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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）：1至6个月婴儿的呼吸道和肠道感染每年导致全球200多万人死亡。这些感染中最突出的是流感病毒，三分之一的婴儿在出生后的第一年就受到感染。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