Epidemiological characteristics and serotype distribution of culture-confirmed pediatric pneumococcal pneumonia before and after PCV 10 introduction,a multicenter study in Bogota,Colombia, 2008–2019

BackgroundPneumococcal conjugate vaccines (PCVs) have decreased pneumonia in children. Colombia introduced mass vaccination with PCV10 in 2012.MethodsCases of pneumococcal pneumonia from 10 hospitals were included. Two periods were compared: pre-PCV10: 2008–2011 and post-PCV10: 2014–2019. The objective was to compare epidemiological and clinical characteristics before and after PCV10 vaccination.ResultsA total of 370 cases were included. Serotypes 1 (15, 11.2%) and 14 (33, 24.6%) were the most frequent in the pre-PCV10 period, with only 4 (3%) cases of serotype 19A and 1 case (0.7%) serotype 3. From the pre-PCV10 period to the post-PCV10 period, cases of serotypes 1 (6, 3.1%) and 14 (1, 7.8%) decreased, while cases of serotypes 19A (58, 30.2%), serotype 3 (32, 16.7%) and 6A (7, 3.6%) increased (p < 0.001); complicated pneumonia (CP) increased significantly (13.4% to 31.8%) (p < 0.001); hospitalizations increased from 8 (5.5–15) to 12 (7–22) days (p < 0.001); and the frequency of PICU admission increased from 32.8% to 51.6% (p = 0.001). The use of ampicillin-sulbactam (0.7% to 24%) and ceftriaxone/clindamycin (0.7% to 5.7%) increased in the post-PCV10 period. The duration of empirical antibiotic treatment was 7 (4–11) days in the pre-PCV10 period and increased to 10 (6–17) days (p < 0.001) in the post-PCV10 period. Lethality showed a slight nonsignificant increase (7.5% vs. 9.9%; p = 0.57) in the post-PCV10 period.ConclusionsPCV10 significantly decreased cases of serotypes 1 and 14, with an increase in cases of serotypes 19A, 3 and 6A, which were the predominant serotypes and had greater severity (e.g., admission to the PICU, CP and more resistance, with an increase in the use of broad-spectrum antibiotics and longer hospitalization) and subsequently included in PCV13. Current data support national and regional evidence on the importance of replacing PCV10 with a higher valence that includes 19A, such as PCV13, with the aim of reducing circulation, particularly of this serotype.     

Decline in pneumococcal nasopharyngeal carriage in children 6–23 months with respiratory illnesses following pneumococcal conjugate vaccine implementation

BackgroundFollowing pneumococcal conjugate vaccines (PCVs) implementation, worldwide, pneumococcal carriage rates remained stable, indicating full replacement of vaccine-serotypes (VT) with non-VT. However, data are scarce regarding PCV impact on pneumococcal carriage rates in healthy vs. sick children. We assessed pneumococcal carriage rates dynamics in healthy and sick children 6–23 months, following PCV introduction.MethodsThis is a prospective, population-based surveillance conducted during the years 2009–2017, in southern Israel. Three groups were defined as follows: Children without respiratory infection signs (the healthy/non-respiratory group); Children who had a chest radiography at the hospital (the Hosp-CXR group); and children with community-acquired alveolar pneumonia (CAAP).Rate ratios (RRs; 95% CI) were calculated, comparing between late-13-valent PCV (PCV13) period (2016–2017) and early-PCV period (2009–2010). Rate ratios were adjusted for antibiotic administration, seasonality and ethnicity, and separate calculations were performed for 6–11 and 12–23 month old children.ResultsOverall, 51% of 8627 nasopharyngeal cultures were positive.In 2009–2010 (early-PCV period), the overall carriage rate was 55%; serotypes included in the PCV13 carriage rates were 28%, 31% and 38% in the healthy/non-respiratory, Hosp-CXR, and CAAP groups, respectively.Overall carriage rates in healthy/non-respiratory episodes were stable (~54%) when comparing between 2016 and 17 and 2009–10 (RR = 0.98; 0.84–1.15). In contrast, rates significantly declined for Hosp-CXR (RR = 0.78; 0.63–0.98) and CAAP (RR = 0.65; 0.47–0.89). These trends were driven by ~ 80% VT reductions, coupled with non-VT increase.ConclusionsFollowing 7-valent PCV/ PCV13 introduction, pneumococcal carriage rates declined in respiratory diseases, but not in healthy children and children without respiratory infections. These trends suggest that a reduction in pneumococcal carriage rates during respiratory infections indicates a decline in respiratory infections caused by VT, while carriage rates in non-respiratory cases reflect non-VT predominance, that have low disease potential for respiratory disease.     

Pneumonia hospitalization after introduction of pneumococcal conjugate vaccine in Japan: Descriptive study using a nationwide claims database

BackgroundThe pneumococcal conjugate vaccine (PCV) was introduced to children in Japan in February 2010 for PCV7 and February 2013 for PCV13. This study aimed to investigate the changes in child pneumonia hospitalization in Japan, before and after the introduction of PCV.MethodsWe utilized the JMDC Claims Database, an insurance claims database in Japan, with a cumulative population of approximately 10.6 million as of 2022. We extracted data of approximately 3.16 million children below 15 years of age from January 2006 to December 2019, and evaluated the number of pneumonia hospitalizations per 1,000 persons per year. The primary analysis was a comparison of three categories according to PCVs: before PCV7, before PCV13, and after PCV13 (2006–2009, 2010–2012, and 2013–2019). The secondary analysis was an interrupted time series (ITS) analysis, assessing the slope change in pneumonia hospitalizations per month, with PCV introduction as an intervening factor.ResultsThe cases of pneumonia hospitalizations during the study period was 19,920 (0.6 %); 25 % of these were 0–1 years, 48 % were 2–4 years, 18 % were 5–9 years, and 9 % were 10–14 years. Pneumonia hospitalizations per 1000 population was 6.10 before PCV7 and 4.03 after PCV13, representing a 34 % decrease (p < 0.001). The reduction by age group was –30.1 % in 0–1 years, –20.3 % in 2–4 years, –41.7 % in 5–9 years, and –52.9 % in 10–14 years, significant reduction in all groups. ITS analysis showed a further reduction of –0.17 % per month after the introduction of PCV13 than that before PCV7 (p = 0.006).ConclusionOur study estimated 4–6 pneumonia hospitalizations per 1000 pediatric population in Japan, with a 34 % decrease after the introduction of PCV. This study examined the nationwide effectiveness of PCV, further studies are needed in all age groups.     

Epidemiology of community-acquired pneumonia in the era of extended serotype-covering multivalent pneumococcal conjugate vaccines

BackgroundSouth Korea has been providing 10-valent pneumococcal conjugate vaccine/(PCV10)/13-valent pneumococcal conjugate vaccine (PCV13) to children and 23-valent pneumococcal polysaccharide vaccine (PPSV23) to older adults as part of a national immunization program.MethodsFrom September 2015 to August 2017, a prospective cohort study was conducted for adults aged ≥19 years with community-acquired pneumonia (CAP) at four university hospitals. All-cause and pneumococcal CAP incidence and mortality rates were evaluated on the basis of hospital catchment population. Serotype distribution of pneumococcal CAP was also evaluated.ResultsAmong 2669 patients with CAP, 252 cases (9.4%) were pneumococcal CAP cases. The annual incidences of all-cause and pneumococcal CAP were 194.3 cases and 18.3 cases respectively, per 100,000 persons. Serotyped Streptococcus pneumoniae was identified in 107 cases (42.5%) through culture or a serotype-specific urinary antigen detection assay. Pneumococcal CAP caused by the PCV13 and PPSV23 serotypes were 50 cases (46.7% of serotyped pneumococcal CAP and 19.8% of pneumococcal CAP), and 83 cases (77.6% of serotyped pneumococcal CAP and 32.9% of pneumococcal CAP), respectively. The most prevalent serotype was 3 (n = 21, 19.6% of serotyped pneumococcal CAP), followed by 19A (n = 10, 9.3% of serotyped pneumococcal CAP) and 11A (n = 10, 9.3% of serotyped pneumococcal CAP). Compared with non-pneumococcal CAP patients, pneumococcal CAP patients were more likely to have a higher CURB-65 scores (P = 0.002). The overall 30-day mortality rate of pneumococcal CAP was higher than that of non-pneumococcal CAP (6.3% versus 5.6%; odds ratio [OR], 1.15; 95% confidence interval [CI], 0.67–1.96), but this trend was reversed in patients aged 65–74 years (4.2% versus 8.6%; OR, 0.47; 95% CI, 0.14–1.54).ConclusionsThe disease burden of PCV13-serotype pneumococcal CAP remains significantly high in Korean adults, particularly among elderly people, even after a high uptake of pediatric PCVs.     

Effectiveness of the 23-valent pneumococcal polysaccharide vaccine against community-acquired pneumonia in older individuals after the introduction of childhood 13-valent pneumococcal conjugate vaccine: A multicenter hospital-based case-control study in Japan

BackgroundIn the era of childhood pneumococcal conjugate vaccine (PCV) immunization, especially 13-valent pneumococcal conjugate vaccine (PCV13) immunization, serotype replacement of Streptococcus pneumoniae and herd immunity in adults have been reported worldwide. Therefore, continuous evaluation of the effectiveness of the pneumococcal vaccine in adults is crucial because vaccine effectiveness may change owing to these factors. The purpose of this study was to evaluate the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) against all-cause pneumonia and pneumococcal pneumonia in older individuals with community-acquired pneumonia (CAP) after the introduction of childhood PCV13 in Japan, a topic that has remained largely unexplored.MethodsWe evaluated pneumococcal vaccine effectiveness in this multicenter, matched case-control study conducted in hospitals and clinics. Cases included patients (aged ≥ 65 years) newly diagnosed with CAP between October 2016 and September 2019. A maximum of five non-pneumonia control patients matched for sex, school grade, date of outpatient visit, and medical institution were selected for each case. Conditional logistic regression models were used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) of pneumococcal vaccines for the occurrence of all-cause CAP and pneumococcal CAP.ResultsThe analysis included 740 individuals (142 patients and 598 controls). The median age of participants was 75 years (men: 54%). The adjusted OR for pneumococcal vaccination against all-cause CAP was 1.31 (95% CI: 0.84–2.06), while that for PPSV23 vaccination in the previous 5 years was 1.33 (95% CI: 0.85–2.09). The adjusted OR for PPSV23 vaccination in the previous 5 years against pneumococcal CAP was 0.93 (95% CI: 0.35–2.50).ConclusionsThis study was unable to demonstrate the effectiveness of PPSV23 against all-cause and pneumococcal pneumonia after the introduction of childhood PCV13 in Japan. Nonetheless, additional studies are needed to validate these results.     

Can pneumococcal meningitis surveillance be used to assess the impact of pneumococcal conjugate vaccine on total invasive pneumococcal disease? A case-study from South Africa, 2005–2016

IntroductionSouth Africa introduced seven-valent pneumococcal conjugate vaccine (PCV7) in 2009 and PCV13 in 2011. We aimed to compare the estimated impact of PCV on pneumococcal meningitis (PM) to impact of PCV on total invasive pneumococcal disease (tIPD) based on risk reduction after PCV introduction.MethodsWe conducted national, laboratory-based surveillance for tIPD during 2005–2016. We estimated and compared rates of PCV13 and non-PCV13 serotype disease among tIPD and PM in individuals aged <5 years and ≥5 years, and compared these rates between the 2005–2008 pre-PCV introduction period and two time points after PCV introduction, 2012 and 2016.ResultsWe enrolled 45,853 tIPD cases; 17,251 (38%) were PM. By 2016, IPD caused by all serotypes decreased 55% (95%CI −57% to −53%) for tIPD, and 54% for PM (95%CI −58% to −51%), 0.7% difference between estimates (p = 0.7). No significant differences were observed between PCV7-serotype disease reduction in tIPD and PM in both age groups or the additional 6 serotypes included in PCV13 in <5 year olds in 2012 and 2016. In 2012 there was a significant difference between increases in non-PCV13 serotype disease in those ≥5 years for tIPD and PM (32% greater increase in PM, p < 0.001), but this difference was absent by 2016. There was a significant difference between the estimated decrease in additional PCV13 type disease in 2016 between tIPD and PM for those aged ≥5 years (28% greater reduction in PM, p = 0.008).ConclusionPM showed similar reductions to tIPD seven years after PCV introduction in vaccine serotype disease in those <5 years, and increases in non-vaccine serotype disease in all ages.     

Immunogenicity and safety of 7-valent pneumococcal conjugate vaccine (PCV7) in children aged 2–5 years in China

BackgroundThe widespread use of pneumococcal conjugate vaccines (PCVs) has significantly decreased pneumococcal disease worldwide. However, China has not adopted PCVs in their national immunization schedules and had only approved these vaccines for children aged 2–15 months by 2020.MethodsIn an open-label trial, enrolled healthy children aged 2–5 years old were randomized 1:1 and divided into a 7-valent pneumococcal conjugate vaccine (PCV7) group and a Haemophilus influenzae type b conjugate vaccine (Hib) group. Children in the PCV7 group received a single dose of PCV7, and the Hib group received a single dose of Hib vaccine. Blood samples were collected before and 6 months after vaccination. Immunogenicity and safety of PCV7 were assessed at prespecified time points.ResultsSix months after a single dose of PCV7, children in the PCV7 group for all 7 serotypes, IgG mean concentrations (GMCs) and opsonophagocytic geometric mean titres (GMTs) were significantly higher (P < .001) than at baseline, and the proportion of IgG ≥ 0.35 µg/mL ranged from 90.0% to 100%. Although the antibody level increased with age, preexisting antibodies did not induce hyporesponsiveness to PCV7. In the Hib group, the antibody levels were not significantly different or had changed slightly at 6 months. PCV7 was well tolerated in all age groups, and no serious adverse events (AEs) emerged during this study.ConclusionsA single dose of PCV7 was immunogenic and safe for Chinese children aged 2–5 years, and the preexisting antibodies against the PCV7 serotypes did not change the response to vaccination. The findings supported the effectiveness of PCV7 in this age group. PCVs with broader serotype coverage are expected to expand pneumococcal disease protection.     

Increase in Streptococcus pneumoniae serotype 3 associated parapneumonic pleural effusion/empyema after the introduction of PCV13 in Germany

IntroductionPediatric pneumococcal pneumonia complicated by parapneumonic pleural effusion/empyema (PPE/PE) remains a major concern despite general immunization with pneumococcal conjugate vaccines (PCVs).MethodsIn a nationwide pediatric hospital surveillance study in Germany we identified 584 children <18 years of age with bacteriologically confirmed PPE/PE from October 2010 to June 2018. Streptococcus pneumoniae was identified by culture and/or PCR of blood samples and/or pleural fluid and serotyped.ResultsS. pneumoniae was identified in 256 of 584 (43.8%) children by culture (n = 122) and/or PCR (n = 207). The following pneumococcal serotypes were detected in 114 children: serotype 3 (42.1%), 1 (25.4%), 7F (12.3%), 19A (7.9%), other PCV13 serotypes (4.4%) and non-PCV13 serotypes (7.9%). Between October 2010 and June 2014 serotype 1 (38.1%) and serotype 3 (25.4%) were most prevalent, whereas between July 2014 and June 2018 serotype 3 (62.7%) and non-PCV13 serotypes (15.7%) were dominant. Compared to children with other pneumococcal serotypes, children with serotype 3 associated PPE/PE were younger (median 3.2 years [IQR 2.1–4.3 years] vs. median 5.6 years [IQR 3.8–8.2 years]; p < 0.001) and more frequently admitted to intensive care (43 [89.6%] vs. 48 [73.8%]; p = 0.04). Seventy-six of 114 (66.7%) children with pneumococcal PPE/PE had been vaccinated with pneumococcal vaccines. Thirty-nine of 76 (51.3%) had received a vaccine covering the serotype detected. Thirty of these 39 breakthrough cases were age-appropriately vaccinated with PCV13 and considered vaccine failures, including 26 children with serotype 3, three children with serotype 19A and one child with serotype 1.ConclusionFollowing the introduction of PCV13 in general childhood vaccination we observed a strong emergence of serotype 3 associated PPE/PE in the German pediatric population, including a considerable number of younger children with serotype 3 vaccine breakthrough cases and failures. Future PCVs should not only cover newly emerging serotypes, but also include a more effective component against serotype 3.     

Lack of effectiveness of 13-valent pneumococcal conjugate vaccination against pneumococcal carriage density in Papua New Guinean infants

BackgroundPapua New Guinea (PNG) introduced the 13-valent pneumococcal conjugate vaccine (PCV13) in 2014, with administration at 1, 2, and 3 months of age. PCV13 has reduced or eliminated carriage of vaccine types in populations with low pneumococcal carriage prevalence, carriage density and serotype diversity. This study investigated PCV13 impact on serotype-specific pneumococcal carriage prevalence, density, and serotype diversity in PNG infants, who have some of the highest reported rates of pneumococcal carriage and disease in the world.MethodsNasopharyngeal swabs were collected at 1, 4 and 9 months of age from PCV13-vaccinated infants (n = 57) and age-/season-matched, unvaccinated infants (at approximately 1 month, n = 53; 4 months, n = 57; 9 months, n = 52). Serotype-specific pneumococcal carriage density and antimicrobial resistance genes were identified by qPCR and microarray.ResultsPneumococci were present in 89% of swabs, with 60 different serotypes and four non-encapsulated variants detected. Multiple serotype carriage was common (47% of swabs). Vaccine type carriage prevalence was similar between PCV13-vaccinated and unvaccinated infants at 4 and 9 months of age. The prevalence of non-vaccine type carriage was also similar between cohorts, with non-vaccine types present in three-quarters of samples (from both vaccinated and unvaccinated infants) by 4 months of age. The median pneumococcal carriage density was high and similar at each age group (~7.0 log₁₀ genome equivalents/mL). PCV13 had no effect on overall pneumococcal carriage density, vaccine type density, non-vaccine type density, or the prevalence of antimicrobial resistance genes.ConclusionPNG infants experience dense and diverse pneumococcal colonisation with concurrent serotypes from 1 month of age. PCV13 had no impact on pneumococcal carriage density, even for vaccine serotypes. The low prevalence of vaccine serotypes, high pneumococcal carriage density and abundance of non-vaccine serotypes likely contribute to the lack of PCV13 impact on carriage in PNG infants. Indirect effects of the infant PCV programs are likely to be limited in PNG. Alternative vaccines with broader coverage should be considered.     

Distribution of serotypes causing invasive pneumococcal disease in older adults from high-income countries and impact of pediatric and adult vaccination policies

BackgroundNeither indirect protection through use of 13-valent and 10-valent pneumococcal conjugate vaccines (PCV13 and PCV10) in pediatric National Immunization Programs (NIPs) nor direct vaccination with the 23-valent polysaccharide vaccine have eliminated vaccine serotype invasive pneumococcal disease (IPD) in older adults. Vaccinating older adults with higher-valency PCV15 and PCV20 could address remaining IPD due to pediatric PCV serotypes plus additional IPD due to serotypes included in these vaccines.MethodsWe collected serotype-specific IPD data in older adults (≥65 years in most countries), from national or regional surveillance systems or hospital networks of 33 high-income countries. Data were from official government websites, online databases, surveillance system reports, published literature, and personal communication with in-country investigators. Average percentages of IPD serotypes were calculated.ResultsAmong 52,905 cases of IPD with a serotype identified, PCV13 serotypes accounted for 33.7% of IPD (55.8% and 30.6% for countries with PCV10 and PCV13 in the pediatric NIP), most commonly serotypes 3 (14.9%) and 19A (7.0%). PCV15 and PCV20 would cover an additional 10.4% and 32.9% of older adult IPD beyond PCV13 serotypes (PCV10 countries: 7.7% and 23.3%; PCV13 countries: 10.6% and 34.6%). The most common of these additional serotypes were 8 (9.9%), 22F (7.9%), 12F (4.6%), and 11A (3.3%). PPSV23 policies for older adults were not correlated with lower IPD percentages due to PPSV23 serotypes.ConclusionsVaccinating older adults with higher-valency PCVs, especially PCV20, could substantially reduce the remaining IPD burden in high-income countries, regardless of current PCV use in pediatric NIPs and adult PPSV23 policies.     

Impact of the pediatric 13-valent pneumococcal conjugate vaccine on serotype distribution and clinical characteristics of pneumococcal pneumonia in adults: The Japan Pneumococcal Vaccine Effectiveness Study (J-PAVE)

BackgroundThe pediatric 13-valent pneumococcal conjugate vaccine (PCV13) was included in the pediatric immunization programme in Japan in late 2013. The impact of vaccination on the serotype distribution and clinical characteristics of pneumococcal pneumonia has not been described.MethodsThe first phase of this multicentre prospective study was conducted at community-based hospitals in Japan from 2011 to 2014. The second phase was conducted from 2016 to 2017. Pneumococcal isolates and clinical data were collected from patients with community-acquired pneumonia who were ≥15 years of age. Patients were classified by pneumococcal serotype to PCV13 serotype, 23-valent pneumococcal polysaccharide vaccine (PPV23) non-PCV13 serotype, and non-vaccine serotype.ResultsA total of 484 patients were enrolled, 241 in the first phase and 243 in the second. The proportion of PCV13 serotypes decreased from 53% to 33% (p < 0.001), whereas PPV23 non-PCV13 serotypes did not change (p = 0.754). PCV13 serotypes were associated with increased risk of elevated blood urea nitrogen (adjusted odds ratio 2.49; 95% confidence interval: 1.49–4.16) and hospitalization (adjusted odds ratio 1.74; 95% confidence interval: 1.02–2.95). These associations were not observed in patients with PPV23 non-PCV13 serotypes.ConclusionsThe occurrence of pneumococcal pneumonia caused by vaccine-covered serotypes dramatically decreased following the introduction of pediatric PCV13. The PCV13 serotypes were associated with pneumonia severity.     

A phase 3, randomized,double-blind study to evaluate the immunogenicity and safety of 3 lots of 20-valent pneumococcal conjugate vaccine in pneumococcal vaccine-naive adults 18 through 49 years of age

IntroductionIntroduction of pneumococcal conjugate vaccines (PCVs), including the 13-valent PCV (PCV13), has considerably reduced pneumococcal disease burden. However, additional serotypes not in PCV13 continue to present a substantial disease burden. The 20-valent PCV (PCV20) was developed to expand protection against pneumococcal disease beyond PCV13. As part of the phase 3 clinical development program, the current study assessed consistency of immune responses across 3 lots of PCV20 and described the safety profile of PCV20.MethodsThis phase 3, randomized, multicenter, double-blind study of pneumococcal vaccine-naive adults 18–49 years of age randomized 1710 participants in a 2:2:2:1 ratio to receive 1 of 3 lots of PCV20 or PCV13. Immunogenicity was assessed through serotype-specific opsonophagocytic activity (OPA) titers before and approximately 1 month (28–42 days) after vaccination. Reported local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 30 days, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination were evaluated.ResultsEquivalence in immune responses (OPA geometric mean titers) for all 20 vaccine serotypes was demonstrated across the 3 PCV20 lots. Robust responses, assessed by OPA geometric mean fold rises, percentage of participants achieving ≥4-fold rises, and percentage of participants with OPA titers ≥lower limit of quantitation, were observed after PCV20. Reported rates of local reactions, systemic events, and AEs were similar between the pooled PCV20 lots and PCV13; most events were mild or moderate. Reported rates of SAEs and NDCMCs were low and similar between the PCV20 and PCV13 groups.ConclusionsThree different lots of PCV20 demonstrated robust and consistent immunogenicity. The safety and tolerability of PCV20 was acceptable and similar to that of PCV13. (Clinicaltrials.gov: NCT03828617).     

Evolution of serotypes in bacteremic pneumococcal adult pneumonia in the period 2001–2014, after introduction of the pneumococcal conjugate vaccine in bizkaia (spain)

The introduction of pneumococcal conjugate vaccines (PCV7 and PCV13) in children has led to a change in the pattern of pneumococcal serotypes causing pneumococcal disease in adults. The aim of this study is to analyze the distribution of pneumococcal serotypes in adults with bacteremic pneumococcal community-acquired pneumonia (BPP) after the introduction of PCVs in childhood, and the impact of age and comorbidity on this distribution. We conducted an observational study of all adults hospitalized with BPP between 2001 and 2014, in two tertiary hospitals. Overall, we identified 451 cases of BPP (2001–2005: 194, 2006–2010: 134, 2011–2014: 123). The rate of appearance of new cases decreased over the study period. In 70% of the cases, the serotypes found were among those included in PCV13. The most prevalent serotypes were 3 (23.1%), 7F (14.6%), 19A (8.4%) and 1 (7.5%). There was a significant trend to decrease in the percentage of BPP cases due to PCV7 from period 2001–2005 to 2011–2014 (p = 0.0166) and a significant trend to increase in the six serotypes added to form PCV 13 (p = 0.0003). Serotype 3 was the most frequent in patients who developed complications during hospitalization. We did not detect a significant increase in cases caused by non-PCV13 serotypes. The most frequent non-PCV13 serotype was 22F. In conclusion, a significant proportion of adults continue to develop BPP with vaccine serotypes despite infant pneumococcal vaccination. There is a need for further strategies to reduce the current burden of this disease on adults.     

Persistent serotype 3 and 19A invasive pneumococcal diseases in adults in vaccine era: Serotype-dependent difference in ceftriaxone susceptibility

BackgroundInvasive pneumococcal disease (IPD) is associated with substantial morbidity and mortality in children and elderly populations. Serotype distribution and antibiotic susceptibility of IPD isolates are changing with the implementation of pneumococcal vaccination and increasing antibiotic use worldwide. We aimed to determine serotype distribution, antibiogram, and molecular epidemiology of pneumococci in the late stage of PCV13 era.MethodsProspective multicenter IPD surveillance study was conducted for adults aged ≥ 19 years from July 2019 to June 2021. Clinical and epidemiologic data were collected. In addition, antibiotic susceptibility test, serotype identification and multi-locus sequence typing (MLST) was taken for pneumococcal isolates.ResultsA total of 160 IPD cases were collected with mean age of 65.1 years (male, 72.5%). Serotyping was taken for 116 available pneumococcal isolates. PCV13 and PPSV23 serotypes were 32.8% (n = 38) and 56.0% (n = 65), respectively. Serotype 3 (13.8%) and 19A (9.5%) were the most common causative agents of IPD, followed by serogroup 11 (6.9%), 23A (6.9%), 10A (4.3%), and 15B (4.3%). Notably, 32.5% of invasive pneumococcal isolates were non-susceptible to ceftriaxone. Serotypes 11A, 11E and 19A pneumococci showed high ceftriaxone non-susceptible rate (80%, 100% and 81.8% respectively), and they were related to sequence type (ST) 166 and ST320. In comparison, most serotype 3 isolates were ceftriaxone susceptible and related to ST180.ConclusionsPCV serotypes, especially 3 and 19A, are still prevalent in adult IPDs, suggesting that individual PCV13 immunization would be necessary for the elderly people and chronically ill patients. Ceftriaxone non-susceptible rate was remarkably high in invasive pneumococcal isolates.     

Recalibrated estimates of non-bacteremic and bacteremic pneumococcal community acquired pneumonia in hospitalized Canadian adults from 2010 to 2017 with addition of an extended spectrum serotype-specific urine antigen detection assay

Objective(s)In the context of age- and risk-based pneumococcal vaccine recommendations in Canada, this study presents updated data from active surveillance of pneumococcal community acquired pneumonia (pCAP) and invasive pneumococcal disease (IPD) in hospitalized adults from 2010 to 2017.MethodsS. pneumoniae was detected using culture (blood and sputum), and urine antigen detection (UAD). Serotyping was performed with Quellung, PCR, or using the PCV13- and PPV23 (non-PCV13)-specific UADs. Laboratory results, demographic, and outcome data were categorized by age (16–49, 50–64, and 65 + ) and by disease [non-bacteremic pCAP, bacteremic pCAP, and IPD(non-CAP)].Results11,129 CAP cases and 216 cases of IPD (non-CAP) were identified. Laboratory testing for S. pneumoniae was performed in 8912 CAP cases, identifying 1264 (14.2%) as pCAP. Of pCAP cases, 811 (64.1%) were non-bacteremic and 455 (35.9%) were bacteremic. Adults 65 + years represented 54.5% of non-bacteremic pCAP, 41.4% of bacteremic pCAP, and 48.6% of IPD cases. Adults 50–64 years contributed 30.3%, 33.1%, and 29.9%, respectively. In pCAP, PCV13 serotypes declined between 2010 and 2014 due to declines in serotypes 7F and 19A, then plateaued from 2015 to 2017 with persistence of serotype 3. In later study years, non-bacteremic pCAP was predominant, and PPV23 (non-PCV13) serotypes increased from 2015 to 2017, with serotypes 22F, 11A, and 9 N being most frequently identified. Compared to non-pCAP, pCAP cases were more likely to be admitted to intensive care units and require mechanical ventilation. These outcomes and mortality were more common in bacteremic pCAP and IPD, versus non-bacteremic pCAP.Conclusion(s)Along with IPD, pCAP surveillance (bacteremic and non-bacteremic) is important as their trends may differ over time. With insufficient herd protection from PCV13 childhood immunization, or use of PPV23 in adults, this study supports direct adult immunization with PCV13 or higher valency conjugate vaccines to reduce the residual burden of pCAP and IPD.     

Kinetics of pneumococcal antibodies among HIV-exposed,uninfected infants in Botswana

BackgroundStreptococcus pneumoniae is a leading cause of severe infections among children. Despite vaccination, HIV-exposed, uninfected (HEU) children have a higher incidence of invasive pneumococcal disease than HIV-unexposed, uninfected (HUU) children. We sought to compare the immunogenicity of 13-valent pneumococcal conjugate vaccine (PCV-13) in HEU and HUU infants.MethodsWe conducted a prospective cohort study of 134 mother-infant dyads in Botswana. Infants received PCV-13 doses at 2, 3, and 4 months through routine clinical care. We measured IgG antibodies specific to vaccine serotypes in sera collected from infants at 0, 5, and 12 months of age. We calculated the proportion of infants with protective IgG levels (≥0.35 µg/mL) to specific pneumococcal serotypes.ResultsAt birth, fewer than half of infants had protective IgG levels to serotypes 1 (38%), 3 (46%), 4 (33%), 5 (23%), 6B (40%), 7F (44%), 9 V (44%), and 23F (46%). Compared to HUU infants (n = 97), HEU infants (n = 37) had lower antibody concentrations at birth to serotypes 5 (p = 0.046) and 19A (p = 0.008) after adjustment for maternal age and infant birth weight. More than 80% of HEU and HUU infants developed protective antibody levels to each of the 13 vaccine serotypes following PCV-13 vaccination. Median concentrations of antibodies to pneumococcal serotypes declined by 55–93% between 5 and 12 months of age, with fewer than half of infants having protective antibody levels to serotypes 1 (47%), 3 (28%), 9 V (44%), 18C (24%), and 23F (49%) at 12 months of age.ConclusionsBoth HEU and HUU infants developed protective antibody responses to PCV-13 administered in a 3 + 0 schedule. However, antibody concentrations to many pneumococcal serotypes waned substantially by 12 months of age, suggesting that a PCV-13 booster dose in the second year of life may be needed to maintain protective pneumococcal antibody levels in older infants and young children.     

Immunogenicity of PCV24, an expanded pneumococcal conjugate vaccine,in adult monkeys and protection in mice

Invasive pneumococcal disease (IPD) is responsible for serious illnesses such as bacteremia, sepsis, meningitis, and pneumonia in young children, older adults, and persons with immunocompromising conditions and often leads to death. Although the most recent pneumococcal conjugate vaccines (PCVs) have been designed to target serotypes identified as the primary causative agents of IPD, the epidemiological landscape continues to change stressing the need to develop new PCVs. We have developed an investigational 24-valent PCV (PCV24) including serotypes 1, 2, 3, 4, 5, 6A, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F all conjugated to CRM197 and evaluated this vaccine in adult monkeys. PCV24 was shown to be immunogenic and induced functional antibody for all vaccine serotypes. Of the serotypes common to PCV13 and V114 (PCV15), PCV24 had a similar immunogenic response with the exceptions of 23F which had higher IgG GMCs for PCV13 and V114, and 7F which had higher GMCs for PCV13. Functional antibody responses were similar for the serotypes in common between PCV24, PCV13 and V114 vaccines, with the exception of serotype 7F which was greater for PCV13. Overall, this study shows that PCV24 provided similar immunogenicity as the lower valent vaccines in adult monkeys with no apparent serotype interference. In addition, PCV24 also provided protection against pneumococcal infection in a mouse challenge model.     

Burden of pneumococcal disease due to serotypes covered by the 13-valent and new higher-valent pneumococcal conjugate vaccines in the United States

The addition of pneumococcal conjugate vaccines (PCVs) to the United States (US) national immunization program led to significant reductions in incidence, mortality, and associated sequelae caused by pneumococcal disease (PD) in children and adults through direct and indirect protection. However, there remains clinical and economic burden due to PD caused by serotypes not included in the current 13-valent PCV (PCV13) formulation. To address this unmet need, 15-valent PCV (PCV15) and 20-valent PCV (PCV20), containing additional serotypes to PCV13, were recently approved in the US for adults and are anticipated for pediatrics in the near future. The study objective was to estimate the annual number of cases, deaths, and economic burden of PD due to serotypes included in PCV13, PCV15, and PCV20 for both US pediatric and adult populations. An Excel-based model was developed to calculate clinical and economic outcomes using published age-group specific serotype coverage; incidence of invasive PD, community-acquired pneumonia, and acute otitis media; case fatality rates; and disease-related costs. The results showed that across all age groups, the estimated annual PD cases and associated deaths covered by PCV13 serotypes were 914,199 and 4320, respectively. Compared with PCV13 serotypes, the additional 2 and 7 serotypes covered by PCV15 and PCV20 were attributed with 550,475 and 991,220 annual PD cases, as well as 1425 and 3226 annual deaths, respectively. This clinical burden translates into considerable economic costs ranging from $903 to $1,928 million USD that could be potentially addressed by PCV15 and PCV20. The additional serotypes included in PCV20 contribute substantially to the clinical and economic PD burden in the US pediatric and adult populations. Despite the success of the PCV13 pediatric national immunization program and increased adult uptake of PCV13 and 23-valent polysaccharide vaccine, broader PCV serotype coverage is needed across all ages to further reduce pneumococcal disease burden.     

A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination

IntroductionA 20-valent pneumococcal conjugate vaccine, PCV20, was developed to expand protection against vaccine-preventable pneumococcal disease. PCV20 contains the components of the 13-valent pneumococcal conjugate vaccine, PCV13, and includes capsular polysaccharide conjugates for 7 additional serotypes. Thus, PCV20 may cover those additional serotypes in individuals previously vaccinated with PCV13 or provide benefits of immunization with a conjugate vaccine to individuals previously immunized with a pneumococcal polysaccharide vaccine. This study described the safety and immunogenicity of PCV20 in adults ≥65 years of age with prior pneumococcal vaccination.MethodsThis phase 3, multicenter, randomized, open-label study was conducted in the United States and Sweden. Adults ≥65 years of age were enrolled into 1 of 3 cohorts based on their prior pneumococcal vaccination history (23-valent pneumococcal polysaccharide vaccine [PPSV23], PCV13, or both PCV13 and PPSV23). Participants were randomized 2:1 within their cohort to receive a single dose of PCV20 or PCV13 in those with prior PPSV23 only, and PCV20 or PPSV23 in those with prior PCV13 only; all participants with prior PCV13 and PPSV23 received PCV20. Safety was assessed by prompted local reactions within 10 days, systemic events within 7 days, adverse events (AEs) within 1 month, and serious AEs (SAEs) and newly diagnosed chronic medical conditions (NDCMCs) within 6 months after vaccination. Immune responses 1 month after PCV20 were assessed.ResultsThe percentages of participants reporting local reactions, systemic events, and AEs after PCV20 administration were similar across cohorts and comparable with the PCV13 and PPSV23 control groups. SAE and NDCMC rates were low in all groups. Robust immune responses, including opsonophagocytic antibody responses, to the 20 vaccine serotypes were observed 1 month after PCV20 regardless of prior pneumococcal vaccination.ConclusionsPCV20 was well tolerated and immunogenic in adults ≥65 years of age previously vaccinated with different pneumococcal vaccine regimens.Clinicaltrials.gov NCT03835975.     

A phase 3 trial of safety,tolerability, and immunogenicity of V114, 15-valent pneumococcal conjugate vaccine,compared with 13-valent pneumococcal conjugate vaccine in adults 50 years of age and older (PNEU-AGE)

BackgroundPneumococcal conjugate vaccines (PCVs) have greatly reduced the incidence of pneumococcal disease, yet unmet medical need remains due to increased disease caused by non-vaccine serotypes (STs). V114 (VAXNEUVANCE^TM, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA) is a 15-valent PCV containing 13 serotypes in licensed PCV13 and 2 additional serotypes (22F, 33F) which significantly contribute to pneumococcal disease burden. This phase 3 trial compared safety, tolerability, and immunogenicity of V114 to PCV13 in adults ≥50 years of age.MethodsAdults were randomized 1:1 to receive a single dose of V114 or PCV13; randomization was stratified by age (50–64 years, 65–74 years, and ≥75 years). Adverse events (AEs) were collected following vaccination. Serotype-specific opsonophagocytic activity (OPA) and immunoglobulin G (IgG) antibodies were measured prior to and 30 days after vaccination (Day 30). Primary objectives included assessing noninferiority of V114 to PCV13 for the 13 shared serotypes and superiority of V114 to PCV13 for the two unique serotypes. Superiority of V114 to PCV13 for shared serotype 3 was assessed as a secondary objective.ResultsOverall, 1,202 participants were vaccinated (V114 N = 602, PCV13 N = 600). The most commonly reported AEs across both groups were injection-site pain, fatigue, and myalgia. V114 met noninferiority criteria compared to PCV13 for the 13 shared serotypes (using a 2-fold non-inferiority margin for the ratio of OPA geometric mean titers [GMTs] [V114/PCV13] at Day 30) and met superiority for the 2 unique serotypes (using a 2-fold super-superiority margin for the ratio of OPA GMTs [V114/PCV13] at Day 30 and a 0.10 super-superiority margin for the difference in proportions of participants with ≥4-fold rise from prevaccination to Day 30). V114 met superiority criteria compared to PCV13 for serotype 3 (based on a super-superiority margin of 1.2 for the ratio of the OPA GMTs [V114/PCV13] and a superiority margin of 0 for the difference in proportions of participants with ≥4-fold rise). [NCT03950622, EudraCT#2018-004316-22, Japic-CTI#194845].