Humoral responses induced by an enzymatically active, whole-cell killed pneumococcal vaccine

Abstract

Streptococcus pneumoniae is a key pathogen of the human respiratory tract responsible for approximately one million deaths per year, the majority of which occur in young children in developing countries. Vaccination strategies against the pneumococcus currently target the dominant immunogen of the bacterium, the polysaccharide capsule. While this has proved highly effective against vaccine-included serotypes, serotype replacement has prevented continued reductions in rates of pneumococcal disease over the last two decades. In order to continue reducing the prevalence of pneumococcal disease, a novel, serotype-independent vaccination strategy is required. Our lab has previously described a new, gamma-irradiated pneumococcal vaccine termed γ-PNΔPsaA. This vaccine contains a whole-cell, unencapsulated pneumococcal antigen inactivated using gamma-irradiation, and induces a serotype-independent immune response against highly conserved, sub-capsular protein antigens. Gamma-irradiation inactivates micro-organisms primarily through direct damage to genetic material, introducing strand breakages and preventing genome replication. Unlike genetic material, proteins are more resistant to direct damage and remain intact throughout the irradiation process. Data from this study showed that irradiated pneumococci retain functional enzymes utilised for virulence and gene expression, and it was shown that some genes may be more susceptible to direct damage than others. Furthermore, irradiated pneumococci appear to be capable of responding to environmental signals by modifying gene expression accordingly. Despite retaining functional enzymes and transcriptional abilities, irradiated pneumococci do not appear to be capable of metabolising carbohydrates. As the vast majority of pathogenic strains of pneumococci are encapsulated, it was essential to examine the functionality of γ-PNΔPsaA-specific antibodies against encapsulated pneumococci. Immune serum was generated by vaccinating mice via different routes, and antibody binding to pneumococcal cells expressing various capsule phenotypes was assessed. It was shown that both capsule structure and IgG subclass profiles play a role in influencing antibody binding against encapsulated pathogens. Of particular interest, it appears that certain IgG subclass profiles may be more effective at binding sub-capsular antigens on pneumococci expressing a wider variety of capsule phenotypes.