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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.

In Quebec, a pneumococcal conjugate vaccine (PCV) program was implemented in December 2004. The recommended schedule is 2+1 doses for low-risk infants. PCV-7 was first used (including catch-up for children <5 years of age), replaced by PCV10 in June 2009, and by PCV13 in January 2011 (no catch-up in both instances). From the beginning, >90% of children received the recommended number of doses. To assess the effectiveness of the three PCVs sequentially used to prevent invasive infectious disease (IPD). IPD cases in children 2–59 months during the years 2005–2013 were eligible. Controls were randomly identified in the provincial health insurance registry. Parents were interviewed and immunization records reviewed. Vaccine effectiveness (VE) was computed using multivariate logistic regression models. Out of 889 IPD cases reported, full participation was obtained for 516 cases (58%) and for 1767 controls. Against vaccine-type IPD, VE (≥1 dose) was 90% (82–95%) for PCV7, 97% (84–99%) for PCV10 and 86% (62–95%) for PCV13. Against 19A IPD, VE was, respectively, 42% (−9% to 69%), 71% (24–89%), and 74% (11–92%). VE (≥2 doses) against PCV13-type IPD was 85% for PCV10 (66–94%), 85% for PCV13 (55–94%), and 89% (58–97%) for a mixed PCV10+PCV13 schedule. All three PCV vaccines showed high level of protection against IPD caused by serotypes included in their formulation and there was a high level of cross-protection against 19A for PCV10. No substantial difference was seen between PCV10, PCV13, or a mixed PCV10+PCV13 schedule.

•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.

Background. The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed to replace the 7-valent pneumococcal conjugate vaccine (PCV7) based on serological noninferiority criteria. To date no randomized PCV13 pediatric trial has included clinical endpoints. Methods. This randomized double-blind trial compared the impact of PCV13 versus PCV7 on nasopharyngeal (NP) colonization and immunogenicity. Healthy infants were randomized (1:1) to receive PCV7 or PCV13 at ages 2, 4, 6, and 12 months; NP swabs were collected at 2, 4, 6, 7, 12, 13, 18, and 24 months, and blood was drawn at 7 and 13 months. Rates of NP acquisition and prevalence, and serotype-specific immunoglobulin G (IgG) concentrations were assessed. Results. The per protocol analysis population included 881 PCV13 and 873 PCV7 recipients. PCV13 significantly reduced NP acquisition of the additional PCV13 serotypes 1, 6A, 7F, and 19A; the cross-reacting serotype 6C; and the common PCV7 serotype 19F. For serotype 3, and the other PCV7 serotypes, there were no significant differences between the vaccine groups. There were too few serotype 5 events to draw inference. The impact on prevalence at predefined time points was similar to that observed with NP acquisition. PCV13 elicited significantly higher IgG responses for PCV13 additional serotypes and serotype 19F, and similar or lower responses for 6/7 PCV7 serotypes. Conclusions. PCV13 resulted in lower acquisition and prevalence of NP colonization than PCV7 did for 4 additional PCV13 serotypes, and serotypes 6C and 19F. It was comparable with PCV7 for all other common serotypes. These findings predict vaccine effectiveness through both direct and indirect protection. Clinical Trials Registration. NCT00508742.

The same pneumococcal conjugate vaccines (PCVs) have been used in adults and children in many settings. Differences in the epidemiology of pneumococcal disease between populations necessitates an adult-specific PCV. We aimed to assess the safety, tolerability, and immunogenicity of V116, an investigational 21-valent PCV designed for adults. This randomised, double-blind, active comparator controlled, international phase 3 trial enrolled adults with or without stable chronic medical conditions at 112 clinical sites in 11 countries or territories. Random assignment was performed using a central electronic interactive response technology system. Cohort 1 (≥50 years) was stratified by age (50–64, 65–74, 75–84, and ≥85 years) and randomised 1:1 to receive one intramuscular dose of V116, or the active comparator, PCV20. Cohort 2 (18–49 years) was randomised 2:1 to receive one intramuscular dose of V116 or PCV20. Pneumococcal serotype-specific opsonophagocytic activity (OPA) and IgG responses were measured before (day 1) and after vaccination (day 30). Four primary immunogenicity outcomes were assessed per-protocol. First, in cohort 1, non-inferiority of V116 to PCV20 was tested using serotype-specific OPA geometric mean titres (GMT) ratios for serotypes common to both vaccines; the lower bound of the 95% CI had to be greater than 0·5 for non-inferiority. Second, superiority of V116 to PCV20 was tested for OPA GMT ratios for the serotypes unique to V116; the lower bound of the 95% CI had to be greater than 2·0 for superiority. Third, superiority of V116 to PCV20 was evaluated by the proportions of participants with a four-fold or greater rise from day 1 to day 30 for serotypes unique to V116; the lower bound of the 95% CI of the differences in proportions (V116 – PCV20) had to be greater than 10% for superiority. Finally, in cohort 2, immunobridging was assessed for all 21 serotypes in V116 for adults aged 18–49 years to 50–64 years; the lower bound of the 95% CI for the OPA GMTs had to be greater than 0·5 for non-inferiority. The safety analysis included all randomly assigned participants who received study vaccine. The primary safety outcome was the proportion of participants with solicited injection site and solicited systemic adverse events until day 5 and vaccine-related serious adverse events up to 6 months after vaccination. This trial is registered at ClinicalTrials.gov (NCT05425732). Between July 13, and Nov 22, 2022, 2754 individuals were screened and 2663 participants were randomly assigned. 2656 individuals were vaccinated (1179 in V116 cohort 1; 1177 in PCV20 cohort 1; 200 in V116 cohort 2; and 100 in PCV20 cohort 2). V116 met non-inferiority criteria compared with PCV20 for the ten serotypes common to both vaccines at day 30 in cohort 1 (p<0·0001 for each common serotype). V116 met superiority criteria compared with PCV20 in cohort 1 for ten of the 11 serotypes unique to V116 at day 30 (OPA GMT ratio: p<0·0001 for all unique serotypes except 15C, which was p=0·41; four-fold or greater rise in OPA from day 1–30: p<0·0001 for all serotypes except 15C, which was p=0·67). Immune responses in V116 participants aged 18–49 years were non-inferior compared with V116 participants aged 50–64 years for all V116 serotypes (p<0·0001 for all V116 serotypes). In cohort 1, 685 (58·2%) of participants in V116, and 778 (66·2%) of participants in PCV20 reported one or more adverse event. In cohort 2, 164 (82·0%) participants in V116 and 79 participants (79·0%) in PCV20 reported one or more adverse event. Six deaths were reported, all in cohort 1, none of which were considered vaccine-related (in V116: one due to sepsis, one due to cerebrovascular accident, one due to myocardial infarction, and one due to hepatic cirrhosis and hepatic encephalopathy; in PCV20: one due to cardiac arrest and one due to abdominal abscess). There were no vaccine-related serious adverse events. V116 was non-inferior to PCV20 for the ten serotypes common to both vaccines and superior to PCV20 for all serotypes unique to V116, except for 15C. Immune responses successfully immunobridged between younger and older adults for all serotypes in V116. V116 was generally well tolerated with safety profile similar to PCV20. Merck Sharp & Dohme, subsidiary of Merck & Co, Rahway, NJ, USA (MSD).

Pneumococcal disease (PD) prevention remains an unmet medical need in older adults. V116 is an adult-specific, 21-valent pneumococcal conjugate vaccine (PCV) specifically designed to provide protection against pneumococcal serotypes associated with a large proportion of residual invasive pneumococcal disease (IPD). This phase 3 study evaluated the safety, tolerability, and immunogenicity of V116 compared with 23-valent pneumococcal polysaccharide vaccine (PPSV23) in Japanese older adults (NCT05633992). In this phase 3, randomized, double-blind, active comparator-controlled study, 450 vaccine-naïve adults ≥65 years of age were randomized 1:1 to receive a single dose of V116 or PPSV23. Primary immunogenicity objectives were to assess opsonophagocytic activity (OPA) and demonstrate: i) non-inferiority for V116 versus PPSV23 across 12 common serotypes, and cross-reactive serotype 15B in V116, based on geometric mean titers (GMTs) at Day 30; and ii) superiority for nine serotypes unique to V116 based on the proportions of participants exhibiting ≥4 fold rises in serotype-specific OPA responses between baseline and Day 30 (excluding serotype 15C) or based on GMTs at Day 30 (serotype 15C only). The primary safety outcome measured the proportion of participants with adverse events (AEs). V116 was non-inferior compared with PPSV23 for the 12 common serotypes and for the cross-reactive serotype 15B. V116 was superior compared with PPSV23 for the nine unique serotypes (including serotype 15C). The proportion of participants with AEs was comparable between V116 and PPSV23, and there were no vaccine-related serious AEs or deaths. In vaccine-naïve Japanese adults ≥65 years of age, V116 is well tolerated, with a safety profile comparable to PPSV23, and elicits immune responses to all V116 serotypes and the cross-reactive serotype 15B. V116 has the potential to broaden protection against PD in Japan through the inclusion of serotypes responsible for the majority of residual PD in adults. •IPD burden is highest in adults ≥65 years of age; this group accounts for 29 % of Japan's population.•Residual PD remains an unmet medical need, partly caused by non-vaccine-type serotypes.•Serotypes in V116 are responsible for ∼80 % of residual IPD in individuals ≥15 years of age in Japan.•V116 has the potential to broaden protection against residual PD in adults.

Pneumococcal conjugate vaccines are an important but costly part of childhood vaccination. This trial assessed immunogenicity of fractional-dose regimens — a key consideration as countries transition out of Gavi support.

We evaluated invasive pneumococcal disease (IPD) during 8 years of infant pneumococcal conjugate vaccine (PCV) programs using 10-valent (PCV10) and 13-valent (PCV13) vaccines in 10 countries in Europe. IPD incidence declined during 2011-2014 but increased during 2015-2018 in all age groups. From the 7-valent PCV period to 2018, IPD incidence declined by 42% in children <5 years of age, 32% in persons 5-64 years of age, and 7% in persons >65 years of age; non-PCV13 serotype incidence increased by 111%, 63%, and 84%, respectively, for these groups. Trends were similar in countries using PCV13 or PCV10, despite different serotype distribution. In 2018, serotypes in the 15-valent and 20-valent PCVs represented one third of cases in children <5 years of age and two thirds of cases in persons >65 years of age. Non-PCV13 serotype increases reduced the overall effect of childhood PCV10/PCV13 programs on IPD. New vaccines providing broader serotype protection are needed.

•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.

This phase 3, randomized, partially double-blind study investigated the safety, tolerability, and immunogenicity of 20-valent pneumococcal conjugate vaccine (PCV20) in healthy toddlers ≥12–<24 months of age who had previously received 2 infant doses of 13-valent PCV (PCV13). Participants were randomized to receive 1 or 2 doses of PCV20 (the second dose was administered 56–70 days after the first dose), or 1 dose of PCV13. The primary pneumococcal immunogenicity endpoint was the percentages of participants with predefined serotype-specific immunoglobulin G (IgG) concentrations (≥0.35 μg/mL) for the 7 additional serotypes 1 month after the last vaccination. Percentages of participants with predefined IgG concentrations for the 13 matched serotypes, IgG geometric mean concentrations, and opsonophagocytic activity (OPA) geometric mean titers were also evaluated for all 20 vaccine serotypes. Safety endpoints included local reactions, systemic events, adverse events, and serious adverse events. Overall, 356 participants were randomized (2-dose PCV20, n = 121; 1-dose PCV20, n = 118; PCV13, n = 117). One month after 1 PCV20 dose, ≥75.9 % of participants had IgG concentrations ≥0.35 μg/mL for all 7 additional serotypes, except serotype 12F (54.6 %). After 2 PCV20 doses, the percentage of participants with IgG concentrations ≥0.35 μg/mL for the 7 additional serotypes was ≥91.2 %. PCV20 elicited IgG and OPA responses for all 20 serotypes including serotype 12F. IgG distributions were well differentiated and substantially higher in PCV20 groups than the PCV13 group for the 7 additional serotypes, and generally similar between all groups for the 13 matched serotypes. In conclusion, a single toddler dose of PCV20 after 2 infant PCV13 doses elicited immune responses expected to help provide protection against the 7 additional serotypes and to provide similar protection against the 13 matched serotypes as PCV13. These data support a transition from PCV13 to PCV20 at the toddler dose. The safety and tolerability profile of PCV20 was similar to PCV13. Trial registration:Clinicaltrials.gov, NCT05408429. •PCV20 safety, tolerability, and immunogenicity in healthy toddlers was investigated.•Participants had previously received 2 infant doses of PCV13.•PCV20 single toddler dose expected to help protect against 7 additional serotypes.•PCV20 expected to provide similar protection as PCV13 against 13 matched serotypes.•The safety/tolerability profile of PCV20 toddler doses was similar to PCV13.