Evaluation of Pneumococcal Surface Protein A as a Vaccine Antigen against Secondary Streptococcus pneumoniae Challenge during Influenza A Infection

Abstract

Secondary bacterial pneumonia is responsible for significant morbidity and mortality during seasonal and pandemic influenza. Due to the unpredictability of influenza A virus evolution and the time-consuming process of manufacturing strain-specific influenza vaccines, recent efforts have been focused on developing anti-Streptococcus pneumoniae immunity to prevent influenza-related illness and death. Bacterial vaccination to prevent viral-bacterial synergistic interaction during co-infection is a promising concept that needs further investigation. Here, we show that immunization with pneumococcal surface protein A (PspA) fully protects mice against low-dose, but not high-dose, secondary bacterial challenge using a murine model of influenza A virus-S. pneumoniae co-infection. We further show that immunization with PspA is more broadly protective than the pneumococcal conjugate vaccine (Prevnar). These results demonstrate that PspA is a promising vaccine target that can provide protection against a physiologically relevant dose of S. pneumoniae following influenza infection.

Impact of Influenza on Pneumococcal Vaccine Effectiveness during Streptococcus pneumoniae Infection in Aged Murine Lung

“…These results extend the findings from our previous work, which illustrated that an age-associated decrease in NLRP3 inflammasome activation contributed to increased morbidity and mortality of aged adult mice to secondary S. pneumoniae at day 14 post influenza [52]. Similar to previously published studies in young adult mice, we also observed a dramatic reduction in vaccine efficacy against S. pneumoniae in the presence of influenza [17,30,31]. Based on these results, it is possible that the immune priming response that occurs during influenza can have a direct negative impact on adaptive vaccine responses in aged adult lung.…”

“…As recent work has illustrated differential efficacy of Prevnar vaccination in modulating the immune responses of adult mice to a post-influenza infection with a serotype 3 strain of Streptococcus pneumoniae, we chose to examine the impact of Pneumovax on these responses [30,40]. Given these findings, it would be plausible that other vaccines, designed with specific bacterial components, such as pneumococcal surface protein A (PspA) and pneumolysin (Ply) or liposomal encapsulation of polysaccharides (LEPS), may improve efficacy to post-influenza S. pneumoniae infection [31,[43][44][45]. Future work will need to evaluate if additional vaccine types can prove efficacious and further reduce inflammatory cytokine production while improving bacterial clearance post-influenza infection.…”

“…Progression of influenza and viral-mediated changes in the immune response contribute to increased virus-mediated damage to the lung and resulted in greater susceptibility to a secondary pneumococcal infection [18,24,[26][27][28][29]. Further, recent work has demonstrated that, in the absence of influenza, young adult mice immunized with pneumococcal-specific vaccines are highly efficient in pulmonary clearance of the bacteria [30,31]. In the presence of influenza, vaccine protection was dramatically reduced [17,30,31].…”

“…Further, recent work has demonstrated that, in the absence of influenza, young adult mice immunized with pneumococcal-specific vaccines are highly efficient in pulmonary clearance of the bacteria [30,31]. In the presence of influenza, vaccine protection was dramatically reduced [17,30,31]. Vaccine variations, such as immunization with pneumococcal surface protein A (PspA), engineered live-attenuated vaccines, and dual vaccine/cytokine administration, have been shown to fully protect influenza-infected mice against a physiologically relevant dose of S. pneumoniae [31][32][33].…”

“…In the presence of influenza, vaccine protection was dramatically reduced [17,30,31]. Vaccine variations, such as immunization with pneumococcal surface protein A (PspA), engineered live-attenuated vaccines, and dual vaccine/cytokine administration, have been shown to fully protect influenza-infected mice against a physiologically relevant dose of S. pneumoniae [31][32][33]. Taken together, the cascade of innate and adaptive immune responses to an immune imprinting event can greatly impact host susceptibility to secondary infection [7].…”