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Background: Secondary bacterial infections following influenza represent a major cause of mortality in the human population, which, in turn, has led to a call for stockpiling of bacterial vaccines for pandemic preparedness., Methods: To investigate the efficacy of bacterial vaccination for protection against secondary pneumococcal infection, mice were immunized with pneumococcal capsular polysaccharide conjugate vaccine, and then sequentially coinfected 5 weeks later with PR8 influenza virus and A66.1 Streptococcus pneumoniae., Results: In the absence of influenza virus exposure, vaccination with polysaccharide conjugate vaccine was highly effective, as indicated by 100% survival from lethal pneumococcal pneumonia and 10 000-fold greater efficiency in clearance of bacteria from the lung compared to unvaccinated mice. Enhanced clearance after vaccination was dependent upon Fc receptor (FcR) expression. However, following influenza, <40% of vaccinated mice survived bacterial coinfection and FcR-dependent clearance of antibody-opsonized bacteria reduced bacterial levels in the lungs only 5-10 fold. No differences in lung myeloid cell numbers or in FcR cell surface expression were observed following influenza., Conclusions: The results show that induction of antibacterial humoral immunity is only partially effective in protection against secondary bacterial infections that occur following influenza, and suggest that additional therapeutic strategies to overcome defective antibacterial immunity should be explored., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The efficacy of different vaccines in protecting elderly individuals against Streptococcus pneumoniae infections is not clear. In the current study, aged mice (22-25 months old) exhibited significantly increased susceptibility to respiratory infection with serotype 3 S. pneumoniae relative to younger adult mice, regardless of whether mice were naive or immunized with native pneumococcal polysaccharide (PPS; Pneumovax23) or protein-PPS conjugate (Prevnar-13) vaccines. Nonetheless, Pneumovax-immunized aged mice developed limited bacteremia following respiratory challenge and exhibited significantly increased survival following systemic challenge relative to Prevnar-immune aged mice and young mice that had received either vaccine. This was explained by >10-fold increases in PPS-specific immunoglobulin G (IgG) levels in Pneumovax-immunized aged mice relative to other groups. Remarkably, PPS3-specific B-cell expansion, IgG switching, plasmablast differentiation, and spleen and bone marrow antibody-secreting cell frequencies were 10-fold higher in aged mice following Pneumovax immunization relative to young mice, due to significantly increased B-1b cell participation. In summary, this study highlights (1) the need to devise strategies to enhance respiratory immunity in aged populations, (2) the diverse responses young and aged populations generate to Pneumovax vs Prevnar vaccines, and (3) the potential value of exploiting B-1b cell responses in aged individuals for increased vaccine efficacy.

Secondary bacterial infections due to Streptococcus pneumoniae and Staphylococcus aureus, responsible for excess morbidity and mortality during influenza epidemics, are often preceded by excess bacterial density within the upper respiratory tract. Influenza and pneumococcal vaccines reduce secondary infections within the lungs; however, their effects on upper respiratory tract carriage remain unknown. We demonstrate that a live attenuated influenza vaccine significantly reduces pneumococcal growth and duration of carriage during subsequent influenza to levels seen in influenza-naive controls. No benefit was seen after pneumococcal conjugate vaccine. Our results suggest that live attenuated influenza vaccines may significantly reduce bacterial disease during influenza epidemics.

The antibody response to pneumococcal glycoconjugate (Pnc) was characterized by analyzing pneumococcal polysaccharide (PPS)-- and protein carrier-specific IgG subclass profiles and their relationship. Mice were immunized intranasally (inl) or subcutaneously (sc) with Pnc with mutants of Escherichia coli heat-labile enterotoxin, LT-R72 and LT-K63, as mucosal adjuvants. Subcutaneous immunization with Pnc alone induced predominantly IgG1, whereas native PPS administered sc induced very low IgG titers that were exclusively of the IgG3 subclass. Compared with sc immunization with Pnc alone, inl immunization with Pnc and LT mutants induced significantly higher systemic IgG2a, IgG3, and IgA antibodies to both PPS and the carrier, whereas the IgG1 titers were comparable. There also was a significant correlation between PPS- and protein carrier--specific antibody responses for all IgG subclasses. This demonstrates that LT mutants can be used to both enhance and modulate the antibody response to the PS moiety of glycoconjugate vaccines.