Systemic and Mucosal Protective Immunity to Pneumococcal Surface Protein A

Abstract

To date our studies demonstrate that PspA is a highly immunogenic molecule in mice and that it can elicit immunity to otherwise fatal infections following iv, ip, in, and it challenge. Although the molecule is serologically variable, it is sufficiently cross-reactive so that immunization with a single PspA can protect against strains of highly diverse serotypes. It is anticipated that a vaccine composed of a mixture of carefully chosen PspA molecules will be able to elicit protective immunity to virtually all pneumococci. If this vaccine proved efficacious in man, it would provide a more simple and less costly means of immunizing against pneumococcal infection than using recombinant vaccines. This could be especially important in the developing world where the cost of successful vaccines must be no more than pennies per dose. If PspA is found to be less efficacious than capsular polysaccharides, it may be valuable as a protein component of a PS-protein conjugate vaccine. In this capacity, PspA might expand the breath of protection elicited by a vaccine composed of only a few polysaccharide-protein conjugates representing capsule types most commonly associated with infectious pneumococci.

Additive Attenuation of Virulence of Streptococcus pneumoniae by Mutation of the Genes Encoding Pneumolysin and Other Putative Pneumococcal Virulence Proteins

“…The N-terminal portion of the choline-binding protein PspA has been predicted to have a coiled-coil structure reminiscent of the M proteins of group A streptococci (46), and this might be expected to protrude through the capsule. Although the Nterminal region is highly variable, PspA contains conserved epitopes which elicit antibodies protective against multiple S. pneumoniae serotypes (13,45). CbpA is structurally similar to PspA; the C-terminal choline-binding domains have Ͼ90% amino acid sequence identity, and although there is no sequence similarity, the N-terminal portion of CbpA is also predicted to have a coiled-coil structure (22,39).…”

“…PspA is a member of a family of structurally related choline-binding surface proteins (19,20,46,47); its precise function is uncertain, although it has recently been shown to be capable of binding human lactoferrin (21). Both Ply and PspA are protective immunogens, and mutagenesis of the genes which encode them attenuates virulence of S. pneumoniae (1,3,7,9,10,12,13,31,45). The major pneumococcal autolysin (LytA) is also a choline-binding protein (19,20) which contributes to virulence by mediating the release of Ply and possibly also inflammatory cell wall degradation products (4,9,26).…”

Relative Roles of Genetic Background and Variation in PspA in the Ability of Antibodies to PspA To Protect against Capsular Type 3 and 4 Strains of Streptococcus pneumoniae

“…HR108 is a 105-aa (residues 314 to 418) fragment of the ␣-helical domain of PspA/TIGR4, which was shown to contain the most important cross-protective epitopes (29). HR108 is homologous to the region of family 1 PspA/Rx1 to which its major cross-protective epitopes have also been mapped (11,22). The PspA regions homologous to HR108 have been used to classify PspAs into clades and families (18).…”

Diversity of PspA: Mosaic Genes and Evidence for Past Recombination in Streptococcus pneumoniae

“…PspA is present on all pneumococcal strains and is serologically variable (15). Mouse models have shown that cross-reactive anti-PspA antisera are also cross-protective (reviewed in references 8,9,60). Human antisera from a phase I vaccine trial were also competent for protecting mice from pneumococcal infection by challenge strains of various PspA types (5a).…”