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Nature Communications Nov 2023Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide. Polysaccharide conjugate vaccines (PCVs) are highly effective at...
Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide. Polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease, but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten this success. We investigated the hypothesis that following vaccine, adapted pneumococcal genotypes emerge with the potential for vaccine escape. We genome sequenced 2804 penumococcal isolates, collected 4-8 years after introduction of PCV13 in Blantyre, Malawi. We developed a pipeline to cluster the pneumococcal population based on metabolic core genes into "Metabolic genotypes" (MTs). We show that S. pneumoniae population genetics are characterised by emergence of MTs with distinct virulence and antimicrobial resistance (AMR) profiles. Preliminary in vitro and murine experiments revealed that representative isolates from emerging MTs differed in growth, haemolytic, epithelial infection, and murine colonisation characteristics. Our results suggest that in the context of PCV13 introduction, pneumococcal population dynamics had shifted, a phenomenon that could further undermine vaccine control and promote spread of AMR.
Topics: Child; Humans; Animals; Mice; Infant; Child, Preschool; Streptococcus pneumoniae; Pneumococcal Infections; Anti-Bacterial Agents; Malawi; Virulence; Drug Resistance, Bacterial; Pneumococcal Vaccines; Serogroup; Nasopharynx; Carrier State
PubMed: 37978177
DOI: 10.1038/s41467-023-43160-y -
Infection and Immunity Apr 2021remains a leading cause of bacterial pneumonia despite the widespread use of vaccines. While vaccines are effective at reducing the incidence of most serotypes included...
remains a leading cause of bacterial pneumonia despite the widespread use of vaccines. While vaccines are effective at reducing the incidence of most serotypes included in vaccines, a rise in infection due to nonvaccine serotypes and moderate efficacy against some vaccine serotypes have contributed to high disease incidence. Additionally, numerous isolates of are antibiotic or multidrug resistant. Several conserved pneumococcal proteins prevalent in the majority of serotypes have been examined for their potential as vaccines in preclinical and clinical trials. An additional, yet-unexplored tool for disease prevention and treatment is the use of human monoclonal antibodies (MAbs) targeting conserved pneumococcal proteins. Here, we isolated the first human MAbs (PhtD3, PhtD6, PhtD7, PhtD8, and PspA16) against the pneumococcal histidine triad protein (PhtD) and the pneumococcal surface protein A (PspA), two conserved and protective antigens. MAbs to PhtD target diverse epitopes on PhtD, and MAb PspA16 targets the N-terminal segment of PspA. The PhtD-specific MAbs bind to multiple serotypes, while MAb PspA16 serotype breadth is limited. MAbs PhtD3 and PhtD8 prolong the survival of mice infected with pneumococcal serotype 3. Furthermore, MAb PhtD3 prolongs the survival of mice in intranasal and intravenous infection models with pneumococcal serotype 4 and in mice infected with pneumococcal serotype 3 when administered 24 h after pneumococcal infection. All PhtD and PspA MAbs demonstrate opsonophagocytic activity, suggesting a potential mechanism of protection. Our results identify new human MAbs for pneumococcal disease prevention and treatment and identify epitopes on PhtD and PspA recognized by human B cells.
Topics: Antibodies, Monoclonal; Antibody Specificity; Dose-Response Relationship, Immunologic; Epitopes; Host-Pathogen Interactions; Humans; Hydrolases; Pneumococcal Infections; Protein Binding; Serogroup; Streptococcus pneumoniae
PubMed: 33649050
DOI: 10.1128/IAI.00747-20 -
Journal of Biomedical Science Aug 2021Streptococcus pneumoniae is a common cause of post-influenza secondary bacterial infection, which results in excessive morbidity and mortality. Although 13-valent...
BACKGROUND
Streptococcus pneumoniae is a common cause of post-influenza secondary bacterial infection, which results in excessive morbidity and mortality. Although 13-valent pneumococcal conjugate vaccine (PCV13) vaccination programs have decreased the incidence of pneumococcal pneumonia, PCV13 failed to prevent serotype 3 pneumococcal disease as effectively as other vaccine serotypes. We aimed to investigate the mechanisms underlying the co-pathogenesis of influenza virus and serotype 3 pneumococci.
METHODS
We carried out a genome-wide screening of a serotype 3 S. pneumoniae transposon insertion mutant library in a mouse model of coinfection with influenza A virus (IAV) to identify the bacterial factors required for this synergism.
RESULTS
Direct, high-throughput sequencing of transposon insertion sites identified 24 genes required for both coinfection and bacterial infection alone. Targeted deletion of the putative aminotransferase (PA) gene decreased bacterial growth, which was restored by supplementation with methionine. The bacterial burden in a coinfection with the PA gene deletion mutant and IAV in the lung was lower than that in a coinfection with wild-type pneumococcus and IAV, but was significantly higher than that in an infection with the PA gene deletion mutant alone. These data suggest that IAV infection alters host metabolism to benefit pneumococcal fitness and confer higher susceptibility to pneumococcal infection. We further demonstrated that bacterial growth was increased by supplementation with methionine or IAV-infected mouse lung homogenates.
CONCLUSIONS
The data indicates that modulation of host metabolism during IAV infection may serve as a potential therapeutic intervention against secondary bacterial infections caused by serotype 3 pneumococci during IAV outbreaks in the future.
Topics: Animals; Coinfection; Female; Genome, Bacterial; Influenza A virus; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Pneumococcal Infections; Streptococcus pneumoniae; Transcriptome
PubMed: 34452635
DOI: 10.1186/s12929-021-00756-0 -
Cytokine Nov 2020Community-acquired pneumonia (CAP) diagnosis remains a challenge in paediatrics. Chest radiography is considered gold standard for definition of pneumonia, however no...
Community-acquired pneumonia (CAP) diagnosis remains a challenge in paediatrics. Chest radiography is considered gold standard for definition of pneumonia, however no previous study assessed the relationship between immune response and radiographic-confirmed-pneumonia. We assessed association between cytokines/chemokines levels and radiographic abnormalities in children with CAP. Children < 5-years-old hospitalized with CAP were investigated in a prospective study at the Federal University of Bahia Hospital, Brazil. On admission, clinical data and biological samples were collected to investigate 20 aetiological agents and determine serum cytokines/chemokines levels; chest radiographs were performed. Among 158 patients, radiographic diagnosis of pneumonia was confirmed in 126(79.7%) and 17(10.8%) had pleural effusion. Viral, bacterial and pneumococcal infection were detected in 80(50.6%), 78(49.4%) and 37(23.4%) cases. By comparing the median concentrations of serum cytokines/chemokines between children with or without pleural effusion, interleukin(IL)-6 was higher (26.6[18.6-103.7] vs 3.0[0.0-19.8]; p < 0.001) among those with pleural effusion; and between children with or without radiographic-confirmed-pneumonia, IL-6 was higher in the first subgroup (4.5[0.0-23.4] vs 0.0[0.0-3.6]; p = 0.02) after having excluded cases with pleural effusion. Stratified analyses according to aetiology showed IL-6 increase in the radiographic-confirmed-pneumonia subgroup inside the pneumococcal infection (28.2[5.9-64.1] vs 0.0[0.0-0.0]; p = 0.03) subgroup. By multivariable analysis, with IL-6 as dependent variable, pneumococcal infection and pleural effusion showed independent association with IL-6 elevation [respective OR: 5.071 (95%CI = 2.226-11.548; p < 0.001) and 13.604 (95%CI = 3.463-53.449; p = 0.0001)]. Considering the cases without pleural effusion, the area under the curve of IL-6 to predict pneumococcal infection was 0.76 (95%CI = 0.66-0.86; p < 0.001). IL-6 increase is a potential biomarker of pneumococcal infection among children with CAP without pleural effusion upon admission.
Topics: Biomarkers; Brazil; Chemokines; Child, Preschool; Community-Acquired Infections; Cytokines; Female; Hospitalization; Humans; Infant; Male; Pneumococcal Infections; Pneumonia, Pneumococcal; Prospective Studies; Radiography
PubMed: 32712459
DOI: 10.1016/j.cyto.2020.155191 -
BMC Infectious Diseases Sep 2022Despite recommendations from the German Standing Committee on Vaccination (STIKO), pneumococcal vaccination coverage remains low in vulnerable populations. This study...
BACKGROUND
Despite recommendations from the German Standing Committee on Vaccination (STIKO), pneumococcal vaccination coverage remains low in vulnerable populations. This study estimated the pneumococcal vaccination coverage rate (VCR) and timing among individuals aged 16-59 years in Germany who were recommended to receive pneumococcal vaccination, according to STIKO.
METHODS
A retrospective cohort analysis was conducted using the German InGef database. Individuals aged 16 to 59 years diagnosed with at least one "at-risk" (chronic disease) or "high-risk" (e.g., immunocompromising) condition considered to be at-risk of pneumococcal infection were identified at the time of first diagnosis, between January 1, 2016 and December 31, 2018, and followed up until December 31, 2019. The percentage of cumulative pneumococcal VCR with 95% confidence interval (CI) was reported for each calendar year of follow-up.
RESULTS
There were 334,292 individuals followed for a median of 2.38 (interquartile range (IQR) 1.63-3.13) person years. For individuals aged 16-59 years diagnosed with an incident risk condition in 2016, pneumococcal VCR increased from 0.44% (95% CI 0.41-0.48) in 2016 to 1.24% (95% CI 1.18-1.30) in 2019. In 2019, VCRs were higher in individuals with high-risk conditions compared with at-risk conditions (2.24% (95% CI 2.09-2.40) vs. 0.90% (95% CI 0.85-0.96)). In 2019, VCRs were higher in individuals aged 50 to 59 years compared with individuals aged 16 to 49 years (2.25% (95% CI 2.10-2.41) vs. 0.90% (95% CI 0.84-0.96)). Similar trends were observed in individuals with newly diagnosed risk conditions identified in 2017 and in 2018. Older age, influenza vaccination and increasing number of risk conditions increased the likelihood of pneumococcal vaccination. Median time to vaccination from diagnosis of the risk condition was shorter for high-risk conditions (369.5 days (IQR 155.8-702.0)) compared to at-risk conditions (435.5 days (IQR 196.3-758.8)).
CONCLUSION
Despite recommendations from STIKO, pneumococcal vaccination coverage remains very low and with long delays in vulnerable individuals aged 16-59 in Germany. Further efforts are required to increase immunization levels and shorten time to vaccination among individuals 16-59 years of age developing conditions with higher susceptibility to pneumococcal infection.
Topics: Adolescent; Adult; Humans; Middle Aged; Pneumococcal Infections; Pneumococcal Vaccines; Retrospective Studies; Streptococcus pneumoniae; Vaccination; Vaccination Coverage; Young Adult
PubMed: 36171549
DOI: 10.1186/s12879-022-07736-1 -
Seminars in Respiratory and Critical... Aug 2020With the notable exceptions of the United States and Canada in particular, the global burden of disease in adults due to invasive infection with the dangerous... (Review)
Review
With the notable exceptions of the United States and Canada in particular, the global burden of disease in adults due to invasive infection with the dangerous respiratory, bacterial pathogen, (pneumococcus) remains. This situation prevails despite the major successes of inclusion of polysaccharide conjugate vaccines (PCVs) in many national childhood immunization programs and associated herd protection in adults, as well as the availability of effective antimicrobial agents. Accurate assessment of the geographic variations in the prevalence of invasive pneumococcal disease (IPD) has, however, been somewhat impeded by the limitations imposed on the acquisition of reliable epidemiological data due to reliance on often insensitive, laboratory-based, pathogen identification procedures. This, in turn, may result in underestimation of the true burden of IPD and represents a primary focus of this review. Other priority topics include the role of PCVs in the changing epidemiology of IPD in adults worldwide, smoking as a risk factor not only in respect of increasing susceptibility for development of IPD, but also in promoting pneumococcal antibiotic resistance. The theme of pneumococcal antibiotic resistance has been expanded to include mechanisms of resistance to commonly used classes of antibiotics, specifically β-lactams, macrolides and fluoroquinolones, and, perhaps somewhat contentiously, the impact of resistance on treatment outcome. Finally, but no less importantly, the role of persistent antigenemia as a driver of a chronic, subclinical, systemic proinflammatory/procoagulant phenotype that may underpin the long-term sequelae and premature mortality of those adults who have recovered from an episode of IPD, is considered.
Topics: Adult; Anti-Bacterial Agents; Child; Community-Acquired Infections; Drug Resistance, Microbial; Humans; Pneumococcal Infections; Pneumococcal Vaccines; Risk Factors; Serogroup; Streptococcus pneumoniae; Vaccines, Conjugate; Vaping
PubMed: 32629486
DOI: 10.1055/s-0040-1702193 -
Proceedings of the National Academy of... Jun 2022Pneumococcal conjugate vaccines (PCVs) used in childhood vaccination programs have resulted in replacement of vaccine-type with nonvaccine-type pneumococci in carriage...
Pneumococcal conjugate vaccines (PCVs) used in childhood vaccination programs have resulted in replacement of vaccine-type with nonvaccine-type pneumococci in carriage and invasive pneumococcal disease (IPD). A vaccine based on highly conserved and protective pneumococcal antigens is urgently needed. Here, we performed intranasal immunization of mice with pneumococcal membrane particles (MPs) to mimic natural nasopharyngeal immunization. MP immunization gave excellent serotype-independent protection against IPD that was antibody dependent but independent of the cytotoxin pneumolysin. Using Western blotting, immunoprecipitation, mass spectrometry, and different bacterial mutants, we identified the conserved lipoproteins MalX and PrsA as the main antigens responsible for cross-protection. Additionally, we found that omitting the variable surface protein and vaccine candidate PspA from MPs enhanced protective immune responses to the conserved proteins. Our findings suggest that MPs containing MalX and PrsA could serve as a platform for pneumococcal vaccine development targeting the elderly and immunocompromised.
Topics: Administration, Intranasal; Animals; Bacterial Proteins; Cell Membrane; Conserved Sequence; Cross Reactions; Humans; Immunization; Lipoproteins; Membrane Proteins; Membrane Transport Proteins; Mice; Pneumococcal Infections; Pneumococcal Vaccines; Serogroup; Streptococcus pneumoniae
PubMed: 35648835
DOI: 10.1073/pnas.2122386119 -
Frontiers in Cellular and Infection... 2021In humans, nasopharyngeal carriage of is common and although primarily asymptomatic, is a pre-requisite for pneumonia and invasive pneumococcal disease (IPD). Together,... (Review)
Review
In humans, nasopharyngeal carriage of is common and although primarily asymptomatic, is a pre-requisite for pneumonia and invasive pneumococcal disease (IPD). Together, these kill over 500,000 people over the age of 70 years worldwide every year. Pneumococcal conjugate vaccines have been largely successful in reducing IPD in young children and have had considerable indirect impact in protection of older people in industrialized country settings (herd immunity). However, serotype replacement continues to threaten vulnerable populations, particularly older people in whom direct vaccine efficacy is reduced. The early control of pneumococcal colonization at the mucosal surface is mediated through a complex array of epithelial and innate immune cell interactions. Older people often display a state of chronic inflammation, which is associated with an increased mortality risk and has been termed 'Inflammageing'. In this review, we discuss the contribution of an altered microbiome, the impact of inflammageing on human epithelial and innate immunity to , and how the resulting dysregulation may affect the outcome of pneumococcal infection in older individuals. We describe the impact of the pneumococcal vaccine and highlight potential research approaches which may improve our understanding of respiratory mucosal immunity during pneumococcal colonization in older individuals.
Topics: Aged; Child; Child, Preschool; Humans; Immunity, Innate; Nasopharynx; Pneumococcal Infections; Pneumococcal Vaccines; Streptococcus pneumoniae; Vaccines, Conjugate
PubMed: 34113578
DOI: 10.3389/fcimb.2021.651474 -
Journal of Microbiology, Immunology,... Jun 2023Serotype 3 has persisted to be an important cause of invasive pneumococcal disease in adults in the post-vaccine era. We aimed to investigate clinical and... (Observational Study)
Observational Study
BACKGROUND/PURPOSE
Serotype 3 has persisted to be an important cause of invasive pneumococcal disease in adults in the post-vaccine era. We aimed to investigate clinical and microbiological characteristics of Streptococcus pneumoniae serotype 3 infection in Taiwan and identify the risk factors associated with severe clinical outcome.
METHODS
A multicenter observational study was conducted to analyze serotype 3 isolates collected between 2012 and 2021. Demographics, comorbidities, and risk categories were statistically compared with clinical outcome. Antimicrobial susceptibility testing and multilocus sequence typing were performed.
RESULTS
A total of 146 isolates were collected, including 12 isolates regarded as colonizers. Among 134 infected cases, 54 (40.3%) were aged 65 and older. Mortality was significantly associated with diabetes mellitus, immunosuppression, immunodeficiency, high-risk status, and older age. Susceptibility rates were high to levofloxacin (98.9%), moxifloxacin (100%), vancomycin (100%), and ceftriaxone (97.3%). 25.3% (37/146) of the isolates showed intermediate susceptibility and 0.7% (1/146) showed resistance to penicillin. ST180 was the dominant sequence type. ST13 and ST9625 isolates were less susceptible to penicillin and ceftriaxone.
CONCLUSIONS
Serotype 3 infection showed a high mortality rate, especially in patients with older ages and comorbidities. Although the incidence rates decreased during the COVID-19 pandemic, serotype 3 remained as an important cause of infection after the implementation of PCV13. Developing a more effective vaccine against serotype 3 and monitoring the antimicrobial-resistant sequence types are necessary.
Topics: Adult; Humans; Streptococcus pneumoniae; Ceftriaxone; Serogroup; Pandemics; COVID-19; Pneumococcal Infections; Multilocus Sequence Typing; Risk Factors; Penicillins; Anti-Infective Agents; Anti-Bacterial Agents; Pneumococcal Vaccines; Serotyping; Microbial Sensitivity Tests
PubMed: 36774315
DOI: 10.1016/j.jmii.2023.01.013 -
Scientific Reports Mar 2021Infection with Streptococcus pneumoniae is the leading cause of death in children and burden of disease is greatest where helminth infections are also common. We...
Infection with Streptococcus pneumoniae is the leading cause of death in children and burden of disease is greatest where helminth infections are also common. We investigated the impact of intestinal helminth co-infection on pneumococcal carriage; a risk factor for invasive disease. We used a mouse co-infection model and clinical data to assess the impact of co-infection on carriage density. Co-infection in mice was associated with increased pneumococcal carriage density and dissemination into lungs. Helminth-infected children also exhibited increased carriage density as compared to uninfected children. Anthelmintic treatment may be a cost-effective method of reducing pneumococcal disease burden in lower-income countries.
Topics: Animals; Child; Child, Preschool; Coinfection; Ecuador; Female; Helminthiasis; Humans; Intestinal Diseases, Parasitic; Male; Mice; Pneumococcal Infections; Risk Factors; Streptococcus pneumoniae
PubMed: 33772094
DOI: 10.1038/s41598-021-86508-4