IMMUNITY TO MEASLES VIRUS

本研究旨在探讨麻疹免疫机制 恒河猴体内的病毒。虽然目前的减毒活麻疹 病毒疫苗是世界上最安全、最有效的疫苗之一， 世纪，一些生物学和实践问题限制了它的发展。 在发达国家控制麻疹流行病和 预防麻疹感染引起的发病率和死亡率 发展中国家的婴儿。在母体对 麻疹病毒，为出生后6至9个月的婴儿接种疫苗 失败率很高在美国的市中心， 在发展中国家，接触麻疹使婴儿在第一年 生命处于危险之中。母体获得的中和抗体可以预防 接种减毒病毒疫苗（复制能力差）， 母体获得的抗体滴度可能不足以保护 对抗野生型病毒的感染。母亲获得的IgG 不能阻止麻疹病毒在呼吸道中的初始复制， 道。针对这些问题，我们的目标是研究恒河猴 感染麻疹病毒作为合适的动物模型。麻疹 人源性病毒株在恒河猴中复制并致病 人们对猴子的认识已有70多年了。恒河猴被用来测试 在20世纪60年代早期， 在人体试验之前。但可能是因为经验上的成功 新疫苗的免疫机制和麻疹保护 病毒引起的恒河猴疾病还没有被研究。研究 恒河猴对病毒感染的免疫反应 在短时间内迅速。我们学到的知识和方法 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， 恒河猴1)将滴定麻疹病毒的致病性储备液 通过鼻内接种测定幼龄猴的感染性，然后 保护免受攻击感染将尝试与活的- 减毒疫苗株或福尔马林灭活的麻疹制剂。 2)诱导对麻疹病毒的保护性免疫反应将是 尝试用基因重组菌株进行鼻内免疫 表达麻疹病毒抗原的减毒腺病毒。3)麻疹- 免疫的母鼠将用麻疹血凝素和融合 蛋白质在怀孕期间，以增加转移母体中和 对婴儿的抗体。或者，婴儿将接受免疫接种 在出生时在粘膜上（如在上述步骤2中确定的）。婴儿们将 在3月龄和9月龄时用致病性麻疹病毒攻击。4)到 研究辅助性和细胞毒性T淋巴细胞在麻疹免疫中的作用， 幼龄猴将接受抗CD 4或抗CD 8单克隆抗体 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.