Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC

Vadesilho, Cintia F. M.; Ferreira, Daniela M.; Gordon, Stephen B.; Briles, David E.; Moreno, Adriana T.; Oliveira, Maria Leonor S.; Ho, Paulo Lee; Miyaji, Eliane N.

doi:10.1128/cvi.00239-14

Cited by 23 publications

(29 citation statements)

References 50 publications

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“…Importantly, the PRR that potentially cross-reacts with human myosin is not part of the ␣1␣2 fragment of PspA (34). In mice and humans, MHC-II T-cell epitopes are localized in this particular fragment of PspA (33,(35)(36)(37)(38)(39). Mucosal CD4 ϩ IL-17 ϩ T cells were detected in the human upper respiratory tract and are likely to play a role in protection against bacterial colonization in humans, similar to what we have observed in our mouse studies (40).…”

Section: Figsupporting

confidence: 86%

Th17-Mediated Cross Protection against Pneumococcal Carriage by Vaccination with a Variable Antigen

et al. 2017

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Serotype-specific protection against Streptococcus pneumoniae is an important limitation of the current polysaccharide-based vaccines. To prevent serotype replacement, reduce transmission, and limit the emergence of new variants, it is essential to induce broad protection and restrict pneumococcal colonization. In this study, we used a prototype vaccine formulation consisting of lipopolysaccharide (LPS)-detoxified outer membrane vesicles (OMVs) from Salmonella enterica serovar Typhimurium displaying the variable N terminus of PspA (␣1␣2) for intranasal vaccination, which induced strong Th17 immunity associated with a substantial reduction of pneumococcal colonization. Despite the variable nature of this protein, a common major histocompatibility complex class (MHC-II) epitope was identified, based on in silico prediction combined with ex vivo screening, and was essential for interleukin-17 A (IL-17A)-mediated cross-reactivity and associated with cross protection. Based on 1,352 PspA sequences derived from a pneumococcal carriage cohort, this OMV-based vaccine formulation containing a single ␣1␣2 type was estimated to cover 19.1% of strains, illustrating the potential of Th17-mediated cross protection.KEYWORDS intranasal vaccination, protein antigens, Streptococcus pneumoniae, PspA, colonization, Th17, broad protection, Salmonella outer membrane vesicle (OMV), antigen surface display, autotransporter Hbp R espiratory bacterial infections remain a major cause of severe morbidity and mortality worldwide in both infants and adults (1, 2). Vaccination is considered one of the most cost-effective strategies to reduce the global burden of infectious diseases, the associated health care costs, and the risk of emerging antibiotic-resistant strains (3). Vaccination against Streptococcus pneumoniae is implemented in different parts of the world. However, about 1 million children still die of pneumococcal disease every year (1, 2). Pneumococcal polysaccharide conjugate vaccines are designed based on epidemiological data from the Western world. These vaccines protect against serotypes that are the most prevalent and most frequently associated with severe invasive disease. They induce serotype-specific protection against 13 of the 97 identified serotypes that are circulating worldwide (4). This is an important limitation, and during the last decade, nonvaccine variants of S. pneumoniae that cause severe invasive disease have Citation Kuipers K, Jong WSP, van der Gaast-de Jongh CE, Houben D, van Opzeeland F, Simonetti E, van Selm S, de Groot R, Koenders MI, Azarian T, Pupo E, van der Ley P, Langereis JD, Zomer A, Luirink J, de Jonge MI. 2017. Th17-mediated cross protection against pneumococcal carriage by vaccination with a variable antigen. Infect Immun 85:e00281-17.

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Section: Figsupporting

confidence: 86%

Th17-Mediated Cross Protection against Pneumococcal Carriage by Vaccination with a Variable Antigen

et al. 2017

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“…Among them, the N-terminal α-helical domain is exposed on the surface, and protection-eliciting epitopes of PspA appear to be spread throughout this region [ 29 ]. The induction of antibody production against conformational epitopes present at this region may be important for the promotion of broad protection against pneumococci [ 30 ]. A previous study of 40 pneumococcal meningitis isolates from German children showed that the amino acid sequence identity of the α-helical and proline-rich domains were as low as 32% [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Genetic diversity of pneumococcal surface protein A in invasive pneumococcal isolates from Korean children, 1991-2016

2017

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Pneumococcal surface protein A (PspA) is an important virulence factor of pneumococci and has been investigated as a primary component of a capsular serotype-independent pneumococcal vaccine. Thus, we sought to determine the genetic diversity of PspA to explore its potential as a vaccine candidate. Among the 190 invasive pneumococcal isolates collected from Korean children between 1991 and 2016, two (1.1%) isolates were found to have no pspA by multiple polymerase chain reactions. The full length pspA genes from 185 pneumococcal isolates were sequenced. The length of pspA varied, ranging from 1,719 to 2,301 base pairs with 55.7–100% nucleotide identity. Based on the sequences of the clade-defining regions, 68.7% and 49.7% were in PspA family 2 and clade 3/family 2, respectively. PspA clade types were correlated with genotypes using multilocus sequence typing and divided into several subclades based on diversity analysis of the N-terminal α-helical regions, which showed nucleotide sequence identities of 45.7–100% and amino acid sequence identities of 23.1–100%. Putative antigenicity plots were also diverse among individual clades and subclades. The differences in antigenicity patterns were concentrated within the N-terminal 120 amino acids. In conclusion, the N-terminal α-helical domain, which is known to be the major immunogenic portion of PspA, is genetically variable and should be further evaluated for antigenic differences and cross-reactivity between various PspA types from pneumococcal isolates.

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“…Analysis of strain collections including carriage and invasive isolates from the same region and period may help to further dissect the contribution of PspC subgroups and types to invasive disease potential. Additionally, more insight into epidemiological differences in PspC type prevalence and their contributions to invasive disease may have implications for vaccine design, because PspC is an important vaccine candidate (46)(47)(48). Our study demonstrates PspC subgroup and type distributions in invasive disease analogous to serotype distribution in invasive disease.…”

Section: Discussionmentioning

confidence: 65%

Streptococcus pneumoniae PspC Subgroup Prevalence in Invasive Disease and Differences in Contribution to Complement Evasion

et al. 2018

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The pneumococcal capsular serotype is an important determinant of complement resistance and invasive disease potential, but other virulence factors have also been found to contribute. Pneumococcal surface protein C (PspC), a highly variable virulence protein that binds complement factor H to evade C3 opsonization, is divided into two subgroups: choline-bound subgroup I and LPxTG-anchored subgroup II. The prevalence of different PspC subgroups in invasive pneumococcal disease (IPD) and functional differences in complement evasion are unknown. The prevalence of PspC subgroups in IPD isolates was determined in a collection of 349 sequenced strains of isolated from adult patients. deletion mutants and isogenic switch mutants were constructed to study differences in factor H binding and complement evasion in relation to capsule thickness. Subgroup I was far more prevalent in IPD isolates than subgroup II The presence of capsule was associated with a greater ability of bound factor H to reduce complement opsonization. Pneumococcal subgroup I PspC bound significantly more factor H and showed more effective complement evasion than subgroup II PspC in isogenic encapsulated pneumococci. We conclude that variation in the PspC subgroups, independent of capsule serotypes, affects pneumococcal factor H binding and its ability to evade complement deposition.

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Mapping of Epitopes Recognized by Antibodies Induced by Immunization of Mice with PspA and PspC

Cited by 23 publications

References 50 publications

Th17-Mediated Cross Protection against Pneumococcal Carriage by Vaccination with a Variable Antigen

Th17-Mediated Cross Protection against Pneumococcal Carriage by Vaccination with a Variable Antigen

Genetic diversity of pneumococcal surface protein A in invasive pneumococcal isolates from Korean children, 1991-2016

Streptococcus pneumoniae PspC Subgroup Prevalence in Invasive Disease and Differences in Contribution to Complement Evasion

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