Immunization of Oral Mucosa for Induction of Rectal and Genital Mucosal Immunity

描述(申请人提供)：拟议的研究将调查口腔粘膜免疫作为人类免疫缺陷病毒(HIV)疫苗交付的一种潜在途径。像大多数其他性传播疾病(STD)一样，HIV的主要感染部位是粘膜表面，而且像大多数其他STD一样，没有针对HIV的疫苗。拟议的实验将探索利用口腔粘膜途径通过共同的粘膜免疫系统在远端部位诱导免疫来对抗艾滋病毒/性传播疾病的可能性。我们将表征外周和粘膜(口腔、鼻腔、肺、直肠和阴道)部位对2个口腔粘膜部位(颊窝和舌扁桃体上的粘膜下免疫)疫苗的先天、适应性细胞和体液反应，并将它们与肌肉内(IM)或皮内(ID)接种相同疫苗的反应进行比较。第一组实验在恒河猴身上进行，将使用主要艾滋病毒疫苗方案之一的SIV版本：DNA初始/复制不能的Ad5疫苗Boost。我们将把我们的观察扩展到使用已获许可的灭活流感疫苗(福音区)的人类。作为测试抗原。适应性反应将在血液和粘膜部位进行测量；抗原特异性T细胞将使用ELISpot和细胞内细胞因子染色进行测量，抗体将通过ELISA进行测量。目的1将测试舌扁桃体粘膜下免疫是否在非人灵长类动物和人类中产生强大的外周B细胞和T细胞反应。这一目标将解决舌扁桃体免疫后的外周反应是否与IM或ID免疫引起的反应相似，而比颊窝粘膜下免疫后的反应更强。不同途径引起的适应性反应差异的可能机制将通过研究先天性免疫反应(系统树突状细胞的表型和功能，以及血清细胞因子/趋化因子谱)来研究。目标2将探讨舌扁桃体免疫是否在可测量的高于口腔免疫或IM/ID免疫的水平上诱导粘膜细胞和体液反应。这一目标将决定舌扁桃体途径是否表现出更高的功能性和亲和力，以及该途径是否在远端粘膜部位(直肠和宫颈/阴道)引起反应。项目简介：这些实验将提供数据，说明口腔粘膜疫苗接种是否可以通过共同的粘膜免疫系统在远端部位(如阴道和直肠)诱导免疫，从而提供对性传播生物体的保护。它还将调查当需要鼻部和肺部免疫时，这种免疫路线在预防呼吸道病原体(如流感)方面的有用性。

DESCRIPTION (provided by applicant): The proposed research will investigate oral mucosal immunization as a potential route for delivery of human immunodeficiency virus (HIV) vaccines. Like most other sexually transmitted diseases (STDs), HIV's primary site of infection is at mucosal surfaces, and like most other STDs, there is no vaccine for HIV. The proposed experiments will explore the possible use of the oral mucosal route for immunization against HIV/STDs through induction of immunity at distal sites mediated via the common mucosal immune system. We will characterize innate, adaptive cellular, and humoral responses in the periphery and in mucosal (oral, nasal, pulmonary, rectal, and vaginal) sites to vaccines given at 2 oral mucosal sites (submucosal immunization in the buccal fossa and over the lingual tonsil) and compare them to responses to the same vaccines given intramuscularly (IM) or intradermally (ID). The first set of experiments, in rhesus macaques, will use an SIV version of one of the leading HIV vaccine regimens: DNA prime/replication-incompetent Ad5 vaccine boost. We will extend our observations to humans using a licensed inactivated influenza vaccine (Fluzone.) as a test antigen. Adaptive responses will be measured in the blood and at mucosal sites; antigen-specific T cells will be measured using ELISpot and intracellular cytokine staining and antibody will be measured by ELISA. Aim 1 will test whether submucosal immunization over the lingual tonsil produces robust peripheral B- and T-cell responses in both nonhuman primates (NHPs) and humans. This aim will address whether peripheral responses after lingual tonsil immunization approximate those induced by IM or ID immunization and are greater than those seen after submucosal immunization in the buccal fossa. Possible mechanisms underlying differences in adaptive responses elicited by different routes will be investigated via studies of innate immune responses (systemic dendritic cell phenotype and function, and serum cytokine/chemokine profiles). Aim 2 will address whether lingual tonsil immunization induces mucosal cellular and humoral responses at measurably higher levels than buccal or IM/ID immunization. This aim will determine whether T-cell responses elicited by the lingual tonsil route show higher functionality and avidity, and if this route elicits responses in distal mucosal sites (rectum and cervix/vagina). Project Narrative: These experiments will provide data on whether vaccination of the oral mucosa can provide protection against sexually transmitted organisms, through induction of immunity at distal sites (such as the vaginal and rectum) mediated by the common mucosal immune system. It will also investigate the usefulness of this route of immunization for protection against respiratory pathogens, such as influenza, when immunity in the nose and lungs is desired.