Overcoming maternal antibody-mediated immunosuppression

描述（由申请人提供）：母源抗体对婴儿生命最初几个月的保护至关重要。这在患有无球蛋白血症的婴儿中是最好的例子，他们在出生后的第一年茁壮成长，但在循环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；它们抑制疫苗诱导的婴儿免疫系统的激活。正因为如此，许多必要和挽救生命的疫苗，如麻疹疫苗，是在出生后一年才接种的。这给婴儿留下了一个很长的时间窗口，在此期间，婴儿很容易受到感染，但无法产生必要的抗体反应来保护自己。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，因为它可能导致开发更有效的婴儿疫苗。我们推断母体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。我们的初步数据表明，免疫与可溶性而不是颗粒抗原导致显著的婴儿活化

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.