Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001

Leach, Amanda J.; Morris, Peter S.; McCallum, Gabrielle B.; Wilson, Cate; Stubbs, Liz; Beissbarth, Jemima; Jacups, Susan P.; Hare, Kim M.; Smith‐Vaughan, Heidi

doi:10.1186/1471-2334-9-121

Cited by 51 publications

(27 citation statements)

References 19 publications

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“…Despite being present in low numbers, nonencapsulated forms of PCV7 serotypes are also likely to harbor the antibiotic resistance genes of their parent capsular vaccine serotypes and thus have the potential to transfer antibiotic resistance to newly emerging nonvaccine serotypes. Our 2005 surveillance of pneumococcal carriage by Indigenous children found that 14% of the isolates were non-penicillin susceptible (MIC Ն 0.12 g/ml) and that 6% of the isolates were azithromycin resistant (MIC Ն 2 g/ml) (15). The penicillin resistance data are in stark contrast to the 55.5% rate of non-penicillin susceptibility that we found in wzg-negative NSP and 26% in potentially revertible wzg-positive NSP.…”

Section: Discussioncontrasting

confidence: 54%

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The Nonserotypeable Pneumococcus: Phenotypic Dynamics in the Era of Anticapsular Vaccines

et al. 2010

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Nonserotypeable pneumococci (NSP) are commonly carried by Australian Indigenous children in remote communities. The purpose of this study was to characterize carriage isolates of NSP from Indigenous children vaccinated with the seven-valent pneumococcal conjugate vaccine (PCV7) and to use these data to guide decisions on reporting of NSP. A total of 182 NSP were characterized by BOX typing, antibiogram analysis, and multilocus sequence typing (MLST) of common BOX types. NSP positive for the wzg capsule gene were analyzed by a multiplex PCR-based reverse line blot hybridization assay (mPCR/RLB-H) targeting capsule genes to determine the serotype. Among 182 NSP, 49 BOX types were identified. MLST of 10 representative isolates found 7 STs, including ST448 (which accounted for 11% of NSP). Non-penicillin susceptibility was evident in 51% of the isolates. Pneumococcal wzg sequences were detected in only 23 (13%) NSP, including 10 that contained an ϳ1.2-kb insert in the region. mPCR/RLB-H identified serotype 14 wzy sequences in all 10 NSP, and 1 also contained a serotype 3-specific wze sequence. Among the remaining 13 wzg-positive NSP, few belonged to the serotypes represented in PCV7. It appears that most NSP identified in Australian Indigenous children are from a true nonencapsulated lineage. Few NSP represented serotypes in PCV7 that suppress capsular expression. High rates of carriage and penicillin resistance and the occasional presence of capsule genes suggest a role for NSP in the maintenance and survival of capsulated pneumococci. To avoid the inflation of pneumococcal carriage and antibiotic resistance rates, in clinical trials, we recommend separate reporting of rates of capsular strains and NSP and the exclusion of data for NSP from primary analyses.

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Section: Discussioncontrasting

confidence: 54%

“…Cross-sectional studies report pneumococcal carriage rates of over 80% for these children (15). Pneumococcal serotype diversity contributed to swift serotype replacement following introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2001.…”

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confidence: 99%

The Nonserotypeable Pneumococcus: Phenotypic Dynamics in the Era of Anticapsular Vaccines

et al. 2010

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“…While these vaccines do provide good immune protection, it is restricted to the serotypes included in the vaccine. As a result, serotype replacement is already occurring, and the need for a serotype-independent vaccine is urgent (17,38). …”

mentioning

confidence: 99%

Two DHH Subfamily 1 Proteins Contribute to Pneumococcal Virulence and Confer Protection against Pneumococcal Disease

et al. 2011

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Streptococcus pneumoniae is an important human bacterial pathogen, causing such infections as pneumonia, meningitis, septicemia, and otitis media. Current capsular polysaccharide-based conjugate vaccines protect against a fraction of the over 90 serotypes known, whereas vaccines based on conserved pneumococcal proteins are considered promising broad-range alternatives. The pneumococcal genome encodes two conserved proteins of an as yet unknown function, SP1298 and SP2205, classified as DHH (Asp-His-His) subfamily 1 proteins. Here we examined their contribution to pneumococcal pathogenesis using single and double knockout mutants in three different strains: D39, TIGR4, and BHN100. Mutants lacking both SP1298 and SP2205 were severely impaired in adherence to human epithelial Detroit 562 cells. Importantly, the attenuated phenotypes were restored upon genetic complementation of the deleted genes. Single and mixed mouse models of colonization, otitis media, pneumonia, and bacteremia showed that bacterial loads in the nasopharynx, middle ears, lungs, and blood of mice infected with the mutants were significantly reduced from those of wild-type-infected mice, with an apparent additive effect upon deletion of both genes. Minor strain-specific phenotypes were observed, i.e., deletion of SP1298 affected host-cell adherence in BHN100 only, and deletion of SP2205 significantly attenuated virulence in lungs and blood in D39 and BHN100 but not TIGR4. Finally, subcutaneous vaccination with a combination of both DHH subfamily 1 proteins conferred protection to nasopharynx, lungs, and blood of mice infected with TIGR4. We conclude that SP1298 and SP2205 play a significant role at several stages of pneumococcal infection, and importantly, these proteins are potential candidates for a multicomponent protein vaccine.Streptococcus pneumoniae is a Gram-positive bacterium causing serious invasive diseases, such as pneumonia, septicemia, and meningitis. In addition, this human pathogen is the causative agent of less serious but highly prevalent mucosal infections, such as otitis media (OM) and sinusitis. Young children under the age of 2 years, the elderly, and immunocompromised individuals account for the majority of pneumococcal morbidity and mortality observed worldwide (10). One of the main virulence factors of the pneumococcus is its polysaccharide capsule, of which over 90 serotypes distinct in biochemical structure have been identified to date. The polysaccharide capsule contributes to protection against phagocytosis, enabling the pneumococcus to evade the immune system of the host (23, 24). Current pneumococcal vaccines, such as Pneumovax 23 (23-valent; Merck), Synflorix (10-valent; GlaxoSmithKline, United Kingdom), and Prevnar (7-and 13-valent; Pfizer) target this polysaccharide capsule. While these vaccines do provide good immune protection, it is restricted to the serotypes included in the vaccine. As a result, serotype replacement is already occurring, and the need for a serotype-independent vaccine is urgent (17,38).

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“…In spite of the high degree of effectiveness of PCV7 in reducing pneumococcal diseases (8)(9)(10)(11)(12)), recent reports have described an increase in the rate of disease caused by serotypes not included in this vaccine (13)(14)(15). The current pneumococcal vaccine strategy involves extending protection against emerging serotypes by increasing the valence to target additional serotypes (PCV13 [Pfizer], PCV10 [GlaxoSmithKline], PCV15 [in development by Merck]).…”

mentioning

confidence: 99%

Conjugation of Polysaccharide 6B from Streptococcus pneumoniae with Pneumococcal Surface Protein A: PspA Conformation and Its Effect on the Immune Response

Perciani

Barazzone

Goulart

et al. 2013

Clin Vaccine Immunol

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bDespite the substantial beneficial effects of incorporating the 7-valent pneumococcal conjugate vaccine (PCV7) into immunization programs, serotype replacement has been observed after its widespread use. As there are many serotypes currently documented, the use of a conjugate vaccine relying on protective pneumococcal proteins as active carriers is a promising alternative to expand PCV coverage. In this study, capsular polysaccharide serotype 6B (PS6B) and recombinant pneumococcal surface protein A (rPspA), a well-known protective antigen from Streptococcus pneumoniae, were covalently attached by two conjugation methods. The conjugation methodology developed by our laboratory, employing 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) as an activating agent through carboxamide formation, was compared with reductive amination, a classical methodology. DMT-MM-mediated conjugation was shown to be more efficient in coupling PS6B to rPspA clade 1 (rPspA1): 55.0% of PS6B was in the conjugate fraction, whereas 24% was observed in the conjugate fraction with reductive amination. The influence of the conjugation process on the rPspA1 structure was assessed by circular dichroism. According to our results, both conjugation processes reduced the alpha-helical content of rPspA; reduction was more pronounced when the reaction between the polysaccharide capsule and rPspA1 was promoted between the carboxyl groups than the amine groups (46% and 13%, respectively). Regarding the immune response, both conjugates induced functional anti-rPspA1 and anti-PS6B antibodies. These results suggest that the secondary structure of PspA1, as well as its reactive groups (amine or carboxyl) involved in the linkage to PS6B, may not play an important role in eliciting a protective immune response to the antigens.

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Emerging pneumococcal carriage serotypes in a high-risk population receiving universal 7-valent pneumococcal conjugate vaccine and 23-valent polysaccharide vaccine since 2001

Cited by 51 publications

References 19 publications

The Nonserotypeable Pneumococcus: Phenotypic Dynamics in the Era of Anticapsular Vaccines

The Nonserotypeable Pneumococcus: Phenotypic Dynamics in the Era of Anticapsular Vaccines

Two DHH Subfamily 1 Proteins Contribute to Pneumococcal Virulence and Confer Protection against Pneumococcal Disease

Conjugation of Polysaccharide 6B from Streptococcus pneumoniae with Pneumococcal Surface Protein A: PspA Conformation and Its Effect on the Immune Response

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