Vaccination strategies to overcome immune deficiencies in neonates

描述(由申请人提供)：1至6个月婴儿的呼吸道和肠道感染每年在全球造成200多万人死亡。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第一年感染。虽然疫苗的广泛使用一直是医学界最成功的故事之一，但绝大多数疫苗，包括流感疫苗，都没有获得许可。 对于6个月大的儿童来说，可以说是死亡率和发病率的关键窗口。我们建议的研究的目标是确定能够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会导致严重的发病率和死亡率，我们选择灭活流感病毒作为我们的疫苗接种目标。优化流感病毒疫苗接种策略的指导假设是，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TH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)对激活刺激进行适当成熟的能力降低是新生儿疫苗效力的主要障碍。因此，促进TLR信号的策略是加强疫苗接种的合理途径。TLR信号是DC成熟的主要调节因素。由于TLR也表达在其他类型的细胞上，包括T和B细胞，TLR与淋巴细胞的直接结合为TLR介导的免疫反应的放大提供了另一条途径。这种应用的一个重要方面是使用非人类灵长类动物，这是至关重要的，因为TLR在灵长类动物和小鼠中的分布和功能不同。据我们所知，我们提议的研究将是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。使用这个模型进行的机理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。目的：1.目的：探讨R848和鞭毛蛋白对新生儿体液和细胞免疫应答的调节作用。无论有无鞭毛蛋白、R848或鞭毛蛋白R848，新生儿或成人AGM将接种灭活流感病毒疫苗。加强免疫后，动物将面临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，病毒特异性T和B细胞反应将在挑战后第14天进行评估。目的2.检测鞭毛蛋白和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。在第二个目标中，我们建议进行研究，以确定TLR激动剂对获得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，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。

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.