Despite our advanced knowledge and the availability of highly effective vaccines against many diseases, there is a clear need to develop vaccines with improved safety and efficacy for several infectious agents. We have been investigating the use of gamma-irradiation to inactivate pathogens for vaccine purposes. Our general hypothesis is that the structural damage associated with gamma-irradiation could be controlled by manipulating irradiation conditions, allowing inactivated vaccine candidates to behave like live pathogens in terms of immune stimulation, for induction of highly effective immune responses.
We initially focused on the development of gamma-irradiated influenza A virus vaccine (termed γ-Flu) and published the ability of γ-Flu to induce cross-protective immunity against both homotypic and heterosubtypic infections, including potential pandemic viruses. This superior cross-protective immunity is related to two important factors: 1) limited structural damage and 2) the ability of γ-Flu to deliver conserved internal flu proteins into the MHC-I antigen presentation pathway to activate CD8+ T-cell responses. Interestingly, due to the conserved structure of γ-Flu, our inactivated vaccine retains the ability to induce IFN-I, and this can be utilised to enhance immunogenicity of co-administered antigens. We have also developed a whole-inactivated vaccine against Streptococcus pneumoniae using gamma-irradiated un-encapsulated and genetically modified pneumococci (termed γ-PN). Similarly, we have reported the induction of broadly reactive immune responses following intranasal administration, with conferral of serotype independent pneumococcal protection.
Interestingly, current strategies to reduce the risk of co-infection with influenza and S. pneumoniae are focused on developing vaccines against individual pathogens. Considering the lethal synergism between influenza and pneumococcal infections, we questioned whether we could combine γ-Flu and γ-PN in a single vaccination strategy. To our knowledge, no previous studies attempted or reported the possibility of combining whole inactivated viral and bacterial vaccines. This may have been caused by an old immunological dogma related to possible immune dysregulation and the dominance of the antiviral TH1 responses over the previously assumed anti-bacterial TH2 responses. Considering our current understanding of T-cell biology, immune dysregulation between TH1 and TH2 is no longer relevant when dealing with bacterial infections. Interestingly, our early work illustrated that co-administration of γ-Flu and γ-PN was associated with enhanced pneumococcal-specific immunity, without affecting the level of strain-specific flu protection. Considering that γ-Flu was initially developed to induce cross-reactive CD8+ T-cell responses, we questioned whether mixing γ-Flu and γ-PN could affect influenza-specific T-cell immunity. To our surprise, our data show co-administration of γ-Flu and γ-PN is associated with significantly enhanced influenza-specific cross-protective immunity against severe flu infection models that involve both drifted and heterosubtypic challenge strains. This superior protection observed following vaccine co-administration is associated with enhanced cytokine responses (particularly those important for the recruitment and differentiation of T-cells and antigen presenting cells), enhanced γ-Flu uptake, and enhanced tissue resident memory cell responses in the lung. Importantly, this γ-PN driven enhancement of influenza-specific responses is related to a direct physical interaction between influenza A virus and pneumococci, which is also maintained for our whole inactivated vaccines. Overall, our study illustrates a direct physical interaction between two prominent respiratory pathogens, which could have a major impact on pathogenicity and vaccine design. To our knowledge, our studies represent the first vaccination approach based on mixing whole inactivated virus with whole inactivated bacteria to enhance pathogen-specific immunity.
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