TESTING MUCOSAL VACCINES IN AN ANIMAL MEASLES MODEL

麻疹，如果接种适当的疫苗，是一种可以根除的疾病。问题 与固定和活病毒疫苗已经引起了新的兴趣， 接种麻疹疫苗的方法。 新疫苗应该有效， 在母体抗体存在下施用，因为早期 在地方病流行的情况下，免疫是必不可少的。障碍（可能更多） 虚幻的比真实的）来测试新的疫苗策略， 灵长类动物，实验室动物不会发展麻疹样疾病时， 接种麻疹病毒。 然而，犬瘟热病毒（CDV）， 麻疹病毒和麻疹病毒的近亲，确实产生一种 雪貂麻疹样感染，CDV的天然宿主：CDV通过 同样的途径，感染同样的靶细胞， 传播疾病，并防止再感染是由 用相同的病毒结构蛋白免疫（融合[F]和 血凝素[HA]蛋白），如麻疹。此外，年轻的雪貂 通过母源抗体天然保护其免受CDV感染。 在 因此，CDV是一种理想的麻疹病毒疫苗试验模型 战略布局我们的长期目标是研制有效的麻疹疫苗 所有年龄段的人都能安全使用 我们将开发 适用于粘膜和胃肠外的CDV候选疫苗 使用HA、F和N蛋白进行施用。 粘膜途径将是 探索作为避免母体抗体的抑制作用的手段。 我们将为此目的开发重组牛痘病毒。 我们将 还通过亲和层析纯化F和HA用于胃肠外和粘膜 施用霍乱毒素结合亚基（CTB）作为免疫抑制剂。 佐剂和用于制备ISCOM。然后我们将确定 这些候选疫苗在免疫学幼稚中的保护功效 雪貂和婴儿雪貂保护母亲的抗体。的 将评估粘膜和血清抗体对保护作用的贡献 通过测量总的、HA-和F-特异性血清和分泌性抗体， 病毒中和和融合抑制。我们还将确定F-， HA和N特异性雪貂抗体将增强雪貂的感染 巨噬细胞是体内CDV的主要靶细胞，因为这种 增强可能会影响疫苗接种策略， 在福尔马林注射后出现非典型麻疹 固定麻疹疫苗。

Measles, given the appropriate vaccine, is an eradicable disease. Problems with both fixed and live-virus vaccines have created interest in new approaches to measles vaccination. New vaccines should be effective when administered in the presence of maternal antibody because early immunization is essential in endemic settings. An impediment (perhaps more illusory than real) to testing new vaccine strategies has been that non- primate, laboratory animals do not develop a measles-like illness when inoculated with measles virus. However, canine distemper virus (CDV), a morbillivirus and thus a close relative of measles virus, does produce a measles-like infection in ferrets, a natural host of CDV: CDV is spread by the same route, infects the same target cells, causes a similar disseminated disease, and protection against reinfection is conferred by immunization with the same virus structural proteins (the fusion [F] and hemagglutinin [HA] proteins) as with measles. In addition, young ferrets are naturally protected against CDV infection by maternal antibody. In short, CDV is an ideal model for testing new morbillivirus vaccine strategies. Our long-term goal is to develop an effective measles vaccine that can be safely administered to all age groups. We will develop candidate vaccines for CDV suitable for mucosal and parenteral administration using the HA, F and N proteins. The mucosal route will be explored as a means to avoid the inhibitory effects of maternal antibody. We will develop recombinant vaccinia viruses for this purpose. We will also purify F and HA by affinity chromatography for parenteral and mucosal administration with the cholera-toxin binding-subunit (CTB) as an adjuvant, and for preparation of ISCOMs. We will then determine the protective efficacy of these candidate vaccines in immunologically naive ferrets and in infant ferrets protected by maternal antibody. The contribution of mucosal and serum antibody to protection will be assessed by measuring total, HA- and F-specific serum and secretory antibody, virus-neutralization and fusion inhibition. We will also determine if F-, HA- and N-specific ferret antibodies will enhance infection of ferret macrophages in vitro, a principal target cell of CDV in vivo, because such enhancement could affect vaccination strategy and may have been a factor in the development of atypical measles after administration of formalin- fixed measles vaccines.