Characterization of Staphylococcal protein A cellular interactions to facilitate its development as a vaccine antigen

Abstract

The development of a vaccine from bench to bedside is a lengthy and complex process, which is so rarely fully realized and followed throughout. During the course of this project, we have been able to follow the development of a novel Staphylococcus Aureus vaccine from preclinical development through to its initial phase I/II clinical trial. Indeed, the development of an efficacious S. aureus vaccine has long been sought as the bacterium is reported to have a greater mortality rate within the USA than that of HIV/AIDS, tuberculosis and viral hepatitis combined. Yet, despite a number of previous high-profile attempts there are currently no approved vaccine therapeutics for S. aureus.

We therefore set out with two goals for this study, to first and foremost aid in the development of the vaccine candidate Staphylococcal Protein A (SpA) which has been shown to disrupt the hosts humoral immune response and are second goal was to integrate with GSK?s preclinical team and to aid in the development of models able to advance anti S. aureus research as a whole

SpA?s inherent ability to disrupt the hosts humoral immune response is twofold; firstly, it acts as a B cell super antigen reportedly disrupting B cell development, secondly it sequesters antibodies via their Fcγ domain thus inhibiting opsonophagocytosis. Indeed, the protective effects of active and/or passive vaccination using detoxified SpA mutants have been demonstrated in multiple animal models, these studies however have failed to identify both the mechanism of this protection and whether these protective effects might be reflective of the human response.

Herein we demonstrate that during in vivo murine bloodstream infection SpA is not responsible for observed B cell clonal collapse and corresponding lymphopenia. But that while in the presence of human serum SpA can act as a potent cellular toxin and that through vaccination, we can overcome these toxigenic effects.

To further aid in the preclinical development, we collaborated in the development of two novel models within GSK. The first and most promising was the development of a Human skin model for the analysis of human skin resident T cells. This model while in the early stages allowed for the rapid amplification and analysis of the skin resident T cell response and we hope that GSK while continue with its further development. The Second was the development on site of a murine air pouch model to allow for the exploration of the peripheral innate immune response. It is hoped that by using this model a more robust picture of the early response to peripheral S. aureus infection may be formed and the effects of vaccination explored.

Overall, this study contributes significantly to our understanding of the challenges involved in the preclinical development of an anti S. aureus vaccine, using SpA as the lens to view this process.