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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 . . .

Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6–51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27–45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1–12). Efficacy of the conjugate vaccine was 77% (51–90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21–69) against disease caused by all serotypes, and 15% (7–21) against all-cause admissions. We also found an efficacy of 16% (3–28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants.

Pneumococcal infection is an important cause of death and complications in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. In this placebo-controlled, randomized trial involving 496 predominantly HIV-infected Malawian adults who had recently had an invasive pneumococcal infection, the 7-valent conjugated pneumococcal vaccine was found to have 74% efficacy in preventing subsequent invasive pneumococcal infection with a vaccine-associated serotype. In predominantly HIV-infected Malawian adults who had recently had an invasive pneumococcal infection, the 7-valent conjugated pneumococcal vaccine was found to have 74% efficacy in preventing subsequent invasive pneumococcal infection. Streptococcus pneumoniae is a leading cause of death and complications in adults with human immunodeficiency virus (HIV) infection, particularly in sub-Saharan Africa. 1 , 2 The risk of invasive pneumococcal disease is 30 to 100 times as high in patients with HIV infection as in age-matched controls without such infection. 3 , 4 Recurrent invasive pneumococcal disease is common, with up to 25% of patients having an additional episode, predominantly reinfection, in the subsequent 12 months. 1 , 5 Even among patients who have access to timely and effective care, the case fatality rate with invasive pneumococcal disease is at least 8% 6 and rises to 50% . . .

•Pneumococcal conjugate vaccines elicit effective T cell dependent responses.•Conjugate and free polysaccharide vaccines were compared in older adults.•Conjugate responses were significantly greater for majority of serotypes.•Conjugate vaccine could provide enhanced immunity against pneumococcal disease. Streptococcus pneumoniae is a major cause of morbidity and mortality among adults 50 years of age and older in the United States. Pneumococcal conjugate vaccines are efficacious against pneumococcal disease in children and may also offer advantages in adults. We performed a randomized, modified double-blind trial that compared a single dose of 13-valent pneumococcal conjugate vaccine (PCV13) with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in 831 pneumococcal vaccine naive adults 60–64 years of age. An additional group of 403 adults 50–59 years of age received open-label PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured at baseline, and at 1 month and 1 year after vaccination. In the randomized trial, the month 1 post-vaccination OPA geometric mean titers in the PCV13 group were statistically significantly higher than in the PPSV23 group for 8 of the 12 serotypes common to both vaccines and for serotype 6A, a serotype unique to PCV13, and were comparable for the other 4 common serotypes. The immune response to PCV13 was generally greater in adults 50–59 years of age compared to adults 60–64 years of age. OPA titers declined from 1 month to 1 year after PCV13 administration but remained higher than pre-vaccination baseline titers. PCV13 induces a greater functional immune response than PPSV23 for the majority of serotypes covered by PCV13, suggesting that PCV13 could offer immunological advantages over PPSV23 for prevention of vaccine-type pneumococcal infection.

Patients with respiratory syncytial virus (RSV) infection exhibit enhanced susceptibility to subsequent pneumococcal infections. However, the underlying mechanisms involved in this increased susceptibility remain unclear. Here, we identified potentially novel cellular and molecular cascades triggered by RSV infection to exacerbate secondary pneumococcal pneumonia. RSV infection stimulated the local production of growth arrest-specific 6 (Gas6). The Gas6 receptor Axl was crucial for attenuating pneumococcal immunity in that the Gas6/Axl blockade fully restored antibacterial immunity. Mechanistically, Gas6/Axl interaction regulated the conversion of alveolar macrophages from an antibacterial phenotype to an M2-like phenotype that did not exhibit antibacterial activity, and the attenuation of caspase-1 activation and IL-18 production in response to pneumococcal infection. The attenuated IL-18 production failed to drive both NK cell-mediated IFN-γ production and local NO and TNF-α production, which impair the control of bacterial infection. Hence, the RSV-mediated Gas6/Axl activity attenuates the macrophage-mediated protection against pneumococcal infection. The Gas6/Axl axis could be a potentially novel therapeutic target for RSV-associated secondary bacterial infection.

•Limited evidence suggests that PCVs impact vaccine-type carriage density.•This double-blind PCV study suggests no impact on vaccine-type carriage density.•PCV13 may affect carriage by reducing carrier number but not vaccine-type density.•Carriage density may not impact herd effects. In addition to reducing vaccine-type nasopharyngeal carriage rates, pneumococcal conjugate vaccines (PCVs) may decrease carriage density in vaccinated individuals still carrying vaccine serotypes. However, reduction of carriage density has not been systematically studied. This study compared the effect of PCV13 versus PCV7 on carriage density of the serotypes in PCV13 that are not included in PCV7. This randomized, double-blind study was conducted in southern Israel and included Jewish and Bedouin subjects. Per protocol, 881 and 873 infants received PCV13 and PCV7, respectively, at ages 2, 4, 6, and 12months. Nasopharyngeal cultures at ages 7, 12, 13, 18, and 24months were plated using the 4-quadrant semiquantitative method and graded 0 (negative) to 4 (growth in all plate quadrants). In this post hoc analysis, the least squares means of cumulative colonization densities per serotype and serotype combination of the total population and each ethnic subpopulation in each vaccine group were calculated, and differences between vaccine groups derived from a linear model. PCV13-vaccinated children still carrying the 6 additional PCV13 serotypes unique to PCV13 showed no significant differences in carriage density compared with the PCV7-vaccinated control group. No differences in carriage density were shown between Jewish and Bedouin subpopulations despite higher carriage rates among Bedouin subjects. Although PCV13 vaccination reduces vaccine-type carriage compared with PCV7 vaccination by reducing nasopharyngeal acquisition of the additional PCV13 serotypes as previously reported, the current study lacks evidence of a decrease in carriage density of these serotypes when acquired in vaccinated children. Despite the lack of effect on carriage density observed, surveillance data suggest a dramatic decrease in disease rates after PCV implementation. Thus, the current analysis suggests that PCV’s impact on carriage density has minimal or no impact on vaccine success. (www.ClinicalTrials.gov: NCT00508742)

•Vaccine efficacy (VE) of PCV13 in elderly has been proven before.•VE in elderly with comorbidities was evaluated in this study.•VE of PCV13 was modified by the presence of diabetes mellitus (DM).•VE was significantly higher among subjects with DM.•Significant effect modification was not observed for other evaluated comorbidities. The 13-valent pneumococcal conjugate-vaccine (PCV13) was effective in preventing vaccine-type Community-Acquired Pneumonia (VT-CAP) and Invasive Pneumococcal Disease (VT-IPD) in elderly subjects, but vaccine efficacy (VE) in patients with comorbidities at time of vaccination is unknown. This is a post hoc analysis of the CAPiTA study, a double blind, randomized controlled trial with 84,496 immunocompetent participants aged ⩾65years, receiving PCV13 or placebo vaccination. Presence of diabetes mellitus (DM), heart disease, respiratory disease, liver disease, asplenia, and smoking at the time of immunization was verified on medical records in 139 subjects developing the primary endpoint of VT-CAP. Presence of DM and respiratory disease based on International Classification of Primary Care (ICPC) coding was also determined in 40,427 subjects. In the 139 subjects developing VT-CAP, DM caused significant effect modification (p-value 0.002), yielding VE of 89.5% (95%CI, 65.5–96.8) and 24.7% (95%CI, −10.4 to 48.7) for those with and without DM, respectively. Comparable effect modification (p-value 0.020) was found in the 40,427 subjects with and without ICPC-based classification of DM with VE of 85.6% (95%CI, 36.7–96.7) and of 7.0% (95%CI, −58.5 to 45.5) respectively. Effect modification through respiratory disease was not statistically significant, although the point estimate of VE was lower for those with respiratory disease in both analyses. There was no evidence of effect modification in subjects stratified by heart disease, smoking, and presence of any comorbidity. Among immunocompetent elderly, VE of PCV13 was modified by DM with higher VE among subjects with DM. Significant effect modification was not observed for subjects with heart disease, respiratory disease, smoking, or presence of any comorbidity. CAPiTA trial registration number: www.ClinicalTrials.gov; trial number NCT00744263.

•Conjugate pneumococcal polysaccharide vaccine allows for recall immune response.•This recall response occurs after follow-on use of conjugate or free polysaccharide.•Free polysaccharide vaccine results in lower responses following second dose.•Use of conjugate vaccine has potential to sustain anti-pneumococcal immunity. Unlike free polysaccharide vaccines, pneumococcal polysaccharide conjugate vaccines (PCVs) induce a T cell-dependent immune response and have the potential to provide an extended duration of protection with repeated vaccinations. This was an extension of a previous study in pneumococcal vaccine-naïve adults aged 50–64 years in which adults 60–64 years of age were given 13-valent PCV (PCV13) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) and adults aged 50–59 were given PCV13. In this follow up study conducted about 4 years later, the 60–64 year olds initially given PCV13 received PCV13 or PPSV23, and those initially given PPSV23 received another PPSV23. All adults aged 50–59 years were re-vaccinated with PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and 1 month after vaccination. A second PCV13 given about 4 years after a first vaccination induced OPA titers that were significantly higher than those following the initial vaccination for 7 of 13 serotypes in the older group, and 6 of 13 serotypes in the younger group, and responses to the remaining serotypes were largely non-inferior. In contrast, OPA titers following revaccination with PPSV23 were statistically significantly lower for 9 of the 13 serotypes, and non-inferior for the remaining serotypes, when compared to the responses to the first PPSV23. OPA titers in the older adults who received PPSV23 after initial PCV13 were significantly higher than those following a first PPSV23 for 10 of the 13 serotypes. In adults 50 to 64 years of age, initial vaccination with PCV13 establishes an immune state that results in recall anti-pneumococcal responses upon subsequent vaccination with either conjugated or free polysaccharide vaccine. In contrast, initial vaccination with PPSV23 results in an immune state in which subsequent PPSV23 administration yields generally lower responses compared with the initial responses.

•Free polysaccharide pneumococcal vaccine is generally recommended for older adults.•Conjugate and free polysaccharide vaccines were compared in pre-immunized adults.•Conjugate responses were significantly greater for majority of serotypes.•Conjugate vaccine did not negatively influence response to follow-on dose at 1 year.•Free polysaccharide vaccine diminished response to follow-on conjugate at 1 year. The currently recommended single dose of the 23-valent pneumococcal free polysaccharide vaccine (PPSV23) for adults 65 years of age and older does not provide extended protection into older age. This reflects a significant unmet medical need for alternative strategies to protect older adults against pneumococcal infection, which may be met by the 13-valent polysaccharide conjugate vaccine (PCV13). We performed a randomized, modified double-blind trial in 936 adults aged 70 years and older who had previously received PPSV23 at least 5 years before study entry and were now vaccinated with PCV13 or PPSV23. At 1 year after enrollment, all subjects received a follow-on dose of PCV13. Anti-pneumococcal opsonophagocytic activity (OPA) titers were measured before and at 1 month after each vaccination. Following the enrollment vaccination, OPA titers were significantly greater in the PCV13 group compared to the PPSV23 group for 10 of the 12 serotypes common to both vaccines and to serotype 6A which is unique to PCV13. Responses were noninferior for the other 2 common serotypes. Responses to PCV13 given at 1 year were generally lower in the group that received PPSV23 at enrollment. In adults aged 70 years and older previously vaccinated with PPSV23, PCV13 was significantly more immunogenic than PPSV23 for most of the common serotypes and for serotype 6A. The OPA responses after a follow-on dose of PCV13 one year later indicate that a prior dose of PPSV23, but not PCV13, diminishes the response to the subsequent administration of PCV13.

Background. The 23-valent polysaccharide pneumococcal vaccine (PPV) is currently recommended for elderly persons and persons who are at high risk of infection. However, the effectiveness of the 23-valent PPV remains controversial. We assessed the effectiveness of this vaccine in older adults. Methods. A prospective cohort study was conducted from January 2002 through April 2005; it included all community-dwelling individuals aged ⩾65 years who were assigned to 1 of 8 primary health care centers in Tarragona, Spain (11,241 subjects). The primary outcomes were invasive pneumococcal disease, pneumococcal pneumonia, overall pneumonia rate, and death due to pneumonia. All cases were validated by a check of the clinical records. The association between pneumococcal vaccination and the risk of each outcome was evaluated by means of multivariate Cox proportional hazard models, adjusted for age, sex, comorbidity, immunocompetence, and influenza vaccine status. Results. Pneumococcal vaccination was associated with significant reductions in the risk of hospitalization for pneumonia (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.59–0.92) and in the overall pneumonia rate (HR, 0.79; 95% CI, 0.64–0.98). The incidence of invasive pneumococcal disease was low (64 cases per 100,000 person-years), and a considerable protective effect against invasive pneumococcal disease did not attain statistical significance (HR, 0.60; 95% CI, 0.22–1.65). However, the vaccine showed a significant effectiveness of 45% to prevent pneumococcal pneumonia (HR, 0.55; 95% CI, 0.34–0.88). Finally, vaccination was associated with a significant 59% reduction in the risk of death due to pneumonia among vaccinated subjects (HR, 0.41; 95% CI, 0.23–0.72) Conclusions. These results indicate that the 23-valent PPV effectively prevented pneumococcal pneumonia (with or without bacteremia) and decreased the rates of overall pneumonia and of mortality due to pneumonia in older adults, providing new arguments for systematic vaccination in the elderly population.