; base; cell type; influenza virus vaccine; influenzavirus; insight; mortality; neonate; nonhuman primate; novel; respiratory; response; success; vaccination strategy; vaccine efficacy

DESCRIPTION (provided by applicant): Respiratory and intestinal infections of infants between 1 and 6 months of life account for greater than 2 million deaths annually worldwide. Prominent among these infections is influenza virus, with one third of all infants infected in the first year of life. While wide-spread use of vaccines has been one of the greatest success stories in medicine, the vast majority of vaccines, including those for influenza, are not licensed for children <6 months of age, arguably a critical window for mortality and morbidity. The goal of our proposed studies is to identify adjuvants that can promote effective and safe adaptive immune responses in neonates. Given the significant morbidity and mortality that results from infection of human neonates with influenza, we have chosen inactivated influenza virus as our vaccination target. The guiding hypothesis for the optimization strategy for vaccination against influenza virus is that in the neonate, the inactivated influenza virus vaccine fails to provide th signals necessary for optimal/appropriate dendritic cell maturation and, as a result, fails to promote an effective adaptive immune response. The reduced ability of neonatal dendritic cells (DC) to undergo appropriate maturation in response to activating stimuli represents a major hurdle in vaccine efficacy in the neonate. Strategies that promote TLR signaling, a major regulator of DC maturation, is thus a rational approach to enhance vaccination. As TLR are also expressed on other cell types, including T and B cells, direct engagement of TLR on lymphocytes provides an additional avenue for TLR mediated amplification of the immune response. An important aspect of this application is the use of nonhuman primates, which is vital given the differences in distribution and function in TLR in primates versus mice. To our knowledge, our proposed study would be the first of its kind to develop the infant nonhuman primate for use in the optimization of influenza vaccines. The mechanistic studies that can be carried out using this model will almost certainly provide novel and important insights that cannot be gained using rodent models. Aim1. To determine the ability of R848 and flagellin to modulate the humoral and cell mediated vaccine responses in neonates. Neonatal or adult AGM will be vaccinated with inactivated influenza virus in the presence or absence of flagellin, R848, or flagellin+R848. After boosting, animals will be challenged with influenza virus and viral burden and disease will be assessed over a 14 day period. In addition, virus-specific T and B cell responses will be assessed at d14 post challenge. Aim 2. To determine the ability of flagellin and R848 to directly promote activation of neonate dendritic cells, T cells, and B cells. In aim two we propose studies to determine the mechanistic basis of the adjuvant effect of the TLR agonists on the adaptive immune response. Since it is also possible that flagellin and R848 will have direct effects on lymphocytes, we will determine the ability of the TLR agonists to impact neonatal T and B cell activation/function.

描述（由申请方提供）：全世界每年有超过200万例1至6个月婴儿的呼吸道和肠道感染导致死亡。 这些感染中最突出的是流感病毒，所有婴儿中有三分之一在出生后一年内感染。 虽然疫苗的广泛使用是医学上最成功的故事之一，但绝大多数疫苗，包括流感疫苗，都没有获得许可。 对于6个月以下的儿童来说，可以说是死亡率和发病率的一个关键窗口。我们提出的研究的目标是确定佐剂，可以促进有效和安全的适应性免疫反应的新生儿。 考虑到新生儿感染流感导致的显著发病率和死亡率，我们选择灭活流感病毒作为疫苗接种靶点。 针对流感病毒疫苗接种的优化策略的指导假设是，在新生儿中，灭活流感病毒疫苗不能提供最佳/适当树突状细胞成熟所需的信号，因此，不能促进有效的适应性免疫应答。 新生儿树突状细胞（DC）响应于活化刺激而经历适当成熟的能力降低代表了新生儿中疫苗功效的主要障碍。因此，促进TLR信号传导（DC成熟的主要调节因子）的策略是增强疫苗接种的合理方法。 由于TLR也在其他细胞类型（包括T和B细胞）上表达，TLR在淋巴细胞上的直接接合为TLR介导的免疫应答扩增提供了另外的途径。本申请的一个重要方面是使用非人灵长类动物，鉴于灵长类动物与小鼠中TLR的分布和功能差异，这是至关重要的。 据我们所知，我们提出的研究将是第一个开发婴儿非人灵长类动物用于流感疫苗优化的研究。 可以使用该模型进行的机制研究几乎肯定会提供使用啮齿动物模型无法获得的新的和重要的见解。目标1.确定R848和鞭毛蛋白调节新生儿体液和细胞介导的疫苗应答的能力。 新生儿或成人AGM将在存在或不存在鞭毛蛋白、R848或鞭毛蛋白+R848的情况下接种灭活流感病毒。 在加强免疫后，将用流感病毒和病毒性流感病毒攻击动物。 将在14天内评估负荷和疾病。 此外，将在攻毒后第14天评估病毒特异性T和B细胞应答。 目标二。确定鞭毛蛋白和R848直接促进新生儿树突状细胞、T细胞和B细胞活化的能力。在目标二中，我们提出研究以确定TLR激动剂对适应性免疫应答的佐剂作用的机制基础。 由于鞭毛蛋白和R848也可能对淋巴细胞有直接作用，我们将确定TLR激动剂影响新生儿T和B细胞活化/功能的能力。