The Neonatal Fc Receptor and Complement Fixation Facilitate Prophylactic Vaccine-Mediated Humoral Protection against Viral Infection in the Ocular Mucosa

Abstract

The capacity of licensed vaccines to protect the ocular surface against infection is limited. Common ocular pathogens such as herpes simplex virus type 1 (HSV-1) are increasingly recognized as major contributors to visual morbidity worldwide. Humoral immunity is an essential correlate of protection against HSV-1 pathogenesis and ocular pathology, yet the ability of antibody to protect against HSV-1 is deemed limited due to the slow IgG diffusion rate in the healthy cornea. We show that a live-attenuated HSV-1 vaccine elicits humoral immune responses that are unparalleled by a glycoprotein subunit vaccine vis-à-vis antibody persistence and host protection. The live-attenuated vaccine was utilized to assess the impact of immunization route on vaccine efficacy. The hierarchical rankings of primary immunization route with respect to efficacy were: subcutaneous ≥ mucosal > intramuscular. Prime-boost vaccination via sequential subcutaneous and intramuscular administration yielded greater efficacy than any other primary immunization route alone. Moreover, our data also support a role of complement in prophylactic protection as evidenced by intracellular deposition of C3d in the corneal epithelium of vaccinated animals following challenge and delayed viral clearance in C3-deficient mice. We also identify that the neonatal Fc receptor (FcRn) is upregulated in the cornea following infection or injury concomitant with increased antibody perfusion. Lastly, selective siRNA-mediated knockdown of FcRn in the cornea impeded protection against ocular HSV-1 challenge in vaccinated mice. Collectively, these findings establish a novel mechanism of humoral protection in the eye involving FcRn and may facilitate vaccine and therapeutic development for other ocular surface diseases.

Anterior segment optical coherence tomography: its application in clinical practice and experimental models of disease

“…In this study, SD‐OCT provided a higher sensitivity for detecting clinical corneal pathology compared to histological analysis, with corneal oedema visible at six hours post‐infection using SD‐OCT, but only after 12 hours post‐infection in histology sections . In a mouse model of HSV‐1 keratitis, SD‐OCT demonstrated corneal oedema and prominent hyper‐intensities, reflective of leukocytic infiltrates, at 24 hours post‐infection . Resolution of inflammation was also monitored using SD‐OCT in mice up to 30 days post‐injection with a vaccine against HSV‐1 …”

“…In a mouse model of HSV‐1 keratitis, SD‐OCT demonstrated corneal oedema and prominent hyper‐intensities, reflective of leukocytic infiltrates, at 24 hours post‐infection . Resolution of inflammation was also monitored using SD‐OCT in mice up to 30 days post‐injection with a vaccine against HSV‐1 …”

Reply to “Highly Efficacious Novel Vaccine, Humoral Immunity, and Ocular Herpes Simplex Virus 1: Reality or Myth?”

“…Our work models a prophylactic vaccination in which the primary end goal is to prevent establishment of viral latency using a murine model of ocular HSV-1 challenge. Our studies show that humoral immunity is requisite for efficient control of primary ocular HSV-1 infection and reduction of latency through a novel mechanism involving the neonatal Fc receptor and complement (3,5). As stated in our original publication, "Focus on humoral immunity as a correlate of protection against HSV-1-induced ocular disease and latency has been eclipsed over the past decade by a focus on T cell responses" (3).…”

“…We concede that there are decisive variables that still require focused attention in the field of HSV vaccine research. These include the meager antigenic breadth of single-glycoprotein-subunit vaccines (14), sex differences (15), original antigenic sin and poor efficacy of therapeutic subunit vaccines in HSV-1/2-seropositive individuals (16,17), the utility and safety of novel adjuvants (18,19), and differential immunologic mechanisms and effective correlates of protection for primary mucosal and dermal infection by HSV-1 and HSV-2 (5,20). Resolving these issues and advancing effective vaccines to clinical trials will require rigorous yet equitable scholarly review, erudite assimilation of the literature, and the honest spirit of collegiality.…”

Corneal Epithelial Cells Exhibit Myeloid Characteristics and Present Antigen via MHC Class II

“… 29 , 30 We have recently shown that CD326/epithelial cell adhesion molecule (EpCAM) is an excellent cell-surface marker for identifying CECs by flow cytometry—circumventing the need for intracellular cytokeratin staining. 31 In the same study, we found that HSV-1 infection leads to an acute increase in the total number of CECs, 31 but the phenotype and physiology of these CECs originating under inflammatory conditions have not been characterized. Here, we investigate ectopic “myeloid” antigen expression on CECs as a possible outcome of EMT following ocular surface injury, allergy, and HSV-1 infection and explore the downstream immunologic consequences.…”