Overcoming maternal antibody-mediated immunosuppression

描述（由申请人提供）：母源性抗体对于在婴儿出生后的头几个月内保护婴儿至关重要。这在无丙种球蛋白血症的婴儿中得到了最好的例证，他们在生命的第一年茁壮成长，但在循环的母体抗体水平下降后死于反复感染。然而，母体抗体有一个缺点：它们抑制了疫苗诱导的婴儿免疫系统的激活。正因为如此，许多必要的和挽救生命的疫苗，如麻疹，都是在出生后一年内推迟接种的。这就留下了一个很宽的时间窗口，在此期间，婴儿容易受到感染，但无法发展必要的抗体反应，以保护自己。了解如何在母体抗体存在的情况下激活婴儿免疫系统是一个关键的研究领域，因为它可能导致更有效的婴儿疫苗的开发。我们推断母体抗体介导的抑制可能部分是由于用于接种的抗原的形式。我们的初步数据表明，用可溶性而非颗粒性抗原免疫可导致婴儿的显著活化。 免疫系统基于此，我们的中心假设是，母体抗体介导的新生儿免疫系统的免疫抑制可以被克服，并且可以通过用可溶性抗原而不是颗粒抗原免疫新生儿来产生强大的长期保护性免疫。我们将通过追求三个具体目标来检验我们的中心假设。在目标1中，我们将充分表征在母体抗体存在下由可溶性抗原诱导的婴儿免疫应答。在目标2中，我们将使用H1N1、H3 N2和H5 N1流感病毒攻击模型来探测这种保护性免疫的程度。最后，在目标3中，我们将确定在非人灵长类动物恒河猴婴儿中可以克服母体抗体介导的抑制的程度。拟议的工作是重要的，因为从这些研究中获得的知识将使我们能够开发克服母体抗体抑制的疫苗，并可用于成功地为婴儿接种疫苗。 公共卫生相关性：母体抗体在怀孕期间通过胎盘和出生后通过母乳转移到婴儿身上，对于保护出生后最初几个月的婴儿至关重要。但这也有不利的一面;母体抗体抑制了婴儿对疫苗的免疫反应。我们有初步的数据表明，母体抑制是可以克服的，这项拨款提案的目的是了解这种救赎在小鼠和非人类灵长类动物婴儿中的程度和机制。

DESCRIPTION (provided by applicant): Maternally derived antibodies are crucial for protecting infants during their first months of life. This is best exemplified in infants with agammaglobulinemia, who thrive during the first year of life but succumb to repeated infections after the levels of circulating maternal antibodies wane. There is however, one downside to maternal antibodies; they suppress vaccine-induced activation of the infant immune system. Because of this, many necessary and life-saving vaccines such as measles are given at delayed times, up to a year after birth. This leaves a wide window of time during which the infant is vulnerable to infection but unable to develop the antibody response necessary for its own protection. Understanding how to activate the infant immune system in the presence of maternal antibodies is a critical area of research because it could lead to the development of more efficacious infant vaccines. We reasoned that maternal antibody-mediated suppression could in part be due to the form of the antigen used for vaccination. Our preliminary data show that immunization with soluble but not particulate antigens lead to significant activation of the infant immune system. Based upon this, our central hypothesis is that maternal antibody mediated immunosuppression of the new born immune system can be overcome and that robust long-term protective immunity can be generated by immunizing the new born with soluble rather than particulate antigens. We will test our central hypothesis by pursuing three specific aims. In Aim 1, we will fully characterize the infant immune responses induced by soluble antigens in the presence of maternal antibodies. In Aim 2, we will probe the extent of this protective immunity using H1N1, H3N2 and H5N1 influenza virus challenge models. Finally, in Aim 3, we will determine the extent to which maternal antibody mediated suppression can be overcome in non-human primate, rhesus macaque infants. The proposed work is significant because knowledge gained from these studies will enable us to develop vaccines that overcome maternal antibody suppression and can be used to successfully vaccinate infants. PUBLIC HEALTH RELEVANCE: Maternal antibodies, transferred to the baby via the placenta during pregnancy and via breast milk following birth, are crucial for protecting the infant during their first months of life. But there is a down side to this; maternal antibodies suppress infant immune responses to vaccines. We have preliminary data that suggests that maternal suppression can be overcome, and the purpose of this grant proposal is to understand the extent and mechanism behind this redemption in mice and in non-human primate infants.