Development of a Sublingual Measles Vaccine

说明（由申请人提供）：麻疹是一种高度传染性的人类疾病，通过呼吸道传播，仍然是传染病造成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的疾病造成的第二大常见死亡原因。简单、低成本、无针的替代疫苗接种战略可能有助于显著减少麻疹在死亡率和发病率方面的严重全球影响。绝大多数疫苗都是通过注射提供的，包括麻疹疫苗。无针疫苗接种还将有助于克服与注射有关的许多问题，包括因针刺伤害或不适当/不安全使用注射剂而造成的意外疾病传播（例如肝炎和艾滋病毒）、生物有害利器废物处理、注射部位疼痛以及需要熟练的卫生保健工作者。在这个项目中，我们建议测试舌下麻疹疫苗是一种可行的替代注射疫苗的假设。在具体目标1中，我们将开发舌下麻疹疫苗配方，其目标是实现所需的晶片物理特性（例如，晶片凝聚力和目标溶解/崩解率），从晶片中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，麻疹疫苗干晶片制剂和液体麻疹疫苗液滴将舌下注射给棉大鼠，并在产生免疫反应的能力方面与皮下注射疫苗进行比较。在具体目标3中，将对未患麻疹的恒河猴舌下注射麻疹疫苗干晶片制剂。将对血清和灌洗液样本进行麻疹特异性抗体和T细胞反应分析。还将对灌洗液样本进行麻疹RNA评估。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挑战研究，以验证保护性免疫；2)用绿色荧光蛋白（GFP）标记的麻疹疫苗病毒舌下给药，以阐明感染和复制的部位；3)将这种舌下疫苗接种方法推广到腮腺炎和风疹，开发一种三价舌下疫苗；4)探索其他传染病如流感、人乳头瘤病毒、黄热病和炭疽的舌下疫苗接种。

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.