IMMUNITY TO MEASLES VIRUS

这项建议旨在探索麻疹的免疫机制。 恒河猴体内的病毒。尽管目前的减毒活麻疹 病毒疫苗是世界上最安全、最有效的疫苗之一。 二十世纪，几个生物学和实际问题限制了它 发达国家和中国麻疹疫情控制效果比较 预防儿童麻疹感染的发病率和死亡率 发展中国家的婴儿。在有母体免疫力的情况下 麻疹病毒，在婴儿出生后头6至9个月接种疫苗 有很高的失败率。在美国的市中心和 发展中国家，接触麻疹会使婴儿出生第一年 生命处于危险之中。母亲获得的中和抗体可以预防 使用减毒病毒疫苗(复制能力差)，但是 母体获得的抗体效价可能不足以保护 抵抗野生型病毒的感染。母体获得性免疫球蛋白 不能阻止麻疹病毒在呼吸道中的初始复制 一条小路。针对这些问题，我们的目标是研究恒河猴 以麻疹病毒感染为合适的动物模型。那就是麻疹 人类来源的病毒株在恒河猴身上复制并产生疾病 人们对猴子的了解已经有70多年的历史了。恒河猴被用来测试 20世纪60年代初麻疹减毒活疫苗株S， 在人体现场试验之前。但可能是因为经验上的成功 新型疫苗、免疫机制和预防麻疹的研究进展 病毒引起的恒河猴疾病一直没有被追查。研究 恒河猴对病毒感染的免疫反应取得进展 在很短的时间内迅速地。我们所学到的知识和方法 猴艾滋病将直接应用于麻疹病毒的研究 恒河猴的免疫力。将有4个实验程序使用 恒河猴。1)将对麻疹病毒的病原体进行滴定 通过鼻腔接种对幼猴的传染性，然后 针对挑战感染的保护将尝试与现场- 减毒疫苗株或福尔马林灭活麻疹制剂。 2)将诱导对麻疹病毒的保护性免疫反应 试图用基因重组菌株进行鼻腔免疫 表达麻疹病毒抗原的减毒型腺病毒。3)麻疹- 免疫水坝将用麻疹血凝素和融合剂加强免疫 孕期蛋白质增加母体中和转移 对其婴儿产生抗体。或者，婴儿将接受免疫接种。 出生时在粘膜上(如上面第二步所确定的)。这些婴儿将会是 在3个月和9个月龄时感染致病性麻疹病毒。4)至 研究辅助性和细胞毒性T淋巴细胞在麻疹免疫中的作用 幼猴将接受抗CD4或抗CD8的单抗 静脉注射抑制这些细胞的功能，然后接种 麻疹病毒。

This proposal is designed to explore the mechanisms of immunity to measles virus in rhesus macaques. Although the current live-attenuated measles virus vaccine is one of the safest and most efficacious vaccines of the twentieth century, several biological and practical issues limit its efficacy in the epidemic control of measles in developed countries and in the prevention of morbidity and mortality due to measles infection of infants in developing countries. In the presence of maternal immunity to measles virus, vaccination of infants in the first 6 to 9 months of life has a significant failure rate. In inner cities of the U.S. and in developing countries, exposure to measles puts infants in the first year of life at risk. Maternally-acquired neutralizing antibody can prevent take of the attenuated virus vaccine (which replicates poorly) but maternally-acquired antibody titers may not be sufficient to protect against infection with wild-type viruses. And maternally-acquired IgG cannot prevent initial replication of measles virus in the respiratory tract. In response to these issues, we aim to study the rhesus monkey infected with measles virus as an appropriate animal model. That measles virus strains of human origin replicate and produce disease in rhesus monkeys has been known for over 70 years. Rhesus monkeys were used to test vaccine strains of live-attenuated measles virus in the early 1960's, prior to human field trials. But probably because of the empirical success of the new vaccine, mechanisms of immunity and protection from measles virus - induced disease in rhesus monkeys have not been pursued. Research on the rhesus monkey's immune response to viral infection has progressed rapidly in a short time. The knowledge and methods that we have learned with simian AIDS will apply.directly to the study of measles virus immunity in rhesus monkeys. There will be 4 experimental procedures using rhesus monkeys. 1) A pathogenic stock of measles virus will be titrated for infectivity in juvenile monkeys by intranasal inoculation, and then protection from challenge infection will be attempted with the live- attenuated vaccine strain or a formalin-inactivated measles preparation. 2) Induction of a protective immune response to measles virus will be attempted by intranasal immunization with a genetically recombinant strain of attenuated adenovirus expressing measles virus antigens. 3) Measles- immunized dams will be boosted with measles hemagglutinin and fusion proteins during pregnancy to increase transfer of maternal neutralizing antibody to their infants. Alternatively, infants will be immunized mucosally (as determined in step 2 above) at birth. The infants will be challenged with pathogenic measles virus at 3 and 9 months of age. 4) To study the roles of helper and cytotoxic T lymphocytes in measles immunity, juvenile monkeys will receive anti-CD4 or anti-CD8 monoclonal antibodies I.V. to suppress the functions of these cells, and then be inoculated with measles virus.