Suppression of measles virus vaccination by maternal antibodies

描述（由申请人提供）：麻疹病毒（MV）感染每年导致80万人死亡。婴儿不能通过早期免疫得到保护，因为母体抗体（即使在非保护性滴度下）会抑制疫苗接种。虽然这种现象在人类和兽医学中的许多重要疫苗中都有发现，但到目前为止，其潜在机制尚不清楚。我们的目标是阐明控制疫苗接种抑制的调控机制，作为改善免疫策略的必要条件。我们的具体假设是，病毒-抗体复合物通过IgG的恒定区（Fc）抑制B细胞应答是抑制血清转化的原因，并且与MV特异性IgM的共免疫可以克服这种抑制。我们的初步数据支持这一点，表明单克隆MV特异性IgG可以抑制疫苗接种，并且单克隆MV特异性IgM在母体抗体存在下在疫苗接种后诱导中和抗体。为了分析体内疫苗接种的抑制，我们使用近交系棉鼠（Sigmodon hispidus），因为它们是鼻内感染后MV在呼吸道中复制的唯一啮齿动物。通过被动转移MV特异性血清或单克隆抗体模拟母体抗体。这使我们能够通过ELISA区分被动转移的人/小鼠抗体和主动诱导的棉鼠抗体。异源抗体的衰减比同源抗体快，并且可以定量免疫时的抗体量。在该动物模型中，我们将解决以下具体目标：1.定义IgG通过Fc γ RIIB抑制B细胞应答的机制。我们将定义IgG恒定区在抑制中的作用和抗体密度在抑制B细胞应答中的作用。2.定义IgM刺激B细胞应答的机制。我们将确定IgM与补体受体2结合的作用以及抗体的数量和密度在刺激B细胞应答中所起的作用。将在具有母体抗体的新生儿中检测异源（小鼠）IgM与同源（棉鼠）IgM联合应用的影响。

DESCRIPTION (provided by applicant): Measles virus (MV) infection causes 800,000 deaths per year. Infants cannot be protected by early immunization due to the fact that maternal antibodies (even at non-protective titers) inhibit vaccination. Although this phenomenon is seen with many vaccines of importance in human and veterinary medicine, so far the underlying mechanism is unknown. Our goal is to elucidate the regulatory mechanisms controlling inhibition of vaccination as a necessary requisite to improve immunization strategies. Our specific hypothesis is that the inhibition of the B cell response by virus-antibody complexes through the constant region (Fc) of IgG is responsible for inhibition of seroconversion and that co-immunization with IgM specific for MV can overcome this inhibition. This is supported by our preliminary data demonstrating that monoclonal MV specific IgG can inhibit vaccination and that monoclonal MV specific IgM induces neutralizing antibodies after vaccination in the presence of maternal antibodies. To analyse inhibition of vaccination in vivo we use inbred cotton rats (Sigmodon hispidus) because they are the only rodents in which MV replicates in the respiratory tract after intranasal infection. Maternal antibodies are simulated by passive transfer of MV specific serum or monoclonal antibodies. This allows us to distinguish between passively transferred human/mouse and actively induced cotton rat antibodies by ELISA. The decay of heterologous antibody is faster than homologous antibody and the amount of antibody at the time of immunization can be quantified. In this animal model we will address the following specific aims: 1. Define the mechanism of inhibition of B cell responses by IgG through FcyRIIB. We will define the role of the constant region of IgG for inhibition and the role antibody density plays in inhibition of B cell responses. 2. Define the mechanism of stimulation of B cell responses by IgM. We will define the role of binding of IgM to complement receptor 2 and the role number and density of antibody plays in stimulation of B cell responses. The effect of co-application of heterologous (mouse) IgM in relation to homologous (cotton rat) IgM will be tested in neonates with maternal antibodies.