Abstract
ABSTRACTCurrent vaccination against Streptococcus pneumoniae uses vaccines based on capsular polysaccharides from selected serotypes and has led to nonvaccine serotype replacement disease. We have investigated an alternative serotype-independent approach, using multiple-antigen vaccines (MAV) prepared from S. pneumoniae TIGR4 lysates enriched for surface proteins by a chromatography step after culture under conditions that induce expression of heat shock proteins (Hsp; thought to be immune adjuvants). Proteomics and immunoblot analyses demonstrated that, compared to standard bacterial lysates, MAV was enriched with Hsps and contained several recognized protective protein antigens, including pneumococcal surface protein A (PspA) and pneumolysin (Ply). Vaccination of rodents with MAV induced robust antibody responses to multiple serotypes, including nonpneumococcal conjugate vaccine serotypes. Homologous and heterologous strains of S. pneumoniae were opsonized after incubation in sera from vaccinated rodents. In mouse models, active vaccination with MAV significantly protected against pneumonia, while passive transfer of rabbit serum from MAV-vaccinated rabbits significantly protected against sepsis caused by both homologous and heterologous S. pneumoniae strains. Direct comparison of MAV preparations made with or without the heat shock step showed no clear differences in protein antigen content and antigenicity, suggesting that the chromatography step rather than Hsp induction improved MAV antigenicity. Overall, these data suggest that the MAV approach may provide serotype-independent protection against S. pneumoniae.
Highlights
Streptococcus pneumoniae is a common cause of community-acquired pneumonia (CAP), septicemia, and meningitis [1], as well as of noninvasive diseases, such as acute otitis media (AOM) and bronchitis [2]
Heat shock was used to enrich for heat shock proteins (Hsp), and anion-exchange chromatography was used to enrich for negatively charged S. pneumoniae antigens (e.g., pneumococcal surface protein A (PspA) and Ply) (Fig. 1A)
Immunoblots determined which elution fractions contained the highest concentration of the Hsp60 and Hsp70 proteins and demonstrated a marked increase in the expression of both the Hsp60 and Hsp70 content in the multiple-antigen vaccine (MAVhs) compared to the bacterial heat-killed lysate (HKL) (Fig. 1B and C)
Summary
Streptococcus pneumoniae is a common cause of community-acquired pneumonia (CAP), septicemia, and meningitis [1], as well as of noninvasive diseases, such as acute otitis media (AOM) and bronchitis [2]. Over 90 different serotypes of S. pneumoniae, determined by the characteristics of the capsular polysaccharide (CPS), have been identified [3]. There are currently two vaccines available to prevent S. pneumoniae infections: the pneumococcal polysaccharide vaccine (PPV) and the pneumococcal conjugate vaccine (PCV). Each consists of capsular polysaccharide antigen from a limited panel of S. pneumoniae serotypes. In the United Kingdom, PPV remains the first choice for adult vaccination [4], and PCV is routinely included in childhood immunization schedules worldwide, as it has greater efficacy than PPV in infants. In developing countries the high cost of PCV restricts its availability, and in addition, serotype coverage is reduced, as PCV was designed to include the most prevalent serotypes in North America [5]. Serotype replacement in response to PCV vaccination
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