A Study of Heterologous Immunity Induced by Neonatal BCG Vaccination

描述(申请人提供)：传染病是新生儿和婴儿全球发病率和死亡率的主要原因。在生命的第一年，对传染病的易感性增加，以及难以诱导快速和保护性的疫苗反应，这在很大程度上是由于免疫系统不成熟。在理解如何在出生后不久和整个婴儿期增强保护性免疫反应方面，存在着重大的知识空白。越来越多的人认识到，一个人对一种病原体的免疫反应可以通过先前接触无关病原体的历史来形成，这被称为异源免疫。异源免疫反应可能在新生儿和婴儿早期形成和成熟可塑性免疫系统方面发挥重要作用。卡介苗(BCG)是一种活的减毒分枝杆菌疫苗，通常在出生后两周内接种，是世界上使用最广泛的疫苗。据报道，卡介苗接种除了对传播形式的结核病提供临床保护外，还能降低婴儿总死亡率，并被认为具有有益的异种免疫效果。这一探索性建议的具体目的是描述新生儿接种卡介苗是否会改变对后续无关婴儿疫苗的特异性免疫反应。这项拟议的研究将开始描述新生儿接种卡介苗的异种免疫效应。将进行一项嵌套式病例对照研究，比较已接种和未接种卡介苗的婴儿对破伤风类毒素、口服减毒活脊髓灰质炎病毒和乙肝疫苗首剂(预接剂)的T细胞和抗体反应。这项研究将利用收集的现有外周血单个核细胞(PBMC)和血浆样本，作为正在进行的登革热病毒婴儿感染前瞻性临床研究的一部分。现有的血液样本来自没有感染登革热病毒的婴儿，否则不会用于登革热研究。疫苗抗原特异性T细胞功能和表型将通过最先进的流式细胞术在PBMC样本中进行评估。用酶联免疫吸附试验检测血浆标本中的免疫球蛋白抗体。这项探索性研究的发现将支持开展一项更明确的研究，以描述异种免疫对新生儿和婴儿的影响和潜在机制。这项建议是朝着更好地了解新生儿的人类免疫学和开发新的新生儿和婴儿疫苗接种方法迈出的第一步。扩大和提高在生命最初几个月诱导对传染病的保护性免疫的能力将对全球健康产生重大影响。 公共卫生相关性：传染病是世界各地新生儿和婴儿严重疾病和死亡的主要原因。由于免疫系统不成熟，新生儿和婴儿对传染病的易感性更高，对疫苗的反应也很差。更好地了解影响新生儿和婴儿免疫反应的因素可以导致新的疫苗接种战略和改善全球婴儿和儿童健康。

DESCRIPTION (provided by applicant): Infectious diseases are a major cause of global morbidity and mortality in neonates and infants. The heightened susceptibility to infectious diseases over the first year of life, and difficulties inducing rapid and protective vaccine responses, are largely due to an immature immune system. Significant gaps in knowledge exist in understanding how to enhance protective immune responses soon after birth and throughout infancy. There is growing recognition that an individual's immune response to one pathogen can be shaped by the prior exposure history to unrelated pathogens, and this has been termed heterologous immunity. Heterologous immune responses are likely to play a significant role in shaping and maturing the malleable immune system over neonatal life and early infancy. Bacillus Calmette-Guerin (BCG) is a live attenuated mycobacterial vaccine typically given within the first two weeks of life, and it is the most widely used vaccine in the world. In addition to providing clinical protection against disseminated forms of tuberculosis, BCG vaccination has also been reported to reduce overall infant mortality and suggested to have beneficial heterologous immune effects. The specific aim of this exploratory proposal is to delineate if neonatal BCG vaccination alters the specific immune responses to subsequent unrelated infant vaccines. The proposed study will begin to delineate heterologous immune effects of neonatal BCG vaccination. A nested case-control study will be conducted comparing T-cell and antibody responses to the first (priming) doses of tetanus toxoid, live attenuated oral polio virus, and hepatitis B vaccination in infants with prior neonatal BCG vaccination and those without neonatal BCG vaccination. The study will utilize existing peripheral blood mononuclear cells (PBMC) and plasma samples that have been collected as part of an ongoing prospective clinical study of dengue virus infections during infancy. The existing blood samples are from infants without dengue virus infections and would not otherwise be used in the dengue study. Vaccine antigen-specific T-cell functions and phenotypes will be assessed by state-of-the-art flow cytometry assays in the PBMC samples. IgG antibody responses will be measured by ELISA in the plasma samples. The findings in this exploratory study will support the development of a more definitive study to delineate the effects and underlying mechanisms of heterologous immunity in neonates and infants. This proposal is a first step towards a better understanding of human immunology in the newborn and developing new approaches to neonatal and infant vaccination. Expanding and improving the ability to induce protective immunity against infectious diseases in the first few months of life will have a significant impact on global health. PUBLIC HEALTH RELEVANCE: Infectious diseases are a major cause of severe illness and death in newborns and infants around the world. Newborns and infants have a heightened susceptibility to infectious diseases, and poor responses to vaccines, due to an immature immune system. A better understanding of the factors that shape neonatal and infant immune responses can lead to new vaccination strategies and improved global infant and child health.