Immunogenicity of Subunit Vaccine Delivered by FcRn

描述（由申请方提供）：由于80-90%的感染性疾病是在粘膜表面开始的，因此正在寻求预防侵入性粘膜病原体的疫苗策略。此外，我们通过粘膜屏障递送疫苗抗原以诱导有效粘膜免疫的能力有限。该提案的长期目标是确定FcRn-IgG跨细胞途径是否代表针对粘膜病原体的亚单位疫苗的新递送途径。最初认为新生儿Fc受体（FcRn）通过胎盘将母体IgG转运至胎儿或通过肠道转运至新生儿。然而，FcRn在成人和动物的多种组织和细胞中表达，并介导IgG跨极化上皮细胞系的双向转运。基于这些证据，我们假设这种IgG转运途径可能允许FcRn将与IgG-Fc融合的病毒抗原穿过粘膜屏障递送至下层粘膜相关淋巴组织。这种运输的后果可能会让位于免疫原性。单纯疱疹病毒2型（HSV-2）是一种性传播疾病，因此，HSV-2感染的主要部位是生殖道粘膜。糖蛋白gD将用于探测对免疫的应答并定义保护性免疫应答。本提案的具体目的是确定FcRn递送gD-Fc抗原穿过生殖器或呼吸道粘膜屏障以产生针对粘膜给药的强毒HSV-2攻毒的保护性免疫的能力。本研究的结果将有助于理解粘膜免疫调节;所获得的知识将有助于开发针对粘膜病原体（如人类免疫缺陷病毒-1、衣原体、流感等）的有效新型疫苗策略，感染或侵入粘膜表面。

DESCRIPTION (provided by applicant): Vaccine strategies to prevent invasive mucosal pathogens are being sought due to the fact that 80-90% of infectious diseases are initiated at mucosal surfaces. In addition, our ability to deliver vaccine antigens across the mucosal barrier for induction of the effective mucosal immunity is limited. The long-term goal of this proposal is to determine whether the FcRn-IgG transcellular pathway represents a novel delivery path for a subunit vaccine against mucosal pathogens. The neonatal Fc receptor (FcRn) was initially considered to transport maternal IgG to a fetus through the placenta or to newborns via the intestine. However, FcRn is expressed in a variety of tissues and cells in adult humans and animals, and mediates the bi-directional transport of IgG across polarized epithelial cell lines. Based on these evidences, we hypothesize that such IgG transport pathway may allow FcRn to deliver a viral antigen fused to an IgG-Fc across the mucosal barrier to the underlying mucosa-associated lymphoid tissue. The consequences of such transport could give way to immunogenicity. Herpes simplex virus type-2 (HSV-2) is a sexually-transmitted disease, and thus, the primary site of HSV-2 infection is the mucosa of the genital tract. The glycoprotein gD will be used to probe responses to immunization and to define protective immune responses. The specific aim of this proposal is to determine the ability of FcRn to deliver gD-Fc antigen across the genital or the respiratory mucosal barrier to engender protective immunity against mucosally-administered virulent HSV-2 challenge. The results from this study will be relevant to understanding mucosal immune regulation; the knowledge gained will be useful in development of effective novel vaccine strategies for mucosal pathogens, such as human immunodeficiency virus-1, Chlamydia, influenza etc., that infect at or invade across mucosal surfaces.