Development of a Sublingual Measles Vaccine

描述（申请人提供）：麻疹是一种高度传染性的人类疾病，通过呼吸道途径传播，仍然是传染病导致的十大死亡原因之一（2007年为197，000人），也是5岁以下儿童因疫苗可预防疾病导致的第二大最常见死亡原因。简单、低成本、无针替代疫苗接种战略可能有助于显著降低麻疹在死亡率和发病率方面的严重全球影响。绝大多数疫苗是通过注射提供的，包括麻疹疫苗。无针疫苗接种也将有助于克服与注射相关的许多问题，包括意外疾病传播（例如，肝炎和艾滋病毒），原因包括针头刺伤或注射剂使用不当/不安全、生物危害性锐器废物处理、注射部位疼痛以及需要熟练的医护人员。在这个项目中，我们建议测试的假设，舌下麻疹疫苗是一个可行的替代注射疫苗。在具体目标1中，我们将开发舌下麻疹疫苗制剂，其目标是实现所需的薄片物理性质（例如，薄片内聚性和目标溶解/崩解速率），从薄片可接受地恢复疫苗效力，并了解唾液对疫苗病毒滴度的影响。在具体目标2中，将对棉鼠舌下接种麻疹疫苗干胶片制剂和液体麻疹疫苗液滴，并与皮下注射疫苗进行免疫应答能力比较。在具体目标3中，将舌下给予未患麻疹的恒河猴麻疹疫苗干胶片制剂。将分析血清和灌洗液样品的麻疹特异性抗体和T细胞应答。还将评价灌洗液样本的麻疹RNA。该项目的成功结果为后续研究开辟了许多途径，包括：1）在接种疫苗一年后对舌下免疫和阴性对照猕猴进行攻击研究，以验证保护性免疫; 2）舌下接种绿色荧光蛋白（GFP）标记的麻疹疫苗病毒，以阐明感染和复制的位点; 3）将舌下接种方法扩展到腮腺炎和风疹，以开发单一的三价舌下接种疫苗; 4）探索舌下接种其他传染病，如流感、人乳头瘤病毒、黄热病和炭疽。 公共卫生相关性：麻疹是第二大致命的疫苗可预防疾病，2007年全球有197 000人死亡（大多数是5岁以下儿童）。替代无针粘膜免疫策略可能有助于减少麻疹对全球健康的严重影响，并有助于克服与针头和注射器注射相关的许多问题，这是大多数疫苗（包括麻疹疫苗）的管理方式。我们建议开发舌下麻疹疫苗制剂，并在适当的动物模型（棉鼠和恒河猴）中测试这些疫苗的免疫原性。舌下接种可广泛适用于许多其他传染病，包括腮腺炎、风疹、流感、人乳头瘤病毒、黄热病和炭疽。

DESCRIPTION (provided by applicant): Measles is a highly contagious, human disease that is spread by the respiratory route and remains among the top 10 causes of deaths (197,000 in 2007) due to infectious diseases and the second most common cause of death due to vaccine-preventable disease in children under the age of 5 years. Simple, low-cost, needle-free alternative vaccination strategies may help to significantly reduce the severe global impact of measles in terms of mortality and morbidity. The vast majority of vaccines are delivered by injection, including measles vaccine. Needle-free vaccinations would also help to overcome many of the problems associated with injections, including accidental disease transmission (e.g., hepatitis, and HIV) due to needle-stick injuries or improper/unsafe use of injectables, biohazardous sharps waste disposal, pain at injection site, and need for skilled healthcare workers. In this project we propose to test the hypothesis that sublingual measles vaccine is a viable alternative to the injectable vaccine. In Specific Aim 1, we will develop sublingual measles vaccine formulations with the goals of achieving desired wafer physical properties (e.g., wafer cohesiveness, and target dissolution/disintegration rates), acceptably recovering vaccine potency from the wafer, and understanding the effect of saliva on vaccine virus titer. In Specific Aim 2, measles vaccine dry wafer formulations and liquid measles vaccine droplets will be administered sublingually to cotton rats and compared to subcutaneous injection of the vaccine in terms of their ability to generate an immune response. In Specific Aim 3, a measles vaccine dry wafer formulation will be administered sublingually to measles-naive rhesus macaques. Sera and lavage samples will be analyzed for measles-specific antibody and T cell responses. Lavage samples will also be evaluated for measles RNA. A successful outcome to this project opens up a number of avenues for follow-on research including: 1) conducting a challenge study of the sublingually immunized and negative control macaques one year after vaccination to verify protective immunity; 2) studies with green fluorescent protein (GFP) labeled measles vaccine virus administered sublingually to elucidate the sites of infection and replication; 3) extension of this sublingual vaccination approach to mumps and rubella to develop a single trivalent sublingual vaccine; 4) exploration of sublingual vaccination for other infectious diseases such as influenza, human papillomavirus, yellow fever, and anthrax. PUBLIC HEALTH RELEVANCE: Measles is the second most fatal vaccine-preventable disease, with 197,000 deaths globally in 2007 (mostly children under 5 years old). Alternative needle-free, mucosal immunization strategies may help reduce the severe impact of measles in global health, and help to overcome many of the problems associated with needle and syringe injections, which are how most vaccines are administered, including measles vaccine. We propose to develop sublingual measles vaccine formulations and to test these in appropriate animal models (cotton rats and rhesus macaques) for immunogenicity. Sublingual vaccination may be broadly applicable to a number of other infectious diseases, including mumps, rubella, influenza, human papillomavirus, yellow fever, and anthrax.