Immunogenicity of Subunit Vaccine Delivered by FcRn

描述（由申请人提供）：由于80-90%的传染病起源于粘膜表面，因此正在寻求预防侵袭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是有限的。本提案的长期目标是确定FcRn-IgG跨细胞途径是否代表一种针对粘膜病原体的亚单位疫苗的新递送途径。新生儿Fc受体（FcRn）最初被认为是通过胎盘将母体IgG转运给胎儿或通过肠道转运给新生儿。然而，FcRn在成人和动物的多种组织和细胞中表达，并介导IgG在极化上皮细胞系中的双向转运。基于这些证据，我们假设这种IgG转运途径可能允许FcRn将融合到IgG- fc的病毒抗原传递到粘膜屏障下的粘膜相关淋巴组织。这种转运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将用于探测免疫应答和确定保护性免疫应答。本提案的具体目的是确定FcRn通过生殖器或呼吸道粘膜屏障递送gD-Fc抗原的能力，以产生保护性免疫，抵抗粘膜给药的强毒HSV-2攻击。这项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有效的新型粘膜病原体疫苗策略，如人类免疫缺陷病毒-1、衣原体、流感等，这些病原体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.