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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.

•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.

•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.

•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.

To better inform pneumococcal immunization policies, ongoing surveillance for pneumococcal community-acquired pneumonia (CAP) is crucial. To estimate the serotype-specific CAP burden of pneumococcal disease following the introduction of a new 15-valent pneumococcal conjugate vaccine (PCV), V114, a 15-plex serotype-specific urine antigen detection (SSUAD) assay was developed as a tool for surveillance of Streptococcuspneumoniae serotypes. V114–017 (NCT03547167; EudraCT 2017–004915-38) was a phase 3 randomized controlled trial in which participants (18–49 years) received V114 or 13-valent PCV (PCV13; as an active comparator), followed 6 months later by 23-valent pneumococcal polysaccharide vaccine (PPSV23). Here, we report findings from a prespecified sub-study nested within the phase 3 trial that descriptively assessed the impact of nasopharyngeal/oropharyngeal (NP/OP) carriage and pneumococcal vaccination on serotype detection with the SSUAD assay. In total, 301 individuals (all American Indian/Alaska Native) participated in the sub-study. NP/OP and urine samples were collected at 10 timepoints between baseline (prior to vaccination) and Month 7 (30 days following vaccination with PPSV23). NP/OP carriage was determined using qualitative polymerase chain reaction for pneumococcus detection and serotyping, and urine samples were tested in parallel with SSUAD. At any timepoint, NP/OP carriage was <2.0 % for 10 of the V114 serotypes; carriage was ∼2.6 % for serotype 1 and ranged between 4.0 % and 7.0 % for serotypes 4, 5, 9V, and 33F. At baseline, serotype-specific pneumococcal polysaccharide antigens were detected by SSUAD in only six study participants for serotypes 19A, 19F, and 1. SSUAD positivity for serotypes 4, 5, and 9V increased transiently following vaccination with V114/PCV13 and PPSV23, while SSUAD positivity lasted the longest for serotype 19A following PPSV23 vaccination. In general, SSUAD positivity appeared unrelated to NP/OP carriage. Our findings suggest SSUAD can support pneumococcal disease surveillance and vaccine effectiveness research, excluding individuals with recent pneumococcal vaccination to avoid false-positives.

SARS-CoV-2 may cause severe hospitalization, but little is known about the role of secondary bacterial infection in these severe cases, beyond the observation of high levels of reported inflammatory markers, associated with bacterial infection, such as procalcitonin. We did a secondary analysis of a double-blind randomized trial of pneumococcal conjugate vaccine (PCV) to examine its impact on human coronavirus (CoV) infections before the pandemic. In December 2019 a new coronavirus (CoV) emerged as a human pathogen, SARS-CoV-2. There are few data on human coronavirus infections among individuals living with HIV. In this study we probed the role of pneumococcal coinfections with seasonal CoVs among children living with and without HIV hospitalized for pneumonia. We also described the prevalence and clinical manifestations of these infections. A total of 39,836 children who participated in a randomized, double-blind, placebo-controlled clinical trial on the efficacy of a 9-valent pneumococcal conjugate vaccine (PCV9) were followed for lower respiratory tract infection hospitalizations until 2 years of age. Nasopharyngeal aspirates were collected at the time of hospitalization and were screened by PCR for four seasonal CoVs. The frequency of CoV-associated pneumonia was higher in children living with HIV (19.9%) than in those without HIV (7.6%, P  < 0.001). Serial CoV infections were detected in children living with HIV. The case fatality risk among children with CoV-associated pneumonia was higher in those living with HIV (30.4%) than without HIV (2.9%, P  = 0.001). C-reactive protein and procalcitonin levels were elevated in 36.8% (≥40 mg/liter) and 64.7% (≥0.5 ng/ml), respectively, of the fatal cases living with HIV. Among children without HIV, there was a 64.0% (95% CI: 22.9% to 83.2%) lower incidence of CoV-associated pneumonia hospitalizations among PCV9 recipients compared to placebo recipients. These data suggest that Streptococcus pneumoniae infections might have a role in the development of pneumonia associated with endemic CoVs, that PCV may prevent pediatric CoV-associated hospitalization, and that children living with HIV with CoV infections develop more severe outcomes. IMPORTANCE SARS-CoV-2 may cause severe hospitalization, but little is known about the role of secondary bacterial infection in these severe cases, beyond the observation of high levels of reported inflammatory markers, associated with bacterial infection, such as procalcitonin. We did a secondary analysis of a double-blind randomized trial of PCV to examine its impact on human CoV infections before the pandemic. We found that both children living with and without HIV randomized to receive PCV had evidence of less hospitalization due to seasonal CoV, suggesting that pneumococcal coinfection may play a role in severe hospitalized CoV infections.

New vaccines are urgently needed to protect the vulnerable from bacterial pneumonia. Clinical trials of pneumonia vaccines are slow and costly, requiring tens of thousands of patients. Studies of pneumococcal vaccine efficacy against colonization have been proposed as a novel method to down-select between vaccine candidates. Using our safe and reproducible experimental human pneumococcal colonization model, we aimed to determine the effect of 13-valent pneumococcal conjugate vaccine (PCV) on colonization. A total of 100 healthy participants aged 18-50 years were recruited into this double-blind randomized placebo-controlled trial. They were randomly assigned to PCV (n = 49) or hepatitis A (control, n = 50) vaccination and inoculated with 80,000 CFU/100 μl of Streptococcus pneumoniae (6B) per naris. Participants were followed up for 21 days to determine pneumococcal colonization by culture of nasal wash. The PCV group had a significantly reduced rate of 6B colonization (10% [5 of 48]) compared with control subjects (48% [23 of 48]) (risk ratio, 0.22; confidence interval, 0.09-0.52; P < 0.001). Density of colonization was reduced in the PCV group compared with the control group following inoculation. The area under the curve (density vs. day) was significantly reduced in the PCV compared with control group (geometric mean, 259 vs. 11,183; P = 0.017). PCV reduced pneumococcal colonization rate, density, and duration in healthy adults. The experimental human pneumococcal colonization model is a safe, cost-effective, and efficient method to determine the protective efficacy of new vaccines on pneumococcal colonization; PCV provides a gold standard against which to test these novel vaccines. Clinical trial registered with 45340436.