Overcoming maternal antibody-mediated immunosuppression

描述(由申请人提供)：母源抗体对于保护婴儿出生后的头几个月至关重要。这在患有无丙种球蛋白血症的婴儿中是最好的例证，他们在出生后的第一年就会茁壮成长，但在循环中的母体抗体水平下降后，就会死于反复感染。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，都是在出生后延迟接种的，最长可达一年。这给婴儿留下了一段很长的时间窗口，在这段时间内，婴儿容易受到感染，但无法产生保护自己所需的抗体反应。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，因为这可能导致开发更有效的婴儿疫苗。我们推断，母源抗体介导的抑制可能部分是由于用于疫苗接种的抗原的形式。我们的初步数据显示，用可溶性抗原而不是颗粒抗原免疫会显著激活婴儿。 免疫系统。基于此，我们的中心假设是，母源抗体介导的新生儿免疫系统的免疫抑制是可以克服的，通过用可溶性抗原而不是颗粒抗原免疫新生儿可以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，我们将充分描述在母体抗体存在的情况下由可溶性抗原诱导的婴儿免疫反应。在目标2中，我们将使用H1N1、H3N2和H5N1流感病毒攻击模型来探索这种保护性免疫的程度。最后，在目标3中，我们将确定母体抗体介导的抑制在非人类灵长类猕猴婴儿中可以克服的程度。拟议的工作意义重大，因为从这些研究中获得的知识将使我们能够开发出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。

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.