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Background: Streptococcus pneumoniae serotype 8 incidence has increased in Denmark after the introduction of pneumococcal conjugated vaccines (PCV). The mechanism behind the serotype 8 replacement is not well understood. In this study, we aimed to present epidemiological data on invasive pneumococcal disease (IPD) and molecular characterization of 96 serotype 8 clinical isolates., Methods: IPD data from 1999 to 2019 were used to calculate the incidence and age distribution. Whole-genome sequencing (WGS) analysis was performed on 96 isolates (6.8% of the total serotype 8 IPD isolates in the period) to characterize the isolates with respect to pneumococcal lineage traits, a range of genes with potential species discrimination, presence of colonization and virulence factors, and molecular resistance pattern., Results: The serotype 8 IPD incidence increased significantly (P < 0.05) for the age groups above 15 years after the introduction of PCV13, primarily affecting the elderly (65+). All isolates were phenotypically susceptible to penicillin, erythromycin and clindamycin. Molecular characterization revealed seven different MLST profiles with ST53 as the most prevalent lineage (87.5%) among the analyzed serotype 8 isolates. The genes covering the cell-surface proteins: lytA, rspB, pspA, psaA & Xisco and the pneumococcal toxin pneumolysin = ply were present in all isolates, while genes for the membrane transporter proteins: piaA/piaB/piaC; the capsular genes: cpsA (wzg) & psrP; the metallo-binding proteins zmpB & zmpC; and the neuroamidase proteins: nanA/nanB were variably present. Surprisingly, the putative transcriptional regulator gene SP2020 was not present in all isolates (98%). Susceptibility to penicillin, erythromycin and clindamycin was molecularly confirmed., Conclusion: The observed serotype 8 replacement was not significantly reflected with a change in the MLST profile or changes in antibiotic resistance- or virulence determinants.

Background: In November 2011, Malawi introduced the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant schedule. Four to 7 years after introduction (2015-2018), rolling prospective nasopharyngeal carriage surveys were performed in the city of Blantyre. Carriage of Streptococcus pneumoniae vaccine serotypes (VT) remained higher than reported in high-income countries, and impact was asymmetric across age groups., Methods: A dynamic transmission model was fit to survey data using a Bayesian Markov-chain Monte Carlo approach, to obtain insights into the determinants of post-PCV13 age-specific VT carriage., Results: Accumulation of naturally acquired immunity with age and age-specific transmission potential were both key to reproducing the observed data. VT carriage reduction peaked sequentially over time, earlier in younger and later in older age groups. Estimated vaccine efficacy (protection against carriage) was 66.87% (95% CI 50.49-82.26%), similar to previous estimates. Ten-year projected vaccine impact (VT carriage reduction) among 0-9 years old was lower than observed in other settings, at 76.23% (CI 95% 68.02-81.96%), with sensitivity analyses demonstrating this to be mainly driven by a high local force of infection., Conclusions: There are both vaccine-related and host-related determinants of post-PCV13 pneumococcal VT transmission in Blantyre with vaccine impact determined by an age-specific, local force of infection. These findings are likely to be generalisable to other Sub-Saharan African countries in which PCV impact on carriage (and therefore herd protection) has been lower than desired, and have implications for the interpretation of post-PCV carriage studies and future vaccination programs.

Background: HIV-infected children are at a higher risk of Invasive Pneumococcal Disease (IPD) and its mortality, even in the era of antiretroviral therapy. Therefore, an effective vaccination strategy would be beneficial. To investigate the effectiveness of Pneumococcal Conjugate Vaccination (PCV) against IPD among HIV-Infected and HIV-Uninfected Children through a systematic review and meta-analysis., Methods: Observational studies and randomized trials on 7 years old or older children were searched in the Cochrane Library, Web of Science core collection, Embase, Medline/PubMed, and Google Scholar. Critical appraisal was done using the Cochrane risk of bias tool and the Newcastle-Ottawa quality assessment form. Effectiveness and efficacy of at least one dose of PCV was investigated among children with and without HIV considering subgroups of pneumococcal serotypes. We meta-analyzed the effect sizes using random-effects modeling., Results: Efficacy of PCV was estimated as 45.0% (31.2, 56.1) and 52.6% (25.7, 69.8) among HIV-infected and HIV-uninfected children, respectively. Effectiveness of PCV among HIV-infected children as - 6.2% (- 67.6, 32.7) was significantly lower than HIV-uninfected children 65.1% (47.3, 76.9). Effectiveness of PCV among HIV-infected children for IPDs caused by vaccine serotypes was estimated as 7.7(- 66.7, 48.9), and for IPDs caused by non-vaccine serotypes was estimated as - 402.8(- 1856, - 29.2)., Conclusion: Unlike the evidence on the efficacy of PCV against IPD among both of HIV-infected and HIV-uninfected children, its effectiveness against IPD among HIV-infected children is much less limited., Review Registration: The study protocol was registered at PROSPERO (registration ID: CRD42018108187).

Background: Streptococcus pneumoniae, the leading pathogen of bacterial infections in infants and the elderly, is responsible for pneumococcal diseases with severe morbidity and mortality. Emergence of drug-resistant strains presented new challenges for treatment and prevention. Vaccination has proven to be an effective means of preventing pneumococcal infection worldwide. Detailed epidemiological information of antibiotic susceptibilities and serotype distribution will be of great help to the management of pneumococcal infections., Methods: A total of 881 S. pneumoniae isolates were collected from patients at 23 teaching hospitals in 17 different cities from 2011 to 2016. The main specimen types included sputum, blood, broncho-alveolar lavage fluid, pharyngeal swabs, and cerebrospinal fluid. Minimum inhibitory concentrations (MICs) were determined using the agar dilution method. Capsular serotypes were identified using latex agglutination and quellung reaction test. Molecular epidemiology was investigated using multilocus sequence typing., Results: S. pneumoniae isolates were highly resistant to macrolides, tetracycline, and trimethoprim/sulfamethoxazole. The rate of resistance to penicillin was 51.6% (oral breakpoint). However, levofloxacin and moxifloxacin maintained excellent antimicrobial activity and all of the isolated strains were susceptible to vancomycin. Twenty-two serotypes were identified among the 881 isolates. Prevalent serotypes were 19F (25.7%), 19A (14.0%), 15 (6.8%), 6B (3.6%), 6A (3.0%), and 17 (2.8%). The overall vaccine coverage rates for 7- and 13-valent pneumococcal conjugate vaccines were 37.5% and 58.3%, respectively. Vaccine coverage rates in young children and economically underdeveloped regions were higher than those in older adults and developed regions. Vaccine-covered serotypes demonstrated higher resistance compared with uncovered serotypes. Molecular epidemiological typing demonstrated that S. pneumoniae showed significant clonal dissemination and that ST271 (120, 28.3%), ST320 (73, 17.2%) and ST81 (27, 6.6%) were the major STs., Conclusions: High resistance to clinical routine antibiotics was observed for all 881 S. pneumoniae strains. Drug resistance varied among different serotypes and age groups. Prevalent serotypes among the isolates were 19F, 19A, 15, 6B, 6A, and 17. Community-acquired strains should also be included in future studies to gain a better understanding of the prevalence and resistance of S. pneumoniae in China.

Background and Case Presentation: We report a case of septic shock syndrome caused by Streptococcus pneumoniae in a patient who had undergone splenectomy due to an autoimmune lymphoproliferative syndrome (ALPS), which is characterized as a dysfunction of immunoregulation. Although the patient was vaccinated with a conjugated polysaccharide vaccine after the splenectomy, he was still susceptible to S. pneumoniae infection, because the isolated serovar (24F), a serovar long thought to be apathogenic, is not covered by any vaccine currently approved, neither a conjugated nor an unconjugated polysaccharide one., Conclusions: This case demonstrates that, due to presence of different serovars, also infections with bacteria against which patients are vaccinated have to be considered as differential diagnosis. Although vaccine development has extended the coverage of S. pneumoniae from 7 to 23 serovars within recent years, there is still demand for novel vaccines which can provide broader protection also against so-thought "apathogenic" strains, especially for groups at high risk.

We analyzed an attempt to develop and clinically test a pneumococcal conjugate vaccine for the developing world, undertaken by public health institutions from the Netherlands, Sweden, Denmark, Norway and Finland: the Dutch Nordic Consortium (DNC), between 1990 and 2000. Our review shows that the premature termination of the project was due less to technological and scientific challenges and more to managerial challenges and institutional policies. Various impeding events, financial and managerial challenges gradually soured the initially enthusiastic collaborative spirit until near the end the consortium struggled to complete the minimum objectives of the project. By the end of 1998, a tetravalent prototype vaccine had been made that proved safe and immunogenic in Phase 1 trials in adults and toddlers in Finland. The planned next step, to test the vaccine in Asia in infants, did not meet approval by the local authorities in Vietnam nor later in the Philippines and the project eventually stopped.The Dutch DNC member, the National Institute of Public Health and the Environment (RIVM) learned important lessons, which subsequently were applied in a following vaccine technology transfer project, resulting in the availability at affordable prices for the developing world of a conjugate vaccine against Haemophilus influenzae type b. We conclude that vaccine development in the public domain with technology transfer as its ultimate aim requires major front-end funding, committed leadership at the highest institutional level sustained for many years and a competent recipient-manufacturer, which needs to be involved at a very early stage of the development.At the national level, RIVM's policy to consolidate its national manufacturing task through securing a key global health position in support of a network of public vaccine manufacturers proved insufficiently supported by the relevant ministries of the Dutch government. Difficulties to keep up with high costs, high-risk innovative vaccine development and production in a public sector setting led to the gradual loss of production tasks and to the 2009 Government decision to privatize the vaccine production tasks of the Institute.

Background: Bacterial meningitis remains an important infection globally, with the greatest burden in children in low-income settings, including Papua New Guinea (PNG). We present serotype, antimicrobial susceptibility and outcome data from paediatric meningitis patients prior to introduction of Haemophilus influenzae type b (Hib) and pneumococcal conjugate vaccines (PCVs) in PNG, providing a baseline for evaluation of immunisation programs., Methods: Cerebrospinal fluid (CSF) was collected from children admitted to Goroka General Hospital with suspected meningitis between 1996 and 2005. Culture and sensitivity was conducted, and pneumococci and H. influenzae were serotyped. Laboratory findings were linked to clinical outcomes., Results: We enrolled 1884 children. A recognised pathogen was identified in 375 children (19.9%). Streptococcus pneumoniae (n = 180) and Hib (n = 153) accounted for 88.8% of pathogens isolated. 24 different pneumococcal serogroups were identified; non-PCV types 2, 24 and 46 accounted for 31.6% of pneumococcal meningitis. 10- and 13-valent PCVs would cover 44.1% and 45.4% of pneumococcal meningitis respectively. Pneumococcal isolates were commonly resistant to penicillin (21.5%) and 23% of Hib isolates were simultaneously resistant to ampicillin, co-trimoxazole and chloramphenicol. The case fatality rate in patients with a recognised bacterial pathogen was 13.4% compared to 8.5% in culture-negative patients., Conclusions: If implemented in routine expanded programme of immunisation (EPI) with high coverage, current PCVs could prevent almost half of pneumococcal meningitis cases. Given the diversity of circulating serotypes in PNG serotype replacement is of concern. Ongoing surveillance is imperative to monitor the impact of vaccines. In the longer term vaccines providing broader protection against pneumococcal meningitis will be needed.

Background: The use of molecular diagnostic techniques for the evaluation of the impact of pneumococcal conjugate vaccines (PCVs) has not been documented. We aimed to evaluate the impact of PCVs on invasive pneumococcal disease (IPD) using polymerase chain reaction (PCR)-based techniques and compare with results obtained from culture-based methods., Methods: We implemented two independent surveillance programs for IPD among individuals hospitalized at one large surveillance site in Soweto, South Africa during 2009-2012: (i) PCR-based (targeting the lytA gene) syndromic pneumonia surveillance; and (ii) culture-based laboratory surveillance. Positive samples were serotyped. The molecular serotyping assay included targets for 42 serotypes including all serotypes/serogroups included in the 7-valent (PCV-7) and 13-valent (PCV-13) PCV. The Quellung reaction was used for serotyping of culture-positive cases. We calculated the change in rates of IPD (lytA- or culture-positive) among HIV-uninfected children aged <2 years from the year of PCV-7 introduction (2009) to the post-vaccine years (2011 or 2012)., Results: During the study period there were 607 lytA-positive and 1,197 culture-positive cases that were serotyped. Samples with lytA cycle threshold (Ct)-values ≥35 (30.2 %; 123/407) were significantly less likely to have a serotype/serogroup detected for serotypes included in the molecular serotyping assay than those with Ct-values <35 (78.0 %; 156/200) (p < 0.001). From 2009 to 2012 rates of PCV-7 serotypes/serogroups decreased -63.8 % (95 % CI: -79.3 % to -39.1 %) among lytA-positive cases and -91.7 % (95 % CI: -98.8 % to -73.6 %) among culture-positive cases. Rates of lytA-positive non-vaccine serotypes/serogroups also significantly decreased (-71.7 %; 95 % CI: -81.1 % to -58.5 %) over the same period. Such decline was not observed among the culture-positive non-vaccine serotypes (1.2 %; 95 % CI: -96.7 % to 58.4 %)., Conclusions: Significant downward trends in IPD PCV-7 serotype-associated rates were observed among patients tested by PCR or culture methods; however trends of non-vaccine serotypes/serogroups differed between the two groups. Misclassifications of serotypes/serogroups, affecting the use of non-vaccine serotypes as a control group, may have occurred due to the low performance of the serotyping assay among lytA-positive cases with high Ct-values. Until PCR methods improve further, culture methods should continue to be used to monitor the effects of PCV vaccination programs on IPD incidence.

Background: Pneumonia is still the leading cause of death among children in Africa, and pneumococcal serotypes 1 and 5 are frequently isolated from African children with invasive pneumococcal disease below the age of 5 years. The immunogenicity, safety and reactogenicity of 3-dose primary vaccination with the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) were evaluated in infants in Mali and Nigeria., Methods: In an open, randomized, controlled study, 357 infants received DTPw-HBV/Hib and OPV primary vaccination with (PHiD-CV group) or without (control group) PHiD-CV co-administration at 6, 10 and 14 weeks of age. Pneumococcal antibody responses and opsonophagocytic activity (OPA) were measured and adverse events (AEs) recorded., Results: One month post-dose 3, ≥ 97.2% of PHiD-CV-vaccinated infants had an antibody concentration ≥ 0.2 μg/mL for each vaccine pneumococcal serotype except for 6B (82.0%) and 23F (87.6%) versus < 10% in the control group except for serotypes 14 (35.7%) and 19F (22.5%). For each vaccine serotype, ≥ 93.3% of PHiD-CV recipients had an OPA titre ≥ 8, except for serotypes 1 (87.6%) and 6B (85.4%), compared to < 10% in the control group, except for serotypes 7F (42.9%), 9V (24.1%) and 14 (24.5%). Anti-protein D geometric mean antibody concentrations were 3791.8 and 85.4 EL.U/mL in the PHiD-CV and control groups, respectively. Overall incidences of solicited and unsolicited AEs were similar between groups., Conclusions: In sub-Saharan African infants, PHiD-CV was immunogenic for all vaccine pneumococcal serotypes and protein D. Vaccine tolerability was generally comparable between the PHiD-CV and control groups., Trial Registration: ClinicalTrials.gov identifier: NCT00678301.

Introduction: Rheumatoid arthritis (RA) is frequently complicated with infections. The aim of our study was to evaluate vaccination response in patients with RA after B-cell depletion by using rituximab., Methods: Influenza (Afluria) and pneumococcal polysaccharides (Pneumo23) vaccines were given 6 months after rituximab (post-RTX group, n=11) or 6 days before rituximab treatment (pre-RTX group; n=8). RA patients never exposed to RTX composed the control group (n=10). Vaccine-specific cellular responses were evaluated on day 6 after vaccination, and vaccine-specific humoral responses, on day 21., Results: On day 6 after vaccination, formation of influenza-specific B cells was lower in post-RTX group as compared with the pre-RTX group and controls (P=0.04). Polysaccharide-specific B cells were found in 27% to 50%, being equally distributed between the groups. On day 21, the impairment of humoral responses was more pronounced with respect to influenza as compared with the pneumococcal vaccine and affected both IgG and light-chain production. Total absence of influenza-specific IgG production was observed in 55% of the post-RTX group., Conclusions: RTX compromises cellular and humoral vaccine responses in RA patients. However, repeated RTX treatment or previous anti-tumor necrosis factor (anti-TNF) treatment did not accentuate these defects.