Suppression of measles virus vaccination by maternal antibodies

描述(申请人提供)：麻疹病毒感染每年导致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(即使是非保护性滴度)会抑制疫苗接种。虽然这一现象在人类和兽医医学中的许多重要疫苗中都能看到，但其潜在的机制迄今尚不清楚。我们的目标是阐明控制疫苗接种抑制的调控机制，以此作为改进免疫策略的必要条件。我们的特定假设是，病毒-抗体复合体通过免疫球蛋白恒定区(Fc)抑制B细胞反应是抑制血清转换的原因，而与针对MV的IgM联合免疫可以克服这种抑制。我们的初步数据表明，单抗MV特异性免疫球蛋白可以抑制疫苗接种，在母源抗体存在的情况下，单抗MV特异性IgM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情况，我们使用近交系棉鼠(Sigmodon Hispidus)，因为它们是唯一一种MV在鼻腔感染后在呼吸道复制的啮齿动物。母源抗体通过被动转移MV特异性血清或单抗来模拟。这使我们能够通过ELISA法区分被动转移的人/鼠抗体和主动诱导的棉鼠抗体。异种抗体的衰变比同种抗体快，免疫时的抗体数量可以定量。在这个动物模型中，我们将解决以下具体目标：1.明确免疫球蛋白通过FcyRIIB抑制B细胞反应的机制。我们将确定用于抑制的免疫球蛋白恒定区的作用，以及抗体密度在抑制B细胞反应中所起的作用。2.明确IgM刺激B细胞反应的机制。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细胞反应中所起的作用。将在具有母源抗体的新生儿中测试异种(小鼠)免疫球蛋白M与同源(棉鼠)免疫球蛋白M联合应用的效果。

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.