Vaccination strategies to overcome immune deficiencies in neonates

克服新生儿免疫缺陷的疫苗接种策略

基本信息

批准号：
8840143
负责人：
Martha Ann Alexander-Miller
金额：
$ 57.36万
依托单位：
WAKE FOREST UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-15 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8840143
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 adaptive immunity arm base cell type influenza virus vaccine influenzavirus insight mortality neonate nonhuman primate novel respiratory response success vaccination strategy vaccine efficacy vaccine response

项目摘要

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（由申请人提供）：全世界每年有超过 200 万人死于 1 至 6 个月婴儿的呼吸道和肠道感染。这些感染中最突出的是流感病毒，三分之一的婴儿在一岁内受到感染。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，可以说是死亡率和发病率的关键窗口。我们提出的研究的目标是确定可以促进新生儿有效和安全的适应性免疫反应的佐剂。鉴于人类新生儿感染流感导致的显着发病率和死亡率，我们选择灭活流感病毒作为疫苗接种目标。流感病毒疫苗接种优化策略的指导性假设是，在新生儿中，灭活流感病毒疫苗无法提供最佳/适当的树突状细胞成熟所需的信号，因此无法促进有效的适应性免疫反应。新生儿树突状细胞（DC）响应激活刺激而适当成熟的能力降低，这是新生儿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）的策略是加强疫苗接种的合理方法。由于 TLR 也在其他细胞类型上表达，包括 T 细胞和 B 细胞，因此 TLR 与淋巴细胞的直接结合为 TLR 介导的免疫反应放大提供了另一途径。该应用的一个重要方面是使用非人类灵长类动物，考虑到灵长类动物与小鼠的 TLR 分布和功能差异，这一点至关重要。据我们所知，我们提出的研究将是同类中第一个开发婴儿非人类灵长类动物用于优化流感疫苗的研究。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颖且重要的见解。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反应的能力。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。加强免疫后，动物将受到流感病毒和病毒的攻击负担和疾病将在 14 天的时间内进行评估。此外，将在攻击后第 14 天评估病毒特异性 T 和 B 细胞反应。目的 2. 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反应的佐剂作用的机制基础。由于鞭毛蛋白和 R848 也可能对淋巴细胞产生直接影响，因此我们将确定 TLR 激动剂影响新生儿 T 和 B 细胞激活/功能的能力。