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: 8319130
• 负责人: Martha Ann Alexander-Miller
• 金额: $ 62.33万
• 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/8319130
• 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. PUBLIC HEALTH RELEVANCE: Although infants represent a highly susceptible group for serious influenza infections, successful vaccination in this population remains an unrealized goal. These studies utilize TLR ligands as an approach to generate protective immune responses in neonates. Given the high degree of similarity in the function and distribution of TLR in non-human primates, this model will be used for these mechanistic analyses.

描述（由申请人提供）：每年在全球范围内1至6个月的婴儿的呼吸道和肠道感染占200万人的死亡。 这些感染中的突出是流感病毒，其中三分之一的婴儿在生命的第一年感染。 虽然广泛使用疫苗是医学中最大的成功案例之一，但包括流感的疫苗，包括疫苗，包括疫苗，未获得许可 对于<6个月大的儿童，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的是确定可以促进新生儿中有效和安全适应性免疫反应的佐剂。 鉴于人类新生儿感染了流感的显着发病率和死亡率，我们选择了将流感病毒灭活为我们的疫苗接种靶标。 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，灭活的流感病毒疫苗未能提供最佳/适当的树突状细胞成熟所需的TH信号，因此，未能促进有效的自适应免疫反应。 新生儿树突状细胞（DC）响应激活刺激的适当成熟的能力降低是新生儿疫苗疗效的主要障碍。因此，促进TLR信号传导的策略是DC成熟的主要调节剂，是增强疫苗接种的合理方法。 由于TLR在包括T和B细胞在内的其他细胞类型上也表达，TLR在淋巴细胞上的直接参与为TLR介导的免疫反应扩增提供了额外的途径。该应用的一个重要方面是使用非人类灵长类动物，鉴于灵长类动物与小鼠的TLR分布和功能的差异至关重要。 据我们所知，我们提出的研究将是开发婴儿非人类灵长类动物以在优化流感疫苗中使用的第一个。 可以使用该模型进行的机械研究几乎可以肯定会提供新颖而重要的见解，这些见解无法使用啮齿动物模型获得。 AIM1。确定R848和鞭毛蛋白调节新生儿中的体液和细胞介导的疫苗反应的能力。 在存在或不存在鞭毛蛋白，R848或鞭毛蛋白+R848的情况下，新生儿或成人年度股东大会将接种灭活的流感病毒。 提升后，动物将受到流感病毒和病毒的挑战 负担和疾病将在14天内进行评估。 此外，将在D14挑战后评估病毒特异性T和B细胞反应。 目标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细胞的激活的能力。在目标两个方面，我们建议研究确定TLR激动剂对适应性免疫反应的辅助作用的机理基础。 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。 公共卫生相关性：尽管婴儿代表着一个高度易感的严重流感感染群体，但该人群中的成功疫苗仍然是一个未实现的目标。这些研究利用TLR配体作为在新生儿产生保护性免疫反应的方法。 鉴于非人类灵长类动物中TLR功能和分布的高度相似性，该模型将用于这些机械分析。