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Pneumococcal conjugate vaccines reduce the burden of invasive pneumococcal disease, but the sustained effect of these vaccines can be diminished by an increase in disease caused by non-vaccine serotypes. To describe pneumococcal serotype epidemiology in Botswana following introduction of 13-valent pneumococcal conjugate vaccine (PCV-13) in July 2012, we performed molecular serotyping of 268 pneumococcal strains isolated from 221 children between 2012 and 2017. The median (interquartile range) age of the children included in this analysis was 6 (3,12) months. Fifty-nine percent of the children had received at least one dose of PCV-13 and 35% were fully vaccinated with PCV-13. While colonization by vaccine serotypes steadily declined following PCV-13 introduction, 25% of strains isolated more than 3 years after vaccine introduction were PCV-13 serotypes. We also observed an increase in colonization by non-vaccine serotypes 21 and 23B, which have been associated with invasive pneumococcal disease and antibiotic resistance in other settings., Competing Interests: The authors have declared that no competing interests exist.

Background: The objective of this study is to describe incidence and shifts of serotype and clonal distribution of invasive Streptococcus pneumoniae strains in four different age groups (<5 years, 5-17 years, 18-64 years and >65 years) during a period of intermediate PCV13 vaccination coverage (2011-2016) in Catalonia, Spain., Methods: We included all pneumococcal strains systematically sent to the Catalan support laboratory for molecular surveillance of invasive pneumococcal disease (IPD) located at Hospital Sant Joan de Deu, Barcelona. Two study periods were considered: 2011-13, early PCV13 vaccination period (EVP) and 2014-2016, late vaccination period (LVP)., Results: A total of 2142 strains were included in the study. Five years after intermediate introduction of PCV13 in our population, a significant decrease of overall incidence of IPD in children <5 years was observed (incidence rate ratio 0.5, 95% confidence interval 0.4-0.8). However, in seniors older than 65 years, a significant increase of overall incidence of IPD was observed (IRR 1.4, 95% CI 1.1-1.7). The contribution of PCV13 vaccine serotypes to IPD declined significantly in all age groups: from 59% to 38.1% in <5 years; 82.7% to 59% in 5-17 years, 47.8% to 34.1% in 18-64 years and 48.2% to 37% in >65 years. Results found when comparing both periods were consistent with IRRs observed year by year. In children <5 years, the three major serotypes detected were 1, 24F and 19A in EVP vs 24F, 14 and 10A in LVP. Among patients 5-17 years the first three serotypes were 1, 12F and 14 both in EVP and LVP. Among adults 18-64, the three major serotypes detected were 1, 12F and 8 vs 8, 12F and 3, respectively. Finally, in patients >65 years the most frequently isolated serotypes were 3, 19A and 7F vs 3, 14 and 12F, respectively. Regarding clonal complexes (CCs) expressing mainly PCV13 serotypes, significant decreases of the proportions of CC306, CC191 and CC320 were observed, while CC156 showed a significant increase. As for CCs expressing mostly non-PCV13 serotypes, significant increases in ST989, CC53 and CC404 were showed., Conclusions: Despite low vaccine coverage in our setting a significant decrease of incidence of IPD was observed in children younger than 5 years. The modest indirect protection against vaccine serotypes causing IPD in elderly indicate the need for the inclusion of more serotypes in future high-valent PCV and vaccinating old adults should be considered., Competing Interests: Competing Interests: Fernando Moraga-Llop reports participation in expert meetings and symposiums organized by Pfizer and GSK. Carmen Muñoz-Almagro reports travel grants, participation in expert meetings and a research grant from Pfizer laboratories outside the submitted work. Magda Campins reports participation as an investigator in clinical trials from GSK and in expert meetings and symposiums organized by Pfizer and GSK. Juan José García-García reports participation in expert meetings from Pfizer. All other authors declare no competing interests.

Enhanced surveillance of invasive pneumococcal disease (IPD) in adults was conducted during April 2013-March 2018 in 10 of 47 prefectures in Japan, and a total of 1277 IPD patients were enrolled. An emergence of IPD caused by serotype 12F was identified during May 2015-March 2018 through this surveillance. 12F isolates were composed of four related sequence types. In total, 120 patients with 12F IPD were reported during this period. To characterize the clinical features of 12F IPD, the disease characteristics of these patients were compared with those of 1157 patients with non-12F IPD. Compared with the non-12F IPD patients, a significantly lower proportion of 12F IPD patients was aged 65 years or older (55% vs. 70%), vaccinated with 23-valent pneumococcal polysaccharide (4% vs. 14%), had comorbid illness (65% vs. 77%), or were immunocompromised (19% vs. 30%; all P < 0.05). No significant difference in the proportion of case fatalities was found between the two groups. The proportions of those aged 65 years or older (53% vs. 69%) and with bacteremic pneumonia (35% vs. 69%) were significantly lower in 17 patients who died from 12F IPD than in 205 patients who died from non-12F IPD (all P < 0.05). Differences in clinical features were similarly found between 12F IPD patients and patients in low- or intermediate-level invasive potential serogroups. Our data demonstrated that serotype 12F was associated with IPD in younger adults and a lower proportion of comorbid illness, including immunocompromised conditions, in adult IPD, suggesting the high invasive potential of the serotype 12F. In addition, patients who died from 12F IPD were younger and had proportionately more bacteremia without focus. These findings may provide new insight into the pathogenesis of IPD in adults caused by 12F serotype with a high invasive potential., Competing Interests: The authors have declared that no competing interests exist.

Background: Influenza and pneumonia are leading causes of morbidity and mortality among the elderly. Although vaccination is a main strategy to prevent these infectious diseases, concerns remain with respect to vaccine effectiveness., Methods: During three influenza seasons (2014-2015, 2015-2016 and 2016-2017), we evaluated the effectiveness of the influenza and pneumococcal vaccines against pneumonia and acute exacerbation of cardiopulmonary diseases among the elderly aged ≥65 years with influenza-like illness (ILI). Demographic and clinical data were collected prospectively., Results: Among 2,119 enrolled cases, 1,302 (61.4%) and 871 (41.1%) received the influenza vaccine and 23-valent pneumococcal polysaccharide vaccine (PPV23), respectively. During an A/H3N2-dominant season with poor influenza vaccine effectiveness (2014-2015 season), neither the influenza vaccine nor PPV23 showed significant effectiveness against pneumonia or acute exacerbation of cardiopulmonary diseases. During seasons with good influenza vaccine effectiveness (2015-2016 and 2016-2017 seasons), the influenza vaccine was effective in preventing pneumonia, but PPV23 was not. In particular, the influenza vaccine was effective in preventing acute exacerbation of heart diseases (75.0%) during the A/H1N1-dominant 2015-2016 season., Conclusion: The influenza vaccine was effective in preventing pneumonia only during vaccine-matched seasons with good effectiveness against circulating influenza viruses. In addition, the influenza vaccine was cardio-protective during a vaccine-matched A/H1N1-dominant season., Competing Interests: The authors have declared that no competing interests exist.

Pathologically elevated immune activation and inflammation contribute to HIV disease progression and immunodeficiency, potentially mediated by elevated levels of prostaglandin E2, which suppress HIV-specific T cell responses. We have previously shown that a high dose of the cyclooxygenase-2 inhibitor celecoxib can reduce HIV-associated immune activation and improve IgG responses to T cell-dependent vaccines. In this follow-up study, we included 56 HIV-infected adults, 28 antiretroviral therapy (ART)-naïve and 28 on ART with undetectable plasma viremia but CD4 counts below 500 cells/μL. Patients in each of the two study groups were randomized to receive 90 mg qd of the cyclooxygenase-2 inhibitor etoricoxib for six months, two weeks or to a control arm, respectively. T cell activation status, HIV Gag-specific T cell responses and plasma inflammatory markers, tryptophan metabolism and thrombin generation were analyzed at baseline and after four months. In addition, patients received tetanus toxoid, conjugated pneumococcal and seasonal influenza vaccines, to which IgG responses were determined after four weeks. In ART-naïve patients, etoricoxib reduced the density of the activation marker CD38 in multiple CD8+ T cell subsets, improved Gag-specific T cell responses, and reduced in vitro plasma thrombin generation, while no effects were seen on plasma markers of inflammation or tryptophan metabolism. No significant immunological effects of etoricoxib were observed in ART-treated patients. Patients receiving long-term etoricoxib treatment had poorer tetanus toxoid and conjugated pneumococcal vaccine responses than those receiving short-course etoricoxib. Cyclooxygenase-2 inhibitors may attenuate harmful immune activation in HIV-infected patients without access to ART.

Background: To mitigate the burden of pneumococcal infections in Niger, a 13-valent pneumococcal vaccine, PCV13, was introduced for routine child vaccination in July 2014. In order to provide pre-vaccine baseline data and allow appreciation of changes on carriage due to vaccination, we analyzed retrospectively pneumococcal isolates obtained from healthy, 0 to 2 year old children prior to the vaccine introduction., Methods: From June 5, 2007, to May 26, 2008, 1200 nasopharyngeal swabs were collected from healthy 0 to 2 year old children and analyzed by standard microbiological methods. Serotyping was done by SM-PCR and the data were analyzed with R version 2.15.0 (2012-03-30)., Results: Streptococcus pneumoniae was detected in 654/1200 children (54.5%) among whom 339 (51.8%) were males. The ages of the study subjects varied from few days to 26 months (mean = 7.1, median = 6, 95% CI [6.8-7.4]). Out of 654 frozen isolates, 377 (54.8%) were able to be re-grown and analyzed. In total, 32 different serogroups/serotypes were detected of which, the most prevalent were 6/(6A/6B/6C/6D) (15.6%), 23F (10.6%), 19F (9.3%), 14 (9%), 19A (5.6%), 23B (4.0%), 25F/38 (3.7%), 18/(18A/18B/18C/18F) (2.9%) and PCR non-typeable (16.4%). Eleven serogroups/serotypes accounting for 57.3% (216/377) were of PCV13 types. Of the 211/377 (56%) isolates tested for drug sensitivity, 23/211 (10.9%), 24/211 (11.4%), 9/211(4.3%) and 148/210 (70.5%) were respectively resistance to oxacillin, chloramphenicol, erythromycin and tetracycline. Thirteen of the oxacillin resistant isolates were additionally multidrug-resistant. No resistance was however detected to gentamycin500μg and to fluoroquinolones (ø Norfloxacin5μg <7mm). Age > 3 months and presence in family of more than one sibling aged < 6 years were significant risk factors for carriage., Conclusion: A global rate of 54.5% pneumococcal carriage was detected in this study. The introduced PCV13 vaccine should cover 57.3% (216/377) of circulating serogroups/serotypes, among which were those resistant to antibiotics. Age > 3 months and presence in family of children aged < 6 years were significant factors for pneumococcal carriage. The present data should help understanding post vaccine introduction changes in pneumococcal carriage and infections for better action., Competing Interests: The authors have declared that no competing interests exist.

Background: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Chilean National Immunization Program (NIP) in January 2011 with a 3+1 schedule (2, 4, 6 and 12 months) without catch-up vaccination. We evaluated the effectiveness of PCV10 on pneumonia morbidity and mortality among infants during the first two years after vaccine introduction., Methods: This is a population-based nested case-control study using four merged nationwide case-based electronic health data registries: live birth, vaccination, hospitalization and mortality. Children born in 2010 and 2011 were followed from two moths of age for a period of two years. Using four different case definitions of pneumonia hospitalization and/or mortality (all-cause and pneumonia related deaths), all cases and four randomly selected matched controls per case were selected. Controls were matched to cases on analysis time. Vaccination status was then assessed. Vaccine effectiveness (VE) was estimated using conditional logistic regression., Results: There were a total of 497,996 children in the 2010 and 2011 Chilean live-birth cohorts. PCV10 VE was 11.2% (95%CI 8.5-13.6) when all pneumonia hospitalizations and deaths were used to define cases. VE increased to 20.7 (95%CI 17.3-23.8) when ICD10 codes used to denote viral pneumonia were excluded from the case definition. VE estimates on pneumonia deaths and all-cause deaths were 71.5 (95%CI 9.0-91.8) and 34.8 (95% CI 23.7-44.4), respectively., Conclusion: PCV10 vaccination substantially reduced the number of hospitalizations due to pneumonia and deaths due to pneumonia and to all-causes over this study period. Our findings also reinforce the importance of having quality health information systems for measuring VE.

Background: One of the most common causes of morbidity and mortality in children with sickle cell disease (SCD) is infection with the pneumococcal bacterium (Streptococcus pneumoniae). Unfortunately, the polysaccharide-conjugate vaccine appears to be less effective in individuals with SCD when compared to the general population. We sought to better understand the relative efficacy of pneumococcal vaccination in a SCD mouse challenge model., Methods: Transgenic control and SCD mice were monitored for mortality after intranasal pneumococcal infection or pneumococcal vaccination with Prevnar-13 and type-matched challenge. Anti-pneumococcal antibody titers were measured by ELISA and opsonophagocytosis was measured in vitro., Results: Mortality after pneumococcal infection was similar between control and SCD mice. However, after three intramuscular polysaccharide-conjugate vaccinations, all control mice were protected following high-dose intranasal infection, whereas 60% of SCD mice died. Anti-pneumococcal antibody titers showed initial IgG and IgM responses in both groups, but waning titers were observed in the SCD group, even after boosting. When functionally assayed in vitro, serum from SCD mice 13 weeks after a second booster shot maintained little to no ability to opsonize pneumococci, while serum from control mice sustained a significantly higher capacity opsonization. Thus, it appears that SCD mice do not maintain antibody responses to pneumococcal polysaccharides after Prevnar-13 vaccination, thereby leaving them susceptible to mortality after type-matched infection., Conclusion: Our results emphasize the need to better understand the correlates of immune protection in SCD so that pneumococcal vaccines can be improved and mortality reduced in this susceptible population.