Streptococcus pneumoniae
            capsule determines disease severity in experimental pneumococcal meningitis

Streptococcus pneumoniae bacteria can be characterized into over 90 serotypes according to the composition of their polysaccharide capsules. Some serotypes are common in nasopharyngeal carriage whereas others are associated with invasive disease, but when carriage serotypes do invade disease is often particularly severe. It is unknown whether disease severity is due directly to the capsule type or to other virulence factors. Here, we used a clinical pneumococcal isolate and its capsule-switch mutants to determine the effect of capsule, in isolation from the genetic background, on severity of meningitis in an infant rat model. We found that possession of a capsule was essential for causing meningitis. Serotype 6B caused significantly more mortality than 7F and this correlated with increased capsule thickness in the cerebrospinal fluid (CSF), a stronger inflammatory cytokine response in the CSF and ultimately more cortical brain damage. We conclude that capsule type has a direct effect on meningitis severity. This is an important consideration in the current era of vaccination targeting a subset of capsule types that causes serotype replacement.

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Variation in the Presence of Neuraminidase Genes among Streptococcus pneumoniae Isolates with Identical Sequence Types

Infection and Immunity ◽

10.1128/iai.01442-05 ◽

2006 ◽

Vol 74 (6) ◽

pp. 3360-3365 ◽

Cited By ~ 83

Author(s):

Melinda M. Pettigrew ◽

Kristopher P. Fennie ◽

Matthew P. York ◽

Janeen Daniels ◽

Faryal Ghaffar

Keyword(s):

Streptococcus Pneumoniae ◽

Young Children ◽

Invasive Disease ◽

Virulence Determinants ◽

Upper Respiratory Tract ◽

Capsule Type ◽

Virulence Potential ◽

The Relationship ◽

Sequence Types ◽

Specific Virulence

ABSTRACT Streptococcus pneumoniae frequently colonizes the upper respiratory tract of young children and is an important cause of otitis media and invasive disease. Carriage is more common than disease, yet the genetic factors that predispose a given clone for disease are not known. The relationship between capsule type, genetic background, and virulence is complex, and important questions remain regarding how pneumococcal clones differ in their ability to cause disease. Pneumococcal neuraminidase cleaves sialic acid-containing substrates and is thought to be important for pneumococcal virulence. We describe the distribution of multilocus sequence types (ST), capsule type, and neuraminidase genes among 342 carriage, middle ear, blood, and cerebrospinal fluid (CSF) pneumococcal strains from young children. We found 149 STs among our S. pneumoniae isolates. nanA was present in all strains, while nanB and nanC were present in 96% and 51% of isolates, respectively. The distribution of nanC varied among the strain collections from different tissue sources (P = 0.03). The prevalence of nanC was 1.41 (95% confidence interval, 1.11, 1.79) times higher among CSF isolates than among carriage isolates. We identified isolates of the same ST that differed in the presence of nanB and nanC. These studies demonstrate that virulence determinants, other than capsule loci, vary among strains of identical ST. Our studies suggest that the presence of nanC may be important for tissue-specific virulence. Studies that both incorporate MLST and take into account additional virulence determinants will provide a greater understanding of the pneumococcal virulence potential.

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Emergence of a multidrug resistant and virulent Streptococcus pneumoniae lineage mediates serotype replacement after PCV13

10.1101/2021.11.24.21266813 ◽

2021 ◽

Author(s):

Stephanie W Lo ◽

Kate Mellor ◽

Robert Cohen ◽

Alba Redin Alonso ◽

Sophie Belman ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Long Range ◽

Bacterial Genome ◽

Rapid Change ◽

Spatiotemporal Analysis ◽

Invasive Disease ◽

Multidrug Resistant ◽

Global Perspective ◽

Vaccine Strategy ◽

Serotype Replacement

Background Pneumococcal Conjugate Vaccine (PCV) which targets up to 13 serotypes of Streptococcus pneumoniae is very effective at reducing disease in young children; however, rapid increases in replacement with non-PCV serotypes remains a concern. Serotype 24F is one of the major invasive serotypes that mediates serotype replacement in France and multiple other countries. We aimed to identify the major pneumococcal lineage that has driven the increase of serotype 24F in France, and provide context for the findings by investigating the global diversity of serotype 24F pneumococci and characterise the driver lineage from a global perspective and elucidate its spatiotemporal transmission in France and across the world. Methods We whole-genome sequenced a collection of 419 serotype 24F S. pneumoniae from asymptomatic carriers and invasive disease cases among individuals <18 years old in France between 2003 and 2018. Genomes were clustered into Global Pneumococcal Sequence Clusters (GPSCs) and clonal complexes (CCs) so as to identify the lineages that drove the increase in serotype 24F in France. For each serotype 24F lineage, we evaluated the invasive disease potential and propensity to cause meningitis by comparing the proportion of invasive disease cases with that of carriers. To provide a global context of serotype 24F and the driver lineage, we extracted relevant genomes and metadata from the Global Pneumococcal Sequencing (GPS) project database (n=25,590) and additionally sequenced a collection of 91 pneumococcal isolates belonging to the lineage that were responsible for the serotype 24F increase in Spain during the PCV introduction for comparison. Phylogenetic, evolutionary, and spatiotemporal analysis were conducted to understand the mechanism underlying the global spread of serotype 24F, evolutionary history and long-range transmissions of the driver lineage. Findings A multidrug-resistant pneumococcal lineage GPSC10 (CC230) drove the serotype 24F increase in both carriage and invasive disease in France after PCV13 introduction. When compared with other serotype 24F lineages, it exhibited a 1.4-fold higher invasive disease potential and 1.6-fold higher propensity to cause meningitis. Globally, serotype 24F was widespread, largely due to clonal dissemination of GPSC10, GPSC16 (CC66) and GPSC206 (CC7701) rather than recent capsular switching. Among these lineages, only GPSC10 was multidrug-resistant. It expressed 17 serotypes, with only 6 included in PCV13 and none of the expected PCVs covered all serotypes expressed by this lineage. Global phylogeny of GPSC10 showed that all serotype 24F isolates except for one were clustered together, regardless of its country of origin. Long-range transmissions of GPSC10-24F from Europe to Israel, Morocco and India were detected. Spatiotemporal analysis revealed that it took ~5 years for GPSC10-24F to spread across French provinces. In Spain, we detected that the serotype 24F driver lineage GPSC10 underwent a rapid change of serotype composition from serotype 19A to 24F during the introduction of PCV13 (targets 19A but not 24F), indicating that pre-existence of serotype variants enabled GPSC10 to survive and expand under vaccine-selective pressure. Interpretation Our work further shows the utility of bacterial genome sequencing to better understand the pneumococcal lineages behind the serotype changes and reveals that GPSC10 alone is a challenge for serotype-based vaccine strategy. More systematic investigation to identify lineages like GPSC10 will better inform and improve next-generation preventive strategies against pneumococcal diseases. Funding Bill & Melinda Gates Foundation, Wellcome Sanger Institute, and the US Centers for Disease Control.

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Faculty Opinions recommendation of DiiA is a novel dimorphic cell wall protein of Streptococcus pneumoniae involved in invasive disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726307838.793522911 ◽

2016 ◽

Author(s):

Charles Feldman

Keyword(s):

Cell Wall ◽

Streptococcus Pneumoniae ◽

Invasive Disease ◽

Cell Wall Protein

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DiiA is a novel dimorphic cell wall protein of Streptococcus pneumoniae involved in invasive disease

Journal of Infection ◽

10.1016/j.jinf.2016.04.010 ◽

2016 ◽

Vol 73 (1) ◽

pp. 71-81 ◽

Cited By ~ 2

Author(s):

María S. Escolano-Martínez ◽

Arnau Domenech ◽

José Yuste ◽

María I. Cercenado ◽

Carmen Ardanuy ◽

...

Keyword(s):

Cell Wall ◽

Streptococcus Pneumoniae ◽

Invasive Disease ◽

Cell Wall Protein

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Draft Genome Sequences of Six NontypeableHaemophilus influenzaeStrains That Establish Bacteremia in the Infant Rat Model of Invasive Disease: TABLE 1

Genome Announcements ◽

10.1128/genomea.00899-15 ◽

2015 ◽

Vol 3 (5) ◽

Cited By ~ 2

Author(s):

Timothy M. VanWagoner ◽

Daniel J. Morton ◽

Thomas W. Seale ◽

Huda J. Mussa ◽

Brett K. Cole ◽

...

Keyword(s):

Haemophilus Influenzae ◽

Rat Model ◽

Draft Genome ◽

Invasive Disease ◽

Genome Sequences ◽

Infant Rat

Haemophilus influenzaeis an important cause of invasive disease. The infant rat is the accepted model of invasiveH. influenzaedisease. Here, we report the genome sequences of six nontypeableH. influenzaestrains that establish bacteremia in the infant rat.

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A Review of Pneumococcal Vaccines: Current Polysaccharide Vaccine Recommendations and Future Protein Antigens

The Journal of Pediatric Pharmacology and Therapeutics ◽

10.5863/1551-6776-21.1.27 ◽

2016 ◽

Vol 21 (1) ◽

pp. 27-35 ◽

Cited By ~ 43

Author(s):

Calvin C. Daniels ◽

P. David Rogers ◽

Chasity M. Shelton

Keyword(s):

Conjugate Vaccine ◽

Pneumococcal Conjugate Vaccine ◽

Invasive Disease ◽

Polysaccharide Vaccine ◽

Pneumococcal Vaccines ◽

Protein Antigens ◽

Pneumococcal Infections ◽

Serotype Replacement ◽

Vaccine Recommendations ◽

Vaccine Antigens

This review describes development of currently available pneumococcal vaccines, provides summary tables of current pneumococcal vaccine recommendations in children and adults, and describes new potential vaccine antigens in the pipeline. Streptococcus pneumoniae, the bacteria responsible for pneumonia, otitis media, meningitis and bacteremia, remains a cause of morbidity and mortality in both children and adults. Introductions of unconjugated and conjugated pneumococcal polysaccharide vaccines have each reduced the rate of pneumococcal infections caused by the organism S. pneumoniae. The first vaccine developed, the 23-valent pneumococcal polysaccharide vaccine (PPSV23), protected adults and children older than 2 years of age against invasive disease caused by the 23 capsular serotypes contained in the vaccine. Because PPSV23 did not elicit a protective immune response in children younger than 2 years of age, the 7-valent pneumococcal conjugate vaccine (PCV7) containing seven of the most common serotypes from PPSV23 in pediatric invasive disease was developed for use in children younger than 2 years of age. The last vaccine to be developed, the 13-valent pneumococcal conjugate vaccine (PCV13), contains the seven serotypes in PCV7, five additional serotypes from PPSV23, and a new serotype not contained in PPSV23 or PCV7. Serotype replacement with virulent strains that are not contained in the polysaccharide vaccines has been observed after vaccine implementation and stresses the need for continued research into novel vaccine antigens. We describe eight potential protein antigens that are in the pipeline for new pneumococcal vaccines.

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Evaluating post-vaccine expansion patterns of pneumococcal serotypes

10.1101/2020.05.31.20116228 ◽

2020 ◽

Author(s):

Maile T. Phillips ◽

Joshua L. Warren ◽

Noga Givon-Lavi ◽

Adrienn Tothpal ◽

Gili Regev-Yochay ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Invasive Pneumococcal Disease ◽

Jewish Population ◽

Pneumococcal Disease ◽

Pneumococcal Serotypes ◽

Conjugate Vaccines ◽

Pneumococcal Conjugate Vaccines ◽

Vaccine Serotypes ◽

Serotype Replacement ◽

Disease Understanding

ABSTRACTStreptococcus pneumoniae remains a leading cause of morbidity and mortality. Pneumococcal conjugate vaccines (PCVs) are effective but target only a fraction of the more than 90 pneumococcal serotypes. As a result, the introduction of PCVs has been followed by the emergence of non-vaccine serotypes. With higher-valency PCVs currently under development, there is a need to understand and predict patterns of serotype replacement to anticipate future changes. In this study, we evaluated patterns of change in serotype prevalence post-PCV introduction in Israel. We found that the assumption that non-vaccine serotypes increase by the same proportion overestimates changes in serotype prevalence in Jewish and Bedouin children. Furthermore, pre-vaccine prevalence was positively associated with increases in prevalence over the study period. From our analyses, serotypes 12F, 8, 16F, 33F, 9N, 7B, 10A, 22F, 24F, and 17F were estimated to have gained the most cases of invasive pneumococcal disease through serotype replacement in the Jewish population. However, this model also failed to quantify some additional cases gained, suggesting that changes in carriage in children alone may be insufficient to explain serotype replacement in disease. Understanding of serotype replacement is important as higher-valency vaccines are introduced.

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A pneumococcal controlled human infection model in Malawi: Transfer of an established pneumococcal carriage model from Liverpool, UK to Blantyre, Malawi – A feasibility study

Wellcome Open Research ◽

10.12688/wellcomeopenres.15689.1 ◽

2020 ◽

Vol 5 ◽

pp. 25

Author(s):

Ben Morton ◽

Sarah Burr ◽

Kondwani Jambo ◽

Jamie Rylance ◽

Marc Y.R. Henrion ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Feasibility Study ◽

Invasive Disease ◽

Community Acquired Pneumonia ◽

Human Infection ◽

Infection Model ◽

Endpoint Detection ◽

Pneumococcal Carriage ◽

Sampling Protocols ◽

Classical Culture

Streptococcus pneumoniae is the leading cause of morbidity and mortality due to community acquired pneumonia, bacterial meningitis and bacteraemia worldwide. Pneumococcal conjugate vaccines protect against invasive disease, but are expensive to manufacture, limited in serotype coverage, associated with serotype replacement and demonstrate reduced effectiveness against mucosal colonisation. As asymptomatic colonisation of the human nasopharynx is a prerequisite for pneumococcal disease, this is proposed as a marker for novel vaccine efficacy. Our team established a safe and reproducible pneumococcal controlled human infection model at Liverpool School of Tropical Medicine (LSTM). This has been used to test vaccine induced protection against nasopharyngeal carriage for ten years in over 1000 participants. We will transfer established standardised operating procedures from LSTM to Malawi and test in up to 36 healthy participants. Primary endpoint: detection of the inoculated pneumococci by classical culture from nasal wash recovered from the participants after pneumococcal challenge. Secondary endpoints: confirmation of robust clinical and laboratory methods for sample capture and processing. Tertiary endpoints: participant acceptability of study and methods. We will test three doses of pneumococcal inoculation (20,000, 80,000 and 160,000 colony forming units [CFUs] per naris) using a parsimonious study design intended to reduce unnecessary exposure to participants. We hypothesise that 80,000 CFUs will induce nasal colonisation in approximately half of participants per established LSTM practice. The aims of the feasibility study are: 1) Establish Streptococcus pneumoniae experimental human pneumococcal carriage in Malawi; 2) Confirm optimal nasopharyngeal pneumococcal challenge dose; 3) Confirm safety and measure potential symptoms; 4) Confirm sampling protocols and laboratory assays; 5) Assess feasibility and acceptability of consent and study procedures. Confirmation of pneumococcal controlled human infection model feasibility in Malawi will enable us to target pneumococcal vaccine candidates for an at-risk population who stand the most to gain from new and improved vaccine strategies.

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