Pneumococcal capsule blocks protection by immunization with conserved surface proteins

Abstract

Vaccines targeting Streptococcus pneumoniae (Spn) are limited by dependence on capsular polysaccharide and its serotype diversity. More broadly-based approaches using common protein antigens have not resulted in a licensed vaccine. Herein, we used an unbiased, genome-wide approach to find novel vaccine antigens to disrupt carriage modeled in mice. A Tn-Seq screen identified 198 genes required for colonization of which 16 are known to express conserved, immunogenic surface proteins. After testing defined mutants for impaired colonization of infant and adult mice, 5 validated candidates (StkP, PenA/Pbp2a, PgdA, HtrA, and LytD/Pce/CbpE) were used as immunogens. Despite induction of antibody recognizing the Spn cell surface, there was no protection against Spn colonization. There was, however, protection against an unencapsulated Spn mutant. This result correlated with increased antibody binding to the bacterial surface in the absence of capsule. Our findings demonstrate how the pneumococcal capsule interferes with mucosal protection by antibody to common protein targets.

Pneumococcal Phasevarions Control Multiple Virulence Traits, Including Vaccine Candidate Expression

“…3 and 4 ). Our results are in agreement with the findings of Zangari et al, who recently found immunization against conserved surface proteins induced antibody titers unable to prevent colonization by an encapsulated strain, but were able to protect against an acapsular mutant of that same strain (that had comparable levels of antibody targets) ( 50 ). Our findings suggest there is a particular, specialized role for a variant expressing decreased capsule level (SpnIII B).…”

“…Our findings suggest there is a particular, specialized role for a variant expressing decreased capsule level (SpnIII B). It is possible that the protective effect seen by Zangari et al ( 50 ) when targeting conserved surface proteins in an acapsular mutant would also be effective against naturally occurring SpnIII alleles with reduced capsule (such as SpnIII B and C in strain D39). Furthermore, targeting naturally occurring phenotypes that we have shown to be important in biofilm formation and cellular adherence and invasion may prove effective in preventing key stages of S. pneumoniae disease progression, such as colonization.…”

A phasevarion controls multiple virulence traits, including expression of vaccine candidates, in Streptococcus pneumoniae

“…We have demonstrated that even within a single strain (D39; serotype 2), the differences in capsule due to SpnIII allele switching impact neutrophil killing and likely cellular adherence and invasion (Figure 3, 4). Our results are in agreement with the findings of Zangari et al, who recently found immunisation against conserved surface proteins induced antibody titres unable to prevent colonisation by an encapsulated strain, but were able to protect against an acapsular mutant of that same strain (that had comparable levels of antibody targets) [40]. Our findings suggest there is a particular, specialised role for a variant expressing decreased capsule level (SpnIIIB).…”

Pneumococcal Surface Protein A-Hybrid Nanoparticles Protect Mice from Lethal Challenge after Mucosal Immunization Targeting the Lungs

“…These phenomena mitigate the benefits of the vaccines [9], and hence, recombinant pneumococcal protein antigens are considered promising candidates for new serotype-independent vaccines. However, several protein-based or whole-cell vaccines have failed to progress in clinical trials, highlighting the importance of exploring new approaches, especially those that have the potential to block pneumococcal carriage [10], such as mucosal immunization.…”