Direct, indirect and total effects of 13-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in children in Navarra, Spain, 2001 to 2014: cohort and case-control study.

We estimated the direct, indirect and total effects of the 13-valent pneumococcal conjugate vaccine (PCV13) on invasive pneumococcal disease (IPD) in children. A population-based cohort study followed children aged between 2.5 and 59 months between 2001 and 2014 in Navarra, Spain. IPD incidence was compared by PCV status and period. All cases diagnosed from July 2010 to December 2014 and eight matched controls per case were analysed to estimate the adjusted direct effect of PCV13. A total of 120,980 children were followed and 206 IPD cases were detected. Compared with unvaccinated children in the baseline period (2001-2004), overall IPD incidence in 2011-2014 (76% average PCV coverage) declined equally in vaccinated (total effect: 76%; hazard ratio (HR): 0.24; 95% confidence interval (CI): 0.14-0.40) and unvaccinated children (indirect effect: 78%; HR: 0.22; 95% CI: 0.09-0.55). IPD incidence from non-PCV13 serotypes increased among vaccinated children (HR: 2.84; 95% CI: 1.02-7.88). The direct effect of one or more doses of PCV13 against vaccine serotypes was 95% (odds ratio: 0.05; 95% CI: 0.01-0.55). PCV13 was highly effective in preventing vaccine-serotype IPD. The results suggest substantial and similar population-level vaccine benefits in vaccinated and unvaccinated children through strong total and indirect effects.

Impact of 13-valent pneumococcal conjugate vaccination in invasive pneumococcal disease incidence and mortality.

BACKGROUND: The impact of the 13-valent pneumococcal conjugate vaccine (PCV13) at the population level is unclear. We explored PCV13's effect in reducing invasive pneumococcal disease (IPD)-related morbidity and mortality, and whether serotype-specific changes were attributable to vaccination or expected as a part of natural, cyclical variations. METHODS: This was a Danish nationwide population-based cohort study based on the linkage of laboratory surveillance data and the Danish Civil Registration System. Changes in IPD incidence and mortality during baseline (2000-2007), 7-valent pneumococcal conjugate vaccine (PCV7) (2008-2010), and PCV13 (2011-2013) periods were estimated. Predicted incidences of serotypes were estimated controlling for cyclical trends from historical patterns observed during the past 20 years. RESULTS: We observed a 21% reduction (95% confidence interval [CI], 17%-25%) in IPD incidence in the total population after PCV13's introduction, and a 71% reduction (95% CI, 62%-79%) in children aged <2 years, considered as the vaccine effectiveness. We estimated a 28% reduction (95% CI, 18%-37%) in IPD-related 30-day mortality, from 3.4 deaths (95% CI, 3.2-3.6) per 100 000 population in the pre-PCV period to 2.4 (95% CI, 2.2-2.7) in the PCV13 period. The decline in mortality was observed across all age groups but was mainly related to mortality reductions in the nonvaccinated population. For serotypes 1 and 3, there were no significant changes in incidence beyond what would be expected from natural cyclical patterns. Serotype 19A significantly increased following PCV7's introduction, but the incidence declined toward baseline in 2012. CONCLUSIONS: PCV13 has brought greater benefits than we had expected in our setting. We observed a further decline on IPD incidence shortly after the shift from PCV7 to PCV13 in the national immunization program. This decline was accompanied by a substantial population-level decline in pneumococcal-related mortality of nearly 30% among nonvaccinated persons.

Seven-valent pneumococcal conjugate vaccine and nasopharyngeal microbiota in healthy children.

Seven-valent pneumococcal conjugate vaccine (PCV-7) is effective against vaccine serotype disease and carriage. Nevertheless, shifts in colonization and disease toward nonvaccine serotypes and other potential pathogens have been described. To understand the extent of these shifts, we analyzed nasopharyngeal microbial profiles of 97 PCV-7-vaccinated infants and 103 control infants participating in a randomized controlled trial in the Netherlands. PCV-7 immunization resulted in a temporary shift in microbial community composition and increased bacterial diversity. Immunization also resulted in decreased presence of the pneumococcal vaccine serotype and an increase in the relative abundance and presence of nonpneumococcal streptococci and anaerobic bacteria. Furthermore, the abundance of Haemophilus and Staphylococcus bacteria in vaccinees was increased over that in controls. This study illustrates the much broader effect of vaccination with PCV-7 on the microbial community than currently assumed, and highlights the need for careful monitoring when implementing vaccines directed against common colonizers.

Cost-effectiveness analysis of the pediatric 20-valent pneumococcal conjugate vaccine compared with lower-valent alternatives in Argentina.

OBJECTIVES: The 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for infants in Argentina's national immunization program (NIP) in a 2 + 1 schedule since 2012. Licensure of the 15-valent vaccine (PCV15) is anticipated soon, and the 20-valent vaccine (PCV20) recently received regulatory approval. This cost-effectiveness analysis examined the public health and economic implications of transitioning from PCV13 to either PCV15 or PCV20 in Argentina's pediatric NIP. METHODS: A decision-analytic Markov model was used with a 10-year time horizon and a 3.0% annual discount rate for costs and benefits. Vaccine effectiveness estimates were derived from Argentinian surveillance data, PCV13 clinical effectiveness and impact studies, and PCV7 efficacy studies. Population, epidemiologic, and economic inputs were obtained from literature and Argentinian-specific data. The study adopted a healthcare system perspective; sensitivity and scenario analyses were conducted to assess input parameters and structural uncertainty. RESULTS: Compared with PCV13, PCV20 was estimated to avert an additional 7,378, 42,884, and 172,389 cases of invasive pneumococcal disease (IPD), all-cause pneumonia, and all-cause otitis media (OM), respectively, as well as 3,308 deaths, resulting in savings of United States Dollars (USD) 50,973,962 in direct medical costs. Compared with PCV15, PCV20 was also estimated to have greater benefit, averting an additional 6,140, 35,258, and 142,366 cases of IPD, pneumonia, and OM, respectively, as well as 2,624 deaths, resulting in savings of USD 37,697,868 in direct medical costs. PCV20 was associated with a higher quality-adjusted life year gain and a lower cost (i.e., dominance) versus both PCV13 and PCV15. Results remained robust in sensitivity analyses and scenario assessments. CONCLUSION: Over a 10-year horizon, vaccination with PCV20 was expected to be the dominant, cost-saving strategy versus PCV13 and PCV15 in children in Argentina. Policymakers should consider the PCV20 vaccination strategy to achieve the greatest clinical and economic benefit compared with lower-valent options.

Estimating national, regional and provincial cost-effectiveness of introducing childhood 13-valent pneumococcal conjugate vaccination in China: a modelling analysis.

Background: Although 13-valent pneumococcal conjugate vaccine (PCV13) is available in China's private market, it has yet to be introduced into the National Immunization Programme (NIP) and is therefore not available to large parts of the population. This study aimed to estimate the cost-effectiveness of including PCV13 in China's NIP at national and provincial levels. Methods: We adopted a decision-tree Markov model to estimate the cost-effectiveness of adding 3-dose PCV13 in the NIP compared to the status quo in the private market from a societal perspective. The model hypothesized a birth cohort for five years after vaccine introduction. Treatment costs and vaccine program costs were calculated from Chinese Center for Disease Control and Prevention (CDC) and national insurance databases. Disease burden data, incidence rate ratios, and other parameters were derived from published and grey literature. Cases and deaths averted, quality-adjusted life years (QALYs) gained, and incremental cost-effectiveness ratios (ICERs) were estimated at the provincial, regional, and national levels. One-way, scenario and probabilistic sensitivity analyses were conducted to explore model uncertainty. Findings: At the national level, introducing PCV13 in the NIP was predicted to prevent approximately 4807 pneumococcal deaths (66% reduction) and 1,057,650 pneumococcal cases (17% reduction) in the first five years of the 2019 birth cohort. Under the assumed base case price of US$ 25 per dose in the NIP, PCV13 in the NIP was cost-effective nationally with ICER of US$ 5.222 per QALY gained, and was cost-effective in 17 and cost-saving in 4 of the 31 provinces compared to the status quo. One-way and scenario sensitivity analyses indicated robust results when varying all model parameters, and probabilistic sensitivity analysis showed a 98% probability of cost-effectiveness nationally. Interpretation: Our findings highlight the cost-effectiveness of introducing PCV13 in China's NIP. Provincial results supported subnational introduction of PCV13, and priority should be given to less socioeconomically developed provinces. Since vaccination cost is the most influential model parameter, efforts to improve PCV affordability after pooled procurement will benefit public health in a cost-effective manner. Funding: The Bill & Melinda Gates Foundation.

Parental Willingness and Associated Factors of Pediatric Vaccination in the Era of COVID-19 Pandemic: A Systematic Review and Meta-Analysis.

A significant decline in pediatric vaccination uptake due to the COVID-19 pandemic has been documented. Little is known about the parental willingness and associated factors of pediatric vaccination during the COVID-19 pandemic. An extensive literature search in the databases of PubMed, Scopus, Web of Science, and EBSCOhost were conducted. A total of 20 eligible studies published from 2020-2022 were included for systematic summary by a thematic analysis, among which 12 studies were included in a meta-analysis conducted with R-4.2.1. The prevalence of parental willingness to childhood/routine vaccination and seasonal influenza vaccination was 58.6% (95%CI 2.8-98.6%) and 47.3% (95%CI 25.3-70.5%). Moreover, there is no sufficient evidence of significant change in parental willingness to childhood/routine vaccination, human papillomavirus vaccination, or pneumococcal conjugate vaccination during the pandemic. However, a significant increase in parental willingness to vaccinate their children against seasonal influenza was found. In addition to the factors of parental vaccination willingness/hesitancy that are well-studied in literature, children/parents' history of COVID-19 and children's perceived vulnerability to COVID-19 were associated with parental willingness. Developing synergetic strategies to promote COVID-19 vaccination together with other pediatric vaccination is warranted during the pandemic. This may help to improve and/or catch up the vaccine uptake of children during and/or after the COVID-19 pandemic.

Streptococcus pneumoniae vaccination strategies and its expected impact on penicillin non-susceptibility in children under the age of five: Let's recap!

The impact of pneumococcal conjugate vaccines (PCVs) on invasive pneumococcal disease (IPD) burden has been extensively studied in children aged<5 years; however, a pooled estimation of the effect of PCVs on penicillin non-susceptible pneumococci (PNSP) has not yet been performed. We aimed to identify whether the introduction of PCV-10 and PCV-13 had led to the decrease of the overall PNSP rate in children < 5 years. We conducted a systematic review of published surveillance studies reporting the rate of PNSP rates in children < 5 in countries where PCV10/13 were introduced. The overall observed trend onwards the introduction of PCV-10 and PCV-13 is a decrease in PNSP among children < 5 years in surveillance sites located in PCV-13 countries. We identified an increase of PNSP rates (serotype 19A) in PCV-10 settings. Resistant NVT strains are emerging in IPD in children < 5 years mainly serotypes 24F, 15A, 11A and 33F along with serotype 19A in PCV-10 settings. Continuous surveillance is necessary in IPD in children under five to monitor the long-term effect of PCV-10 and PCV-13 on penicillin resistance trends.

Budget impact analysis of pneumococcal conjugate vaccines in Colombia.

Objective: Pneumococcal diseases including invasive pneumococcal disease (IPD), pneumonia, and acute otitis media (AOM) impose a substantial public health burden. This study performed a budget impact analysis of the use of pneumococcal conjugate vaccines (PCVs) in the National Immunization Program (NIP) in Colombia.Methods: We compared the direct medical cost of the scenario without and with PCV vaccination using either pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) or 13-valent pneumococcal conjugate vaccine (PCV-13) over 5 years (2020-2024) from the health-care system perspective. Vaccine efficacy estimates were obtained from published sources and vaccine prices were taken from the Pan-American Health Organization Revolving Fund. Vaccine coverage was assumed to be 90% based on Colombia data.Results: Using PHiD-CV in the NIP in Colombia would reduce the estimated cost for treating pneumococcal disease by US$46.1 m over the 2020-2024 period (US$40.2 m using PCV-13), with a budget impact of US$100.1 m for PHiD-CV (US$121.4 m for PCV-13), and would cost US$3.1 m less per year on vaccine doses than using PCV-13.Conclusion: These findings are potentially valuable for the selection of vaccines for their national immunization programs under conditions of budgetary constraint.

The association between pneumococcal vaccination, ethnicity, and the nasopharyngeal microbiota of children in Fiji.

BACKGROUND: Streptococcus pneumoniae is a significant global pathogen that colonises the nasopharynx of healthy children. Pneumococcal conjugate vaccines, which reduce nasopharyngeal colonisation of vaccine-type S. pneumoniae, may have broader effects on the nasopharyngeal microbiota; however, data are limited. In Fiji, nasopharyngeal carriage prevalence of S. pneumoniae and other colonising species differ between the two main ethnic groups. Here, we examined the association between the 7-valent pneumococcal conjugate vaccine (PCV7) and the nasopharyngeal microbiota of children in Fiji, including for each of the two main ethnic groups-indigenous Fijians (iTaukei) and Fijians of Indian descent (FID). METHOD: The nasopharyngeal microbiota of 132 Fijian children was examined using nasopharyngeal swabs collected from 12-month-old iTaukei and FID children who were vaccinated (3 doses PCV7) or unvaccinated in infancy as part of a phase II randomised controlled trial. Microbiota composition was determined by sequencing the V4 region of the 16S rRNA gene. Species-specific carriage of S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Staphylococcus aureus was determined using real-time quantitative PCR. Associations between microbiota composition and other host and environmental factors were considered in the analysis. RESULTS: PCV7 had no overall impact on microbial diversity or composition. However, ethnic differences were observed in both diversity and composition with iTaukei children having higher relative abundance of Moraxella (p = 0.004) and Haemophilus (p = 0.004) and lower relative abundance of Staphylococcus (p = 0.026), Dolosigranulum (p = 0.004) and Corynebacterium (p = 0.003) compared with FID children. Further, when we stratified by ethnicity, associations with PCV7 could be detected: vaccinated iTaukei children had a lower relative abundance of Streptococcus and Haemophilus compared with unvaccinated iTaukei children (p = 0.022 and p = 0.043, respectively); and vaccinated FID children had a higher relative abundance of Dolosigranulum compared with unvaccinated FID children (p = 0.037). Children with symptoms of an upper respiratory tract infection (URTI) had a significantly different microbiota composition to children without symptoms. The microbiota composition of iTaukei children without URTI symptoms was most similar to the microbiota composition of FID children with URTI symptoms. CONCLUSIONS: Associations between PCV7 and nasopharyngeal microbiota differed within each ethnic group. This study highlights the influence that ethnicity and URTIs have on nasopharyngeal microbiota.

Invasive pneumococcal disease in children under 16 years of age: Incomplete rebound in incidence after the maximum effect of PCV13 in 2012/13 in Germany.

OBJECTIVE: To identify a potential nadir of the impact of pneumococcal conjugate vaccination (PCV) in infancy on invasive pneumococcal diseases (IPD) in children under 16 in Germany. METHODS: Active surveillance on IPD based on two independent data sources with capture-recapture correction for underreporting. Annual incidence rates by age group, serotypes, site of infection, and relative incidence reduction compared to pre-vaccination period (1997-2001) at nadir and for the most recent season are reported. We calculated vaccine coverage at the age of 24 months using health insurance claims data. RESULTS: 96-97% of children had received at least two doses of PCV since 2009. The maximum impact on overall IPD incidence was achieved in 2012/13 (-48% [95% CI: -55%; -39%]) with a rebound to -26% [95% CI: -36%; -16%] in 2015/16. Non-PCV13 serotypes accounted for 84.1% of the IPD cases in 2015/16. The most frequent non-PCV serotypes in IPD in 2014/15 and 2015/16 were 10A, 24F, 15C, 12F, 38, 22F, 23B, and 15B. The impact at nadir was highest in children 0-1 years of age both in meningitis and non-meningitis cases, whereas the impact for other age groups was higher for meningitis cases. The rebound mainly pertained to non-meningitis cases. CONCLUSION: The maximum impact of pneumococcal conjugate vaccination has been attained and signs of a rebound are apparent. Sustained surveillance for IPD in children is warranted to assess whether these trends will continue. There may be a need for vaccines using antigens common to all serotypes.

Efficacy of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine against acute otitis media and nasopharyngeal carriage in Panamanian children - A randomized controlled trial.

We previously reported 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D conjugate vaccine (PHiD-CV) efficacy in a double-blind randomized trial (ClinicalTrials.gov: NCT00466947) against various diseases, including acute otitis media (AOM). Here, we provide further analyses. In the Panamanian subset, 7,359 children were randomized (1:1) to receive PHiD-CV or control vaccine at age 2/4/6 and 15-18 months. Of these, 2,000 had nasopharyngeal swabs collected. AOM cases were captured when parents sought medical attention for children with AOM symptoms; surveillance was enhanced approximately 2 y into the study through regular telephone calls or home visits by study personnel, who advised parents to visit the clinic if their child had AOM symptoms. Mean follow-up was 31.4 months. Clinical AOM (C-AOM) cases were assessed by physicians and confirmed by otorhinolaryngologists. Middle ear fluid samples, taken from children with C-AOM after specific informed consent, and nasopharyngeal samples were cultured for pathogen identification. For 7,359 children, 2,574 suspected AOM cases were assessed by a primary healthcare physician; 649 cases were C-AOM cases as per protocol definition. From the 503 MEF samples collected, 158 resulted in a positive culture. In the intent-to-treat cohort (7,214 children), PHiD-CV showed VE against first C-AOM (24.0% [95% CI: 8.7, 36.7]) and bacterial (B-AOM) episodes (48.0% [20.3, 66.1]) in children <24 months, which declined thereafter with age. Pre-booster VE against C-AOM was 30.7% [12.9, 44.9]; post-booster, -6.7% [-36.4, 16.6]. PHiD-CV VE was 17.7% [-6.1, 36.2] against moderate and 32.7% [-20.5, 62.4] against severe C-AOM. VE against vaccine-serotype pneumococcal NPC was 31.2% [5.3, 50.3] 3 months post-booster, and 25.6% [12.7, 36.7] across all visits. NTHi colonization rates were low and no significant reduction was observed. PHiD-CV showed efficacy against C-AOM and B-AOM in children younger than 24 months, and reduced vaccine-serotype NPC.

Stunting correlates with high salivary and serum antibody levels after 13-valent pneumococcal conjugate vaccination of Venezuelan Amerindian children.

OBJECTIVE: To determine the impact of pre-vaccination nutritional status on vaccine responses in Venezuelan Warao Amerindian children vaccinated with the 13-valent pneumococcal conjugate vaccine (PCV13) and to investigate whether saliva can be used as read-out for these vaccine responses. METHODS: A cross-sectional cohort of 504 Venezuelan Warao children aged 6 weeks - 59 months residing in nine geographically isolated Warao communities were vaccinated with a primary series of PCV13 according to Centers for Disease Control and Prevention (CDC)-recommended age-related schedules. Post-vaccination antibody concentrations in serum and saliva of 411 children were measured by multiplex immunoassay. The influence of malnutrition present upon vaccination on post-vaccination antibody levels was assessed by univariate and multivariable generalized estimating equations linear regression analysis. RESULTS: In both stunted (38%) and non-stunted (62%) children, salivary antibody concentrations correlated well with serum levels for all serotypes with coefficients varying from 0.61 for serotype 3-0.80 for serotypes 5, 6A and 23F (all p < 0.01). Surprisingly, higher serum and salivary antibody levels were observed with increasing levels of stunting in children for all serotypes. This was statistically significant for 5/13 and 11/13 serotype-specific serum and saliva IgG concentrations respectively. CONCLUSION: Stunted Amerindian children showed generally higher antibody concentrations than well-nourished children following PCV13 vaccination, indicating that chronic malnutrition influences vaccine response. Saliva samples might be useful to monitor serotype-specific antibody levels induced by PCV vaccination. This would greatly facilitate studies of vaccine efficacy in rural settings, since participant resistance generally hampers blood drawing.

Vaccine effectiveness of PCV13 in a 3+1 vaccination schedule.

OBJECTIVE: To assess the vaccine effectiveness (VE) of PCV13 for invasive pneumococcal disease (IPD) regarding the extra six serotypes with a 3+1 schedule in Germany. METHODS: Active surveillance for IPD in children <16 years eligible for PCV13 vaccination. We used the Broome method and logistic regression to estimate VE. RESULTS: Data on 164/304 reported IPD cases were informative and met the inclusion criteria. VE for the extra six serotypes was 88% [95% confidence interval (CI): 73; 95] and 83% [56; 94] for at least one and for at least two doses respectively. VE for the complete 3+1 vaccination schedule was not conclusive because of a wide 95% CI. For serotype 3 VE appeared to be zero with an even wider 95% CI. CONCLUSION: PCV13 VE against the extra six serotypes with the 3+1 schedule in Germany was only marginally higher compared to previously published data for the 2+1 schedule.

Nasopharyngeal carriage of Streptococcus pneumoniae and other bacteria in the 7th year after implementation of the pneumococcal conjugate vaccine in the Netherlands.

After introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the infant national immunization program (NIP) in the Netherlands in 2006, Streptococcus pneumoniae strains of the non-vaccine serotype 19A emerged and became the dominant serotype in carriage in children and their parents. Similar patterns were observed in other European countries and the United States. Increases in carriage rates of Staphylococcus aureus and non-typeable (NT) Haemophilus influenzae were also observed. After switching of PCV7 to 10-valent vaccine (PCV10) in 2011, a new carriage surveillance study was performed in the winter of 2012/2013. Nasopharyngeal carriage of S. pneumoniae, H. influenzae, S. aureus, and Moraxella catarrhalis was determined by conventional culture in 330 PCV10-vaccinated 11-month-old children, 330 PCV7-vaccinated 24-month-old children, and their parents. Carriage prevalence was compared with similar carriage studies conducted in 2005, 2009, and 2010/2011. Although serotype 19A remained the most frequently carried pneumococcal serotype in children, prevalence of 19A significantly declined in PCV7-vaccinated 24-month-old children (14% to 8%, p=0.01), but less in PCV10-vaccinated 11-month-old children (12% to 9%, p=0.31). Carriage of H. influenzae remained stable at an elevated level (65% in 11-month-olds and 69% in 24-month-olds), while the carriage of S. aureus returned to pre-PCV7 levels in 11-month-old children (14% in 2010/2011 to 7% in 2012/2013), but not in 24-month-olds (remained at 7%). Our results might indicate a new balance between replacing non-vaccine pneumococcal serotypes and other potential pathogenic bacteria in nasopharyngeal carriage. Carriage studies are valuable tools in assessing vaccine effects on pathogens circulating in the population, for evaluation of PCV impact, and in predicting changes in respiratory and invasive disease.

Incidence of invasive pneumococcal disease in 5-15 year old children with and without comorbidities in Germany after the introduction of PCV13: Implications for vaccinating children with comorbidities.

OBJECTIVE: To describe the burden of suffering from IPD in children aged 5-15 years with and without comorbidities up to 5 years after the introduction of PCV13 in Germany and to identify the potential benefit for PCV13 and PPV23 vaccination. METHODS: The surveillance of IPD for children <16 years was based on two independently reporting sources: active surveillance in pediatric hospitals and a laboratory-based sentinel surveillance system. CASE DEFINITION: IPD with cultural detection of pneumococci at a physiologically sterile site in children from 2010 to 2014 in Germany. Incidence was estimated by capture-recapture analysis with stratification by absence/presence of comorbidities. Coverage of the observed serotypes by different vaccines was assessed. RESULTS: 142 (Capture recapture-corrected: 437) cases were reported: 72.5% were healthy children and 27.5% had a comorbidity. The incidence of IPD related to children with comorbidities was 0.2 per 100,000. One third of these cases had serotypes not included in either vaccine. The remaining cases might benefit from pneumococcal vaccination but one third of all cases was not vaccinated. The additional potential benefit of PPV23 compared to PCV13 with respect to coverage was 10%. CONCLUSION: The incidence of IPD in children with comorbidities in Germany is low. Pneumococcal vaccination uptake in children with comorbidities should be increased, although only about two-thirds of the cases might be preventable by presently available vaccines.