Role of maternal and infant vaccine-induced IgG in protection against pertussis

 描述（由申请人提供）：B。百日咳会导致幼儿患上严重的呼吸道疾病（百日咳），死亡率很高。无细胞百日咳疫苗作为白喉-破伤风疫苗（DTaP）的组成部分，已成为常规儿科免疫接种计划的一部分，已有二十多年。尽管进行了广泛的疫苗接种，但百日咳病例继续出现，大多数发生在未完成初级疫苗接种系列的3个月以下婴儿中。这种发病率增加的原因之一是无细胞百日咳疫苗未能提供强大的长期保护性免疫。在提高人群抗体水平的基础上，建议对母亲和其他家庭成员进行免疫接种，以减少幼儿接触。婴儿和妊娠期间对无细胞百日咳疫苗的免疫应答尚不完全清楚，保护的确切相关性仍有待建立。更好地了解预防B所需的保护性免疫。百日咳感染需要寻求更有效的疫苗。伊加通常被认为是对粘膜病原体的保护所必需的，但是在儿童中用DTaP和成人中用Tdap进行胃肠外接种后产生强烈的全身IgG应答;在动物模型中观察到相同的趋势。在本申请中，我们建议研究疫苗诱导的IgG在抗B保护中的作用。百日咳的背景下，孕产妇和婴儿免疫接种和机制，特别是抗B的抗菌能力。百日咳IgG和涉及通过粘膜易位并进入气道的过程。我们将检验以下假设：母体和婴儿疫苗诱导的IgG通过新生儿Fc受体（FcRn）通过呼吸道粘膜主动转运，发挥功能性抗菌特性并介导对B的保护作用。百日咳感染在具体目标1中，我们将检查通过母体接种诱导并通过胎盘和/或乳汁转移至后代的百日咳特异性IgG在预防百日咳感染中的作用，并检查FcRn参与乳汁IgG从肠腔转运至循环以及循环IgG穿过呼吸道上皮进入气道以预防感染。在具体目标2中，我们将研究DTaP免疫婴儿产生的IgG在预防百日咳中的作用、其功能能力和FcRn介导的呼吸道易位。这项工作有可能确定一种机制，可以解释IgG如何保护对B。百日咳感染

 DESCRIPTION (provided by applicant): B. pertussis causes a severe respiratory disease (whooping cough) in young infants associated with high mortality rates. The acellular pertussis vaccine has been part of the routine pediatric immunization schedule as a component of the Diphtheria-Tetanus vaccine (DTaP) for over two decades. Despite extensive vaccination, pertussis cases continue to emerge, the majority in infants <3 months of age who have not completed the primary vaccination series. One of the proposed reasons for this increased incidence has been the failure of the acellular pertussis vaccine to provide robust long-lasting protective immunity. On the basis of raising antibody levels in the population, immunization of mothers and other household members has been recommended to reduce exposure to young infants. The immune responses to the acellular pertussis vaccine elicited in infants and during pregnancy are not thoroughly known and firm correlates of protection remain to be established. A better understanding of protective immunity necessary to prevent B. pertussis infection is required to seek out more effective vaccines. IgA is commonly viewed as essential for protection against mucosal pathogens, but strong systemic IgG responses are generated following parenteral vaccination with DTaP in children and Tdap in adults; the same trend is seen in animal models. In this application we propose to study the role of vaccine-induced IgG in protection against B. pertussis in the context of both maternal and infant immunization and the mechanisms involved, specifically the antimicrobial capacity of anti-B. pertussis IgG and the processes involved in translocation through the mucosa and into the airways. We will test the hypothesis that maternal and infant vaccine-induced IgG actively transported through the respiratory mucosa via the neonatal Fc receptor (FcRn) deploys functional antimicrobial properties and mediates protection against B. pertussis infection. In Specific Aim 1, we will examine the contribution of pertussis-specific IgG induced through maternal vaccination and transferred to offspring via placenta and/or milk in protection against pertussis infection and examine the involvement of the FcRn in the transport of milk IgG from the intestinal lumen into circulation and of circulating IgG across epithelium in the respiratory tract and into the airways for protection against infection. In Specific Aim 2, we will examine the contribution of IgG produced in infants immunized with DTaP in protection against pertussis, their functional capacity and FcRn-mediated translocation to the respiratory airways. This work has the potential to identify a mechanism that can explain how IgG protects against B. pertussis infection.