Efficient mucosal vaccination mediated by the neonatal Fc receptor

Abstract

Vaccine strategies to prevent invasive mucosal pathogens are being sought because 80–90% of infectious diseases are initiated at mucosal surfaces. However, our ability to deliver an intact vaccine antigen across a mucosal barrier for induction of effective immunity is limited. The neonatal Fc receptor (FcRn) mediates the transport of IgG across polarized epithelial cells lining mucosal surfaces. By mimicking IgG transfer at mucosal surfaces, intranasal immunization with a model antigen, herpes simplex virus type-2 (HSV-2) glycoprotein gD fused with an IgG Fc fragment, in combination with the adjuvant CpG, resulted in complete protection of wild type, but not FcRn knockout, mice that were intravaginally challenged with virulent HSV-2 186. This immunization strategy induced efficient mucosal and systemic antibody, B and T cell immune responses, including memory immune responses, which remained stable at least 6 months post-vaccination and conferred protection for a majority of animals. These results demonstrate that the FcRn-IgG transcellular transport pathway may represent a novel mucosal vaccine delivery route for a subunit vaccine against abundant mucosal pathogens.

The Neonatal FcR-Mediated Presentation of Immune-Complexed Antigen Is Associated with Endosomal and Phagosomal pH and Antigen Stability in Macrophages and Dendritic Cells

“…Our findings indicate that endosomal or phagosomal FcRn in both DCs and Mfs protects ICs from rapid catabolism and leads to optimal Ag processing for the final stage of loading peptides onto the MHC class II molecule. In addition to revealing FcRn activities in IgG protection and transcytosis (7), our data further expand our understanding of immune function by demonstrating an additional function for the FcRn in Ag presentation, which may also help us better understand the mechanisms of FcRn-targeted systemic or mucosal immunizations (57,58). The results presented thus far favor a model in which ICs internalized within endosomes or phagosomes through FcgR-mediated processes that promote FcgR-IC binding activity at the cell surface switch to FcRn-IC binding when the internal environment becomes acidic (Fig.…”

Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody

“…15,16 This property has been successfully exploited for pulmonary delivery, as well as intranasal immunization with Fc-fusion proteins. 17,18 Lastly, FcRn was also reported to transport IgGantigen complexes, thus favoring antigen-presentation, [19][20][21] and to enable phagocytosis of IgG-opsonized bacteria by neutrophils, 22 demonstrating a wide range of functions for this receptor in several immunological and non-immunological mechanisms.…”

Neonatal Fc receptor and IgG-based therapeutics

“…A recent study demonstrated this principle by immunization of mice with a Fc-fusion protein that consisted of herpes simplex virus type-2 glycoprotein gD, which led to the generation of protective antibodies that prevented subsequent intravaginal infection of a virulent HSV-2 strain. 39 The multi-functioning roles of FcRn in different tissues appear to coordinate adaptive immunity, and this process appears to be a rational strategy for vaccine development in the prevention of mucosal infections.…”

“…37 Recent studies showed that FcRn in the vaginal epithelium, similar to that of intestine, can mediate bidirectional transport of IgG and secretion of IgG for immune protection. 38,39 Liver. FcRn in the liver is the major site for the maintenance of albumin homeostasis.…”