A Study of Heterologous Immunity Induced by Neonatal BCG Vaccination

描述（由申请人提供）：传染病是全球新生儿和婴儿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，以及难以引起快速和保护性的疫苗反应，主要是由于不成熟的免疫系统。在了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重大知识差距。越来越多的人认识到，个体对一种病原体的免疫反应可以由先前接触不相关病原体的历史决定，这被称为异源免疫。异源免疫应答可能在新生儿生命和婴儿期早期可塑免疫系统的形成和成熟中发挥重要作用。卡介苗（Bacillus Calmette-Guerin， BCG）是一种减毒分枝杆菌活疫苗，通常在出生后两周内接种，是世界上使用最广泛的疫苗。除了提供临床保护以防止播散性结核病外，据报道卡介苗接种还可降低婴儿总体死亡率，并具有有益的异源免疫效果。这一探索性建议的具体目的是描述新生儿卡介苗接种是否改变了对随后不相关的婴儿疫苗的特异性免疫反应。提出的研究将开始描述新生儿卡介苗接种的异源免疫效应。将进行一项巢式病例对照研究，比较曾接种过新生儿卡介苗和未接种过新生儿卡介苗的婴儿对破伤风类毒素、口服脊髓灰质炎减毒活疫苗和乙肝疫苗首次（启动）剂量的t细胞和抗体反应。该研究将利用现有的外周血单个核细胞（PBMC）和血浆样本，这些样本是正在进行的一项关于婴幼儿登革热病毒感染的前瞻性临床研究的一部分。现有的血液样本来自未感染登革热病毒的婴儿，否则将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检测PBMC样品进行评估。血浆样品中的IgG抗体反应将通过ELISA测定。这项探索性研究的发现将支持开展一项更明确的研究，以描述新生儿和婴儿异体免疫的作用和潜在机制。这项建议是朝着更好地了解新生儿人体免疫学和开发新生儿和婴儿疫苗接种新方法迈出的第一步。扩大和改进在生命最初几个月诱导对传染病产生保护性免疫的能力，将对全球健康产生重大影响。

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.