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To evaluate efficacy of sublingual flagellin to treat acute pneumonia. Mice were treated sublingually with flagellin and challenged intranasally with a lethal dose of pneumococcus. Flagellins lacking TLR5 or NLRC4 activation domains were used to assess their contribution to protection. Sublingual flagellin protected mice in a TLR5-dependent, NLRC4-independent fashion. Neutrophils were required for protection. Flagellin-stimulated lung epithelial cells recapitulated the lung's transcriptional profile suggesting they could be targeted by flagellin . Ligation of TLR5, a pathogen recognition receptor not naturally engaged by pneumococcus, protects mice from invasive pneumonia when administered via sublingual route. This can be a highly cost-effective alternative therapy against pneumonia.

In this double-blind, placebo-controlled trial involving more than 84,000 Dutch adults, the 13-valent pneumococcal conjugate vaccine was found to prevent pneumococcal disease but not the overall occurrence of community-acquired pneumonia. Streptococcus pneumoniae , a major cause of community-acquired pneumonia in the elderly, results in considerable morbidity and mortality. 1 – 4 Pneumococcal community-acquired pneumonia most commonly presents as nonbacteremic disease. 3 Invasive pneumococcal disease, which involves infection of normally sterile sites, occurs in approximately 25% of cases. 3 Immunologic protection against pneumococcal disease is mediated through opsonophagocytic antibodies directed against bacterial capsular polysaccharides that define the pneumococcal serotypes and serve as virulence factors. 5 Vaccines composed of purified capsular polysaccharides, which have been available for more than 50 years, are not immunogenic in young children. 6 – 8 Although some studies have shown that purified capsular polysaccharides . . .

Streptococcus pneumoniae is a leading cause of bacterial pneumonia, meningitis, and sepsis in children worldwide. However, many countries lack national estimates of disease burden. Effective interventions are available, including pneumococcal conjugate vaccine and case management. To support local and global policy decisions on pneumococcal disease prevention and treatment, we estimated country-specific incidence of serious cases and deaths in children younger than 5 years. We measured the burden of pneumococcal pneumonia by applying the proportion of pneumonia cases caused by S pneumoniae derived from efficacy estimates from vaccine trials to WHO country-specific estimates of all-cause pneumonia cases and deaths. We also estimated burden of meningitis and non-pneumonia, non-meningitis invasive disease using disease incidence and case-fatality data from a systematic literature review. When high-quality data were available from a country, these were used for national estimates. Otherwise, estimates were based on data from neighbouring countries with similar child mortality. Estimates were adjusted for HIV prevalence and access to care and, when applicable, use of vaccine against Haemophilus influenzae type b. In 2000, about 14·5 million episodes of serious pneumococcal disease (uncertainty range 11·1–18·0 million) were estimated to occur. Pneumococcal disease caused about 826 000 deaths (582 000–926 000) in children aged 1–59 months, of which 91 000 (63 000–102 000) were in HIV-positive and 735 000 (519 000–825 000) in HIV-negative children. Of the deaths in HIV-negative children, over 61% (449 000 [316 000–501 000]) occurred in ten African and Asian countries. S pneumoniae causes around 11% (8–12%) of all deaths in children aged 1–59 months (excluding pneumococcal deaths in HIV-positive children). Achievement of the UN Millennium Development Goal 4 for child mortality reduction can be accelerated by prevention and treatment of pneumococcal disease, especially in regions of the world with the greatest burden. GAVI Alliance and the Vaccine Fund.

Lung-resident memory B cells (BRM cells) are elicited after influenza infections of mice, but connections to other pathogens and hosts - as well as their functional significance - have yet to be determined. We postulate that BRM cells are core components of lung immunity. To test this, we examined whether lung BRM cells are elicited by the respiratory pathogen pneumococcus, are present in humans, and are important in pneumonia defense. Lungs of mice that had recovered from pneumococcal infections did not contain organized tertiary lymphoid organs, but did have plasma cells and noncirculating memory B cells. The latter expressed distinctive surface markers (including CD69, PD-L2, CD80, and CD73) and were poised to secrete antibodies upon stimulation. Human lungs also contained B cells with a resident memory phenotype. In mice recovered from pneumococcal pneumonia, depletion of PD-L2+ B cells, including lung BRM cells, diminished bacterial clearance and the level of pneumococcus-reactive antibodies in the lung. These data define lung BRM cells as a common feature of pathogen-experienced lungs and provide direct evidence of a role for these cells in pulmonary antibacterial immunity.

Vaccination with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is available in the United Kingdom to adults aged 65 years or older and those in defined clinical risk groups. We evaluated the vaccine effectiveness (VE) of PPV23 against vaccine-type pneumococcal pneumonia in a cohort of adults hospitalised with community-acquired pneumonia (CAP). Using a case-control test-negative design, a secondary analysis of data was conducted from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalised at 2 university teaching hospitals in Nottingham, England, from September 2013 to August 2018. The exposure of interest was PPV23 vaccination at any time point prior to the index admission. A case was defined as PPV23 serotype-specific pneumococcal pneumonia and a control as non-PPV23 serotype pneumococcal pneumonia or nonpneumococcal pneumonia. Pneumococcal serotypes were identified from urine samples using a multiplex immunoassay or from positive blood cultures. Multivariable logistic regression was used to derive adjusted odds of case status between vaccinated and unvaccinated individuals; VE estimates were calculated as (1 - odds ratio) × 100%. Of 2,357 patients, there were 717 PPV23 cases (48% vaccinated) and 1,640 controls (54.5% vaccinated). The adjusted VE (aVE) estimate against PPV23 serotype disease was 24% (95% CI 5%-40%, p = 0.02). Estimates were similar in analyses restricted to vaccine-eligible patients (n = 1,768, aVE 23%, 95% CI 1%-40%) and patients aged ≥65 years (n = 1,407, aVE 20%, 95% CI -5% to 40%), but not in patients aged ≥75 years (n = 905, aVE 5%, 95% CI -37% to 35%). The aVE estimate in relation to PPV23/non-13-valent pneumococcal conjugate vaccine (PCV13) serotype pneumonia (n = 417 cases, 43.7% vaccinated) was 29% (95% CI 6%-46%). Key limitations of this study are that, due to high vaccination rates, there was a lack of power to reject the null hypothesis of no vaccine effect, and that the study was not large enough to allow robust subgroup analysis in the older age groups. In the setting of an established national childhood PCV13 vaccination programme, PPV23 vaccination of clinical at-risk patient groups and adults aged ≥65 years provided moderate long-term protection against hospitalisation with PPV23 serotype pneumonia. These findings suggest that PPV23 vaccination may continue to have an important role in adult pneumococcal vaccine policy, including the possibility of revaccination of older adults.

•This is a systemic literature review on PCV indirect (herd) impact in adults.•Adults IPD and pneumonia rates decreased in most countries post-PCV introduction.•Herd protection depended on PCV uptake rates and time from PCV implementation.•Adults >65years old seem to benefit the most from PCV introduction. Pneumococcal diseases are major causes of morbidity among adults, especially those over 50years of age. While pneumococcal conjugated vaccines (PCV’s) impact on pneumococcal disease rates among children is well established, the extent of its impact on adult pneumococcal related illness remains unclear. The aim of this systematic literature review was to describe the impact of PCV introduction to childhood national immunization programs worldwide on PCV-naive adult population. A systematic literature search was performed using the PubMed database. The search was limited to articles written in English and published between January 2000 and February 2016. Studies evaluating pneumococcal disease rates in individuals over 5years of age were included. Independent extraction of articles was performed by the two authors. Search terms included: Pneumococcal conjugated vaccine, herd, indirect, adults, and pneumonia. Forty-nine articles meeting the selection criteria were identified, 39 regarding invasive pneumococcal disease (IPD, one on meningitis only), 8 regarding pneumonia, and 2 on both IPD and pneumonia. The majority of reports were from the US, UK and Canada. Considerable variability in the data sources, quality and completeness was observed. While most studies reported either statistically significant reduction or insignificant changes in IPD and pneumonia disease rates in adults following PCV nationwide implementation, few studies reported statistically significant increase in pneumococcal disease rates, these were mainly from countries with low PCV coverage rates and/or inadequate surveillance. Invasive pneumococcal diseases and pneumonia rates among the adult population decreased in most countries following PCV introduction into the NIP. This indirect effect on older population seems to be dependent on PCV coverage rates and time from PCV nationwide implementation. Adults >65years old seem to benefit the most from PCV introduction.

Background. The impact of PCV 13 on a number of clinical aspects of pneumococcal pneumonia (PP) in children has not been reported. We compared the serotype distribution, antibiotic susceptibility, and outcomes of children with PP 4 years before and 4 years after the introduction of PCV13. Methods. We identified patients ≤18 years with PP at 8 children's hospitals in the United States (2006–2014). Pneumococcal isolates were collected prospectively. Serotyping and antibiotic susceptibility were performed in a central laboratory. Clinical and laboratory data were collected retrospectively. Annual pneumococcal pneumonia hospitalization rates per 100 000 admissions with 95% confidence intervals were calculated. Dichotomous variables were analyzed by χ2 test and continuous variables with Mann-Whitney U test. Results. A total of 377 patients with PP requiring hospitalization were identified. Hospitalization rates of PP decreased from 53.6 to 23.3 per 100 000 admissions post PCV13 (P < .0001). Complicated PP rates also decreased (P < .0001). Need for intensive care, mechanical ventilation, and invasive procedure remained unchanged after the introduction of PCV13. Comorbidities were more common among children with uncomplicated than complicated pneumonia (52.2% vs. 22.5%, P < .001). Overall, PCV13 serotypes 19A, 3, 7F, and 1 caused 80% of PP. Hospitalization rates of PCV13 serotype pneumonia decreased from 47.2 to 15.7 per 100 000 admissions post PCV13. In 2014, the most common serotypes were 3, 19A and 35B. Conclusions. PP requiring hospitalization significantly decreased in children after PCV13 introduction. Complicated PP rates decreased steadily in 2011–2014. PCV13 serotypes 19A and 3 were still responsible for half of the cases of PP in 2011–2014.

Background. The benefits of using the 23-valent pneumococcal polysaccharide vaccine (PPV23) are controversial. This study assessed clinical effectiveness of PPV23 in preventing community-acquired pneumonia (CAP) among the general population aged ≥60 years. Methods. This was a population-based cohort study involving 27 204 individuals aged ≥60 years in Tarragona, Spain, who were prospectively followed from 1 December 2008 until 30 November 2011. Primary outcomes were hospitalization for pneumococcal CAP (bacteremic and nonbacteremic cases) and all-cause CAP. All CAP cases were radiographically confirmed and validated by checking clinical records. Cox regression was used to evaluate the association between pneumococcal vaccination and the risk of each outcome. Results. Cohort members were followed for a total of 76 033 person-years (29 065 person-years for vaccinated subjects). Incidence rates (per 1000 person-years) were 0.21 for bacteremic pneumococcal CAP (0.14 vs 0.26 among vaccinated and unvaccinated subjects, respectively), 1.45 for nonbacteremic pneumococcal CAP (1.46 vs 1.44), and 7.51 for all-cause CAP (7.19 vs 7.71). In primary analyses including all cohort members, PPV23 did not appear to be effective against any analyzed outcome. However, a beneficial effect emerged in sensitive and stratified analyses. After multivariable adjustments, as compared with those never vaccinated, recent vaccination with PPV23 (<5 years ago) was associated with reduced risks of bacteremic pneumococcal CAP (hazard ratio [HR], 0.38; 95% confidence interval [CI], .09–1.68), nonbacteremic pneumococcal CAP (HR, 0.52; 95% CI, .29–.92), overall pneumococcal CAP (HR, 0.49; 95% CI, .29–.84), and all-cause CAP (HR, 0.75; 95% CI, .58–.98). Conclusions. Our data support a protective effect of recent PPV23 vaccination (within previous 5 years) against both pneumococcal and all-cause CAP.

In 2019, the 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in the Croatian immunization programme, a first for this European PCV-naïve country. This study aimed to evaluate the impact of PCV10 on pneumococcal serotype distribution among asymptomatic children and children with pneumonia and/or acute otitis media. Cross-sectional studies were conducted before and after the PCV10 introduction, with nasopharyngeal swabs collected from 1500 healthy children under 48 months of age. An additional 324 children under 18 years with pneumonia and/or acute otitis media, from whom Streptococcus pneumoniae was isolated, were also included. Isolates were identified by conventional methods, serotyped by Quellung reaction, and tested for antimicrobial susceptibility using disk diffusion and gradient test methods. We report prevalence, absolute risk (prevalence) difference (RD) and relative risk (prevalence) ratio (RR) differences between exposed and control children. Carriage prevalence among healthy children increased from 19.9% to 28.7%, primarily due to a rise in non-vaccine serotypes (NVT). Adjusted probabilities for serotypes 6C (RR 3.18; 95% CI, 1.43–7.06), 11A (RR 2.8; 95% CI, 1.22–6.39), 19A (RR 4.18; 95% CI, 1.18–14.9) and 23A (RR 3.93; 95% CI, 1.87–8.24) were significantly higher in healthy exposed children. Prevalences of these serotypes were also higher in exposed children with pneumonia/acute otitis media. In this cohort, serotype 3 increased (RR 4.6; 95% CI, 2.02–10.3), becoming the leading post-PCV10 isolate in the overall studied population. Serotypes 3 and 19A were almost entirely responsible for complicated pneumonia cases for which the probability increased by 21-fold. Antimicrobial susceptibility remained similar across periods. In the early post-vaccine period significant increase of PCV10 vaccine-related serotypes (6C, 19A) was observed. Continued monitoring is also essential due to concerning rise of serotype 3 in patients with mucosal infections and a higher risk for complicated pneumonia.

Background. Pneumococcal serotypes 1, 3, 5, 7F, and 19A were the most implicated in community-acquired pneumonia (CAP) after implementation of 7-valent pneumococcal conjugate vaccine (PCV7). In France, the switch from PCV7 to 13-valent pneumococcal conjugate vaccine (PCV13) occurred in June 2010. An active surveillance network was set up to analyze the impact of PCV13 on CAP. Methods. An observational prospective study performed in 8 pediatric emergency departments from June 2009 to May 2012 included all children between 1 month and 15 years of age with chest radiography–confirmed pneumonia. Three 1-year periods were defined: pre-PCV13, transitional, and post-PCV13. Results. During the 3-year study period, among the 953 274 pediatric emergency visits, 5645 children with CAP were included. CAP with pleural effusion and documented pneumococcal CAP were diagnosed in 365 and 136 patients, respectively. Despite an increase (4.5%) in number of pediatric emergency visits, cases of CAP decreased by 16% (2060 to 1725) between pre- and post-PCV13 periods. The decrease reached 32% in infants in the same periods (757 to 516; P < .001). Between pre- and post-PCV13 periods, the proportion of CAP patients with a C-reactive protein level >120 mg/dL decreased from 41.3% to 29.7% (P < .001), the number of pleural effusion cases decreased by 53% (167 to 79; P < .001) and the number of pneumococcal CAP cases decreased by 63% (64 to 24; P = .002). The number of additional PCV13 serotypes identified decreased by 74% (27 to 7). Conclusions. Our data suggest a strong impact of PCV13 on CAP, pleural effusion, and documented pneumococcal pneumonia, particularly cases due to PCV13 serotypes.