Generation and Improvement of Effector Function of a Novel Broadly Reactive and Protective Monoclonal Antibody against Pneumococcal Surface Protein A of Streptococcus pneumoniae

Abstract

A proof-of-concept study evaluating the potential of Streptococcus pneumoniae Pneumococcal Surface Protein A (PspA) as a passive immunization target was conducted. We describe the generation and isolation of several broadly reactive mouse anti-PspA monoclonal antibodies (mAbs). MAb 140H1 displayed (i) 98% strain coverage, (ii) activity in complement deposition and opsonophagocytic killing (OPK) assays, which are thought to predict the in vivo efficacy of anti-pneumococcal mAbs, (iii) efficacy in mouse sepsis models both alone and in combination with standard-of-care antibiotics, and (iv) therapeutic activity in a mouse pneumonia model. Moreover, we demonstrate that antibody engineering can significantly enhance anti-PspA mAb effector function. We believe that PspA has promising potential as a target for the therapy of invasive pneumococcal disease by mAbs, which could be used alone or in conjunction with standard-of-care antibiotics.

Protective responses of an engineered PspA recombinant antigen against Streptococcus pneumoniae

“…Although, some researches have indicated that PspA fragment from clade 4, especially those include all cell-surface domain, can induce high cross-reactive antibodies, our results and the conclusions from other researcher [31,32] have shown that anti-sera against PspA from clade 4 is often family-dependent and sometimes restricted to the same clade.…”

“…PspA antigen is a promising vaccine candidate with protein nature against pneumococcal infections to overcome the limitations of polysaccharide-based vaccines [32]. PspA shows considerable antigenic diversity among clinical isolates and it is divided into three families with six clades.…”

“…Since some researches have demonstrated that the immunity elicited by family 1 or family 2 was clade dependent [25,27,31], it is suggested that high antigenic fragments of all clades, that have the greatest impact on cross-reactivity, should be included in a chimeric PspA-based vaccine. Also, the proline-rich region and the A region domain contain more conserved epitopes across the PspA with the effect on cross-reactivity [27,32]. In this context, Zhenyu Piao et al generated three recombinant PspA proteins consist of N-terminal and proline rich region from two PspA families.…”

Room Temperature Stable PspA-Based Nanovaccine Induces Protective Immunity

“…It was demonstrated that PCV7 immunization, which contains the 19F serotype antigen, actually caused an increase in pneumococcal infections by the closely related 19A serotype ( 16 ). Globally, this is of particular concern when considering the development of a universal vaccine, as it is now clear that the prevalence of certain serotypes differs greatly between age, geographic region, and ethnicity ( 3 , 17 , 18 ). PPV23 encompasses the most pneumococcal serotypes of the commercially available vaccines.…”

“…PspA has been of recent interest as a potential vaccine candidate due to its location on the cell surface of all 95 strains of S. pneumoniae currently known and its critical role in pneumococcal pathogenesis ( 3 , 23 , 24 ). Anti-PspA antibodies to clades 1 and 2 of PspA have been shown to be cross-protective against S. pneumoniae strains encompassing all six clades of PspA, and provide protection when passively transferred to naïve mice as a therapeutic intervention following septic S. pneumoniae challenge ( 17 , 25 – 27 ). The ability to provide protection across many serotypes of S. pneumoniae using only two clades of PspA allows for the design of a broadly cross-protective vaccine when compared to vaccines containing numerous capsular polysaccharides.…”