Suppression of measles virus vaccination by maternal antibodies

描述（由申请人提供）：麻疹病毒（MV）感染每年造成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）会抑制疫苗接种。虽然这种现象在人类和兽医学的许多重要疫苗中都能看到，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节机制，这是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细胞反应是抑制血清转化的原因，而与MV特异性IgM联合免疫可以克服这种抑制。我们的初步数据支持了这一点，表明单克隆MV特异性IgG可以抑制疫苗接种，单克隆MV特异性IgM在存在母源抗体的情况下诱导疫苗接种后的中和抗体。为了分析疫苗在体内的抑制作用，我们使用了近交系棉花大鼠（Sigmodon hispidus），因为它们是唯一一种在鼻内感染后MV在呼吸道复制的啮齿动物。母源抗体通过被动转移MV特异性血清或单克隆抗体来模拟。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。异源抗体衰变速度快于同源抗体，免疫时抗体的数量可定量测定。在这个动物模型中，我们将解决以下具体目标：1。明确IgG通过FcyRIIB抑制B细胞反应的机制。我们将定义IgG的恒定区在抑制中的作用以及抗体密度在抑制B细胞反应中的作用。2. 明确IgM刺激B细胞反应的机制。我们将定义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细胞反应中的作用。异种（小鼠）IgM与同源（棉花大鼠）IgM联合应用的效果将在具有母源抗体的新生儿中进行测试。

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.