Pneumococcal diversity: considerations for new vaccine strategies with emphasis on pneumococcal surface protein A (PspA)

Abstract

Streptococcus pneumoniae is a problematic infectious agent, whose seriousness to human health has been underscored by the recent rise in the frequency of isolation of multidrug-resistant strains. Pneumococcal pneumonia in the elderly is common and often fatal. Young children in the developing world are at significant risk for fatal pneumococcal respiratory disease, while in the developed world otitis media in children results in substantial economic costs. Immunocompromised patients are extremely susceptible to pneumococcal infection. With 90 different capsular types thus far described, the diversity of pneumococci contributes to the challenges of preventing and treating S. pneumoniae infections. The current capsular polysaccharide vaccine is not recommended for use in children younger than 2 years and is not fully effective in the elderly. Therefore, innovative vaccine strategies to protect against this agent are needed. Given the immunogenic nature of S. pneumoniae proteins, these molecules are being investigated as potential vaccine candidates. Pneumococcal surface protein A (PspA) has been evaluated for its ability to elicit protection against S. pneumoniae infection in mouse models of systemic and local disease. This review focuses on immune system responsiveness to PspA and the ability of PspA to elicit cross-protection against heterologous strains. These parameters will be critical to the design of broadly protective pneumococcal vaccines.

FIG. 1

Hypothetical representation of the pneumococcal surface depicting several noncapsular antigens shown to elicit protective immune responses in mice. C-polysaccharide (teichoic acid) attached to the cell wall is thought to be similar in structure to F-antigen (lipoteichoic acid), except that the latter contains lipids allowing it to insert in the cell membrane. Neuraminidase has been depicted both in the cytoplasm and beyond the capsule, since it is thought to be secreted by pneumococci. Although its role in virulence is mediated at a distance from pneumococci, pneumolysin is depicted in the cytoplasm of the cell shown here, since its release is dependent on the autolytic activity of autolysin. For PspA, an effort has been made to draw its extension from the surface to scale with respect to the thickness of the cell wall and capsule. It has been hypothesized that the lysines of the PspA α-helix interact with the capsular polysaccharides to stabilize the coverage of the surface by the capsule. This hypothetical function is depicted by showing individual capsular polysaccharide strands interacting with more than one PspA molecule. Since the location of PsaA with respect to other cell surface structures is unknown, its depiction here is completely hypothetical. Reprinted from reference with permission of the publisher.

FIG. 2

Schematic presentation of the domains of PspA delineated from the deduced amino acid sequence of Rx1 pspA. The locations of cross-protective MAb epitopes, determined by mapping studies, are shown. Numbers indicate amino acid residues. The two arrows point to the proline-rich (amino acids 289 to 370) and choline-binding (amino acids 371 to 571) regions, respectively. The functions of these regions are largely unknown but may include mechanistic roles, in addition to those described herein.