Recognition of pneumococcal isolates by antisera raised against PspA fragments from different clades

Abstract

Pneumococcal surface protein A (PspA) is an important vaccine candidate against pneumococcal infections, capable of inducing protection in different animal models. Based on its structural diversity, it has been suggested that a PspA-based vaccine should contain at least one fragment from each of the two major families (family 1, comprising clades 1 and 2, and family 2, comprising clades 3, 4 and 5) in order to elicit broad protection. This study analysed the recognition of a panel of 35 pneumococcal isolates bearing different PspAs by antisera raised against the N-terminal regions of PspA clades 1 to 5. The antiserum to PspA clade 4 was found to show the broadest cross-reactivity, being able to recognize pneumococcal strains containing PspAs of all clades in both families. The cross-reactivity of antibodies elicited against a PspA hybrid including the N-terminal region of clade 1 fused to a shorter and more divergent fragment (clade-defining region, or CDR) of clade 4 (PspA1–4) was also tested, and revealed a strong recognition of isolates containing clades 1, 4 and 5, and weaker reactions with clades 2 and 3. The analysis of serum reactivity against different PspA regions further revealed that the complete N-terminal region rather than just the CDR should be included in an anti-pneumococcal vaccine. A PspA-based vaccine is thus proposed to be composed of the whole N-terminal region of clades 1 and 4, which could also be expressed as a hybrid protein.

Molecular Dissection of Antibody Responses against Pneumococcal Surface Protein A: Evidence for Diverse DH-Less Heavy Chain Gene Usage and Avidity Maturation

“…The B cell epitope recognized by 18 of the 36 (50%) anti-PspA 3-286 mAbs localized to the region corresponding to aa 3-192 of PspA. The B cell epitopes recognized by the remaining 18 mAbs are spread across the surface-exposed portion of PspA (aa residues 1-288), which is consistent with previous studies (21,23,37). Anti-PspA mAbs that recognized PspA did not recognize its subfragments PspA and PspA 98 -192 (Table VI, groups 7 and 8).…”

“…Understanding the molecular diversity of the Ab responses to PspA, a highly protective pneumococcal Ag, has assumed importance as efforts are on to develop a PspAbased pneumococcal vaccine (11,12,37,38). Earlier studies done using a limited number of anti-PspA mAbs have provided some information regarding the location of protection-eliciting B cell epitopes.…”

Occurrence, Distribution, and Origins of Streptococcus pneumoniae Serotype 6C, a Recently Recognized Serotype

“…Similarly, inclusion of serotype 19F in PCV7 has not provided cross-immunogenicity to serotype 19A (1,2,19,25,31,36). Use of other antigenic targets has been suggested, such as pneumococcal surface protein A (PspA), which comprises five clades in two families, and findings suggest that use of just two of the clades provides broad antibody cross-reactivity to all five clades (7). The diversity of antigenic targets in S. pneumoniae and the ability of this species to transform genetically will continue to challenge control of pneumococcal disease with use of vaccines.…”

Controlled Inflammatory Responses in the Lungs Are Associated with Protection Elicited by a Pneumococcal Surface Protein A-Based Vaccine against a Lethal Respiratory Challenge with Streptococcus pneumoniae in Mice

“…Sequencing analyses led to the classification of PspAs in 6 clades that can be grouped into three families (26). Cross-reactivity was reported for molecules that belong to the same family or for specific molecules that induce antibodies that recognize PspAs from different clades (18). Broad-coverage vaccines based on PspA would thus depend on the use of more than one molecule or on the choice of specific PspA molecules (37).…”