Epidemiological and clinical burden of Clostridioides difficile infections and recurrences between 2015 - 2019: the RECUR Germany study.

BACKGROUND: This real-world study assessed the epidemiology and clinical complications of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in hospital and community settings in Germany from 2015 - 2019. METHODS: An observational retrospective cohort study was conducted among adult patients diagnosed with CDI in hospital and community settings using statutory health insurance claims data from the BKK database. A cross-sectional approach was used to estimate the annual incidence rate of CDI and rCDI episodes per 100,000 insurants. Patients' demographic and clinical characteristics were described at the time of first CDI episode. Kaplan-Meier method was used to estimate the time to rCDIs and time to complications (colonic perforation, colectomy, loop ileostomy, toxic megacolon, ulcerative colitis, peritonitis, and sepsis). A Cox model was used to assess the risk of developing complications, with the number of rCDIs as a time-dependent covariate. RESULTS: A total of 15,402 CDI episodes were recorded among 11,884 patients. The overall incidence of CDI episodes declined by 38% from 2015 to 2019. Most patients (77%) were aged ≥ 65 years. Around 19% of CDI patients experienced at least one rCDI. The median time between index CDI episode to a rCDI was 20 days. The most frequent complication within 12-months of follow-up after the index CDI episode was sepsis (7.57%), followed by colectomy (3.20%). The rate of complications increased with the number of rCDIs. The risk of any complication increased by 31% with each subsequent rCDI (adjusted hazard ratio [HR]: 1.31, 95% confidence interval: 1.17;1.46). CONCLUSIONS: CDI remains a public health concern in Germany despite a decline in the incidence over recent years. A substantial proportion of CDI patients experience rCDIs, which increase the risk of severe clinical complications. The results highlight an increasing need of improved therapeutic management of CDI, particularly efforts to prevent rCDI.

Estimating excess mortality and economic burden of Clostridioides difficile infections and recurrences during 2015-2019: The RECUR England study.

OBJECTIVES: To generate real-world evidence on all-cause mortality and economic burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England. METHODS: We conducted a cohort study using retrospective data from Clinical Practice Research Datalink linked to Hospital Episode Statistics. Patients diagnosed with CDI in hospital and community settings during 2015-2018 were included and followed for ≥1 year. All-cause mortality was described at 6, 12, and 24 months. Healthcare resource usage (HCRU) and associated costs were assessed at 12 months of follow-up. A cohort of non-CDI patients, matched by demographic and clinical characteristics including Charlson Comorbidity Index score, was used to assess excess mortality and incremental costs of HCRU. RESULTS: All-cause mortality among CDI patients at 6, 12, and 24 months was 15.87%, 20.37%, and 27.03%, respectively. A higher proportion of rCDI patients died at any point during follow-up. Compared with matched non-CDI patients, excess mortality was highest at 6 months with 1.81 and 2.53 deaths per 100 patient-months among CDI and ≥1 rCDI patients. Hospitalizations were the main drivers of costs, with an incremental cost of £1209.21 per CDI patient. HCRU and costs increased with rCDIs. CONCLUSION: CDI poses a substantial mortality and economic burden, further amplified by rCDIs.

Clostridioides difficile infections, recurrences, and clinical outcomes in real-world settings from 2015 to 2019: The RECUR England study.

OBJECTIVE: To estimate the epidemiological and clinical burden of Clostridioides difficile infections (CDIs) and recurrences (rCDIs) in England. METHODS: This retrospective study included adult patients diagnosed with CDI (community or hospital settings) over 2015-2019 from Clinical Practice Research Datalink and Hospital Episode Statistics databases. Incidences of CDI and rCDI were determined annually. Time to subsequent rCDI was estimated by Kaplan-Meier method. Rates of complications were assessed within 12 months from index episode. Association of risk factors with complications was evaluated using a Cox regression model. RESULTS: A total of 52,443 CDI episodes were recorded among 36,913 patients. Of these, 75% were aged ≥65 years, 59% were women; 73% were treated in community settings. CDI incidence remained stable (111 episodes per 100,000 patients in 2019). Around 21% of patients had ≥1 rCDI. Sepsis (12%) was the most common complication, followed by colectomy and ulcerative colitis. Age, gender, comorbidities, rCDI, preindex medical procedures, hospitalizations and consultations, and CDI treatment in hospital, were found to increase the risk of complication. CONCLUSIONS: CDI remains a concern in England. The study highlights the importance of managing primary and rCDI episodes via effective and improved therapies to prevent fatal complications.

Long-term population impact of infant 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease in adults in Finland.

BACKGROUND: Limited data are available on long-term indirect effects of ten-valent pneumococcal conjugate vaccine (PCV10) programmes. We evaluated changes in invasive pneumococcal disease (IPD) incidence, mortality, and serotype distribution in adults up to 9 years after infant PCV10 introduction. METHODS: Culture-confirmed IPD cases ≥18 years (n = 5610; 85% were pneumonia) were identified through national, population-based laboratory surveillance; data were linked with population registry to conduct nationwide follow-up study. In a time-series model, we compared serotype-specific IPD incidence and associated 30-day mortality rates before and after PCV10 by using negative binomial regression models. RESULTS: During pre-PCV10 period (7/2004-6/2010), overall IPD incidence in adults ≥18 years increased yearly by 4.8%. After adjusting for trend and seasonality, the observed PCV10 serotype IPD incidence in 7/2018-6/2019 was 90% (12/100,000 person-years) lower than the expected rate without PCV10 program. Non-PCV10 serotype incidence was 40% (4.4/100,000 person-years) higher than expected; serotypes 3, 19A, 22F, and 6C accounted for most of the rate increase. However, incidence of non-PCV10 IPD levelled off by end of follow-up. The observed-expected incidence rate-ratio (IRR) was 0·7 (95 %CI 0·5-0.8) for all IPD and 0·7 (95 %CI 0·3-1·3) for IPD-associated 30-day mortality. Case-fatality proportion decreased from 11·9% to 10.0% (p < 0.01). In persons ≥65 years, the IRR was 0·7 (95 %CI 0·5-0.95). CONCLUSIONS: Significant indirect effects were seen for vaccine-serotype IPD and for overall IPD in all adult age groups. For non-vaccine IPD, the incidence stabilized 5 years after infant PVC10 program introduction, resulting in a steady state in which non-vaccine IPD accounted for nearly 90% of overall IPD. Substantial pneumococcal disease burden remains in older adults.

Effectiveness of 10 and 13-valent pneumococcal conjugate vaccines against invasive pneumococcal disease in European children: SpIDnet observational multicentre study.

BACKGROUND: Pneumococcal conjugate vaccines covering 10 (PCV10) and 13 (PCV13) serotypes have been introduced in the infant immunization schedule of most European countries in 2010-11. To provide additional real-life data, we measured the effectiveness of PCV10 and PCV13 against invasive pneumococcal disease (IPD) in children of 12 European sites (SpIDnet). METHODS: We compared the vaccination status of PCV10 and PCV13 serotype IPD (cases) to that of nonPCV13 serotype IPD (controls) reported in 2012-2018. We calculated pooled effectiveness as (1-vaccination odds ratio)*100, and measured effectiveness over time since booster dose. RESULTS: The PCV13 and PCV10 studies included 2522 IPD cases from ten sites and 486 cases from four sites, respectively. The effectiveness of ≥ 1 PCV13 dose was 84.2% (95 %CI: 79.0-88.1) against PCV13 serotypes (n = 2353) and decreased from 93.1% (87.8-96.1) < 12 months to 85.1% (72.0-92.1) ≥ 24 months after booster dose. PCV13 effectiveness of ≥ 1 dose was 84.7% (55.7-94.7) against fatal PCV13 IPD, 64.5% (43.7-77.6), 83.2% (73.7-89.3) and 85.1% (67.6-93.1) against top serotypes 3, 19A and 1, respectively, and 85.4% (62.3-94.4) against 6C. Serotype 3 and 19A effectiveness declined more rapidly. PCV10 effectiveness of ≥ 1 dose was 84.8% (69.4-92.5) against PCV10 serotypes (n = 370), 27.2% (-187.6 to 81.6) and 85.3% (35.2-96.7) against top serotypes 1 and 7F, 32.5% (-28.3 to 64.5) and -14.4% (-526.5 to 79.1) against vaccine-related serotypes 19A and 6C, respectively. CONCLUSIONS: PCV10 and PCV13 provide similar protection against IPD due to the respective vaccine serotype groups but serotype-specific effectiveness varies by serotype and vaccine. PCV13 provided individual protection against serotype 3 and vaccine-related serotype 6C IPD. PCV10 effectiveness was not significant against vaccine-related serotypes 19A and 6C. PCV13 effectiveness declined with time after booster vaccination. This multinational study enabled measuring serotype-specific vaccine effectiveness with a precision rarely possible at the national level. Such large networks are crucial for the post-licensure evaluation of vaccines.

Evaluation of the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine in a cluster-randomised trial.

BACKGROUND: In the nation-wide double-blind cluster-randomised Finnish Invasive Pneumococcal disease trial (FinIP, ClinicalTrials.gov NCT00861380, NCT00839254), we assessed the indirect impact of the 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against five pneumococcal disease syndromes. METHODS: Children 6 weeks to 18 months received PHiD-CV10 in 48 clusters or hepatitis B/A-vaccine as control in 24 clusters according to infant 3+1/2+1 or catch-up schedules in years 2009-2011. Outcome data were collected from national health registers and included laboratory-confirmed and clinically suspected invasive pneumococcal disease (IPD), hospital-diagnosed pneumonia, tympanostomy tube placements (TTP) and outpatient antimicrobial prescriptions. Incidence rates in the unvaccinated population in years 2010-2015 were compared between PHiD-CV10 and control clusters in age groups <5 and ≥5 years (5-7 years for TTP and outpatient antimicrobial prescriptions), and in infants <3 months. PHiD-CV10 was introduced into the Finnish National Vaccination Programme (PCV-NVP) for 3-month-old infants without catch-up in 9/2010. RESULTS: From 2/2009 to 10/2010, 45398 children were enrolled. Vaccination coverage varied from 29 to 61% in PHiD-CV10 clusters. We detected no clear differences in the incidence rates between the unvaccinated cohorts of the treatment arms, except in single years. For example, the rates of vaccine-type IPD, non-laboratory-confirmed IPD and empyema were lower in PHiD-CV10 clusters compared to control clusters in 2012, 2015 and 2011, respectively, in the age-group ≥5 years. CONCLUSIONS: This is the first report from a clinical trial evaluating the indirect impact of a PCV against clinical outcomes in an unvaccinated population. We did not observe consistent indirect effects in the PHiD-CV10 clusters compared to the control clusters. We consider that the sub-optimal trial vaccination coverage did not allow the development of detectable indirect effects and that the supervening PCV-NVP significantly diminished the differences in PHiD-CV10 vaccination coverage between the treatment arms.

Serotype Replacement after Introduction of 10-Valent and 13-Valent Pneumococcal Conjugate Vaccines in 10 Countries, Europe.

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.

Long-term population effects of infant 10-valent pneumococcal conjugate vaccination on pneumococcal meningitis in Finland.

BACKGROUND: No previous studies have reported long-term follow-up of ten-valent pneumococcal conjugate vaccine (PCV10) program impact on pneumococcal meningitis (PM). We assessed the effects of infant PCV10 program on PM incidence, mortality and serotype distribution in children and adults during 7 years after introduction. METHODS: We conducted a population-based observational study. A case of PM was defined as isolation of Streptococcus pneumoniae from cerebrospinal fluid or, a patient with S. pneumoniae isolated from blood and an ICD-10 hospital discharge diagnosis of bacterial meningitis within 30 days before or after positive culture date.We compared age- and serotype-specific incidence and associated 30-day mortality rates in 2011-2017 (PCV10 period) with those in 2004-2010 (pre-PCV10 baseline) by using Poisson regression models. Absolute rate differences and 95% confidence intervals (CIs) were calculated from the parameter estimates by using delta method. RESULTS: During the PCV10 period, the overall incidence of PCV10 serotype meningitis decreased by 68% (95%CI 57%-77%), and the overall PM incidence by 27% (95%CI: 12%-39%). In age groups 0-4, 50-64, and ≥ 18 years, the overall PM incidence was reduced by 64%, 34% and 19%, respectively. In adults ≥ 65 years of age, a 69% reduction in PCV10 serotypes was offset by 157% (56%-342%) increase in non-PCV10 serotypes. The overall PM-related mortality rate decreased by 42% (95%CI 4%-65%). Overall case fatality proportion (CFP) was 16% in pre-PCV10 period and 12% in PCV10 period (p = 0.41); among persons 50-64 years the CFP decreased from 25% to 10% (p = 0.04). CONCLUSIONS: We observed substantial impact and herd protection for vaccine-serotype PM and associated mortality after infant PCV10 introduction. However, in older adults ≥ 65 years of age, PM burden remains unchanged due to serotype replacement.

Impact and effectiveness of a conjugate vaccine against invasive pneumococcal disease in Finland - a modelling approach.

The evaluation of the public health impact of a vaccination program is essential in monitoring its policy relevance. Vaccine impact (VI) is usually assessed in a before-after design, in which data on disease burden without vaccination program is required from a historical reference period. It takes into account the indirect effects and therefore aims to describe the public health performance of the vaccination program in the population. Vaccine effectiveness (VE), measured in parallel settings, quantifies the benefit for an individual of being vaccinated but does not address the indirect effects of a vaccination program. The motivation of this paper is to gain insight into patterns of how VI and VE have manifested under large-scale use of a ten-valent pneumococcal conjugate vaccine in Finnish children. We construct a simple pseudo-dynamic model that mimics typical post-vaccination trends in the incidences of pneumococcal carriage and invasive disease in children when the proportion of vaccine-type carriage decreases. In the context of the model, we define the parameters of interest for VI and VE and explore how their expected values evolve over time. For comparison, we demonstrate the application of VI and VE estimation by using register data.

Indirect Impact of Ten-valent Pneumococcal Conjugate Vaccine Program on Reducing Antimicrobial Use and Tympanostomy Tube Placements in Finland.

BACKGROUND: Acute otitis media (AOM) is the most common reason for antimicrobial use, and tympanostomy tube placement (TTP) is the most common reason for surgery requiring general anesthesia in children. Ten-valent pneumococcal conjugate vaccine (PCV10) was introduced in Finland in 2010 for infants. We evaluated the indirect impact of PCV10 on these surrogate otitis outcomes in unvaccinated children. METHODS: Using before-after design, unvaccinated children ineligible for National Vaccination Program (born January 2006 to May 2010) were followed-up during 2012-2016 (target cohort, age 1.5-7 years). The target cohort was compared with an age- and season-matched unvaccinated reference cohort (born January 2000 to May 2004) during 2006-2010. Antimicrobial purchase data were obtained from the Social Insurance Institution of Finland benefits register. We assessed the relative reduction by generalized Cox regression for outpatient purchases of antibiotics recommended for treatment of AOM in the Finnish guidelines. Data on all TTP procedures were obtained from national hospital discharge register and Social Insurance Institution benefits register. RESULTS: The rate of outpatient purchases of antimicrobials recommended for AOM was 51 in the unvaccinated reference cohort and 44/100 person-years in the unvaccinated target cohort; relative rate reduction was 14.7% [95% confidence interval: 14.0-15.3] and absolute rate reduction 7/100 person-years. The rates of TTP in the reference and target cohorts were 1.66/100 and 1.61/100 person-years, respectively. The relative rate reduction was 3.6% (0.7-6.5). CONCLUSIONS: Antimicrobial use and TTP procedures reduced in unvaccinated children after PCV10 introduction in infants. These indirect effects contribute to the savings in health care resource use for otitis and may also help in combating antimicrobial resistance.

Effectiveness of 10-valent pneumococcal conjugate vaccine estimated with three parallel study designs among vaccine-eligible children in Finland.

BACKGROUND: Ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in 9/2010. We estimated the individual-level effectiveness (VE) of PCV10 in children during eight years of vaccine implementation. METHODS: Data on invasive pneumococcal disease (IPD) were collected from national, population-based surveillance, and vaccination status from the vaccination register. Vaccine-eligible children were followed from six months of age until end of 2018 (born 6/2010 or later, ages 6-102 months). VE was estimated with three parallel approaches: full cohort, nested case-control and indirect cohort designs adjusting with age-group, sex and calendar year. RESULTS: VE against PCV10 serotype IPD was estimated at 93% (95% credible interval 87-97%), 98% (90-100%) and 100% (98-100%), and against PCV10-related serotypes at 46% (-13-72%), 51% (-24-79%), and 78% (-7-97%), with the full cohort, nested case-control, and indirect cohort designs, respectively. The estimated VE against non-PCV10-related (neither PCV10 nor PCV10-related) serotypes was negative but included zero effectiveness (full cohort VE -67%, -711-52%; nested case-control VE -77%, -929-59%). VE against all IPD was estimated with these two methods at 54% (24-71%) and 61% (26-79%). Over time, VE against PCV10 IPD remained stable but VE against all IPD decreased. DISCUSSION: All designs provided estimates that were concordant with each other, but those with the full cohort design were usually the most precise. PCV10 offered sustained high VE against PCV10-serotype IPD on vaccinated children during the first decade after introduction into the programme.

Effect of childhood pneumococcal conjugate vaccination on invasive disease in older adults of 10 European countries: implications for adult vaccination.

BACKGROUND: Pneumococcal conjugate vaccines (PCVs) have the potential to prevent pneumococcal disease through direct and indirect protection. This multicentre European study estimated the indirect effects of 5-year childhood PCV10 and/or PCV13 programmes on invasive pneumococcal disease (IPD) in older adults across 13 sites in 10 European countries, to support decision-making on pneumococcal vaccination policies. METHODS: For each site we calculated IPD incidence rate ratios (IRR) in people aged ≥65 years by serotype for each PCV10/13 year (2011-2015) compared with 2009 (pre-PCV10/13). We calculated pooled IRR and 95% CI using random-effects meta-analysis and PCV10/13 effect as (1 - IRR)*100. RESULTS: After five PCV10/13 years, the incidence of IPD caused by all types, PCV7 and additional PCV13 serotypes declined 9% (95% CI -4% to 19%), 77% (95% CI 67% to 84%) and 38% (95% CI 19% to 53%), respectively, while the incidence of non-PCV13 serotypes increased 63% (95% CI 39% to 91%). The incidence of serotypes included in PCV13 and not in PCV10 decreased 37% (95% CI 22% to 50%) in six PCV13 sites and increased by 50% (95% CI -8% to 146%) in the four sites using PCV10 (alone or with PCV13). In 2015, PCV13 serotypes represented 20-29% and 32-53% of IPD cases in PCV13 and PCV10 sites, respectively. CONCLUSION: Overall IPD incidence in older adults decreased moderately after five childhood PCV10/13 years in 13 European sites. Large declines in PCV10/13 serotype IPD, due to the indirect effect of childhood vaccination, were countered by increases in non-PCV13 IPD, but these declines varied according to the childhood vaccine used. Decision-making on pneumococcal vaccination for older adults must consider the indirect effects of childhood PCV programmes. Sustained monitoring of IPD epidemiology is imperative.

Register-Based Ecologic Evaluation of Safety Signals Related to Pneumococcal Conjugate Vaccine in Children.

BACKGROUND: In clinical trials of Pneumococcal Conjugate Vaccines (PCV), some adverse events have been reported more frequently in the PCV vaccinated. Ten-valent PCV (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. OBJECTIVE: We conducted an ecologic register-based study to investigate further the reported adverse events after PCV. METHODS: This study included data obtained from the Finnish nationwide, population-based registers. First diagnoses of febrile seizures, breath-holding, urticarial rash, asthma and Kawasaki's disease were included as outcomes obtained from the hospital discharge register. Data from Finnish Population Register during 2000-2014 for children age from 3 months to 10 years were used to estimate annual incidence rates. Incidence rate ratios of the outcomes were calculated between the target cohort of children eligible for PCV10 during 2010-2014 and a reference cohort before the NVP introduction (2004-2008). RESULTS: No increases in the incidence of the adverse events after PCV10 introduction were found except for urticarial rash (incidence rate 2.48 vs. 1.60/1000 pyrs; incidence rate ratio, 1.54;95% CI 1.42-1.67). This increase was seen also in the unvaccinated older age groups in the post-vaccination era. The higher incidence of urticarial rash after the PCV10 introduction was due to the inclusion of diagnoses made in general medicine specialty in the discharge register because of a concomitant administrative change. CONCLUSION: The results do not support public health concerns related to the previously reported adverse events. Concomitant changes in health care administration and coding introduced bias, which was controlled after further evaluation of the data. We consider this register-based approach with realworld data feasible in the signal validation process after any signal detection.

Vaccine-preventable disease incidence of pneumococcal conjugate vaccine in the Finnish invasive pneumococcal disease vaccine trial.

Estimation of the full disease burden caused by Streptococcus pneumoniae is challenging due to the difficulties in assigning the aetiology especially in lower and upper respiratory infections. We estimated the pneumococcal disease burden by using the vaccine-preventable disease incidence (VPDI) of PHiD-CV10 vaccine (GSK) in our clinical trial setting. Finnish Invasive Pneumococcal disease (FinIP) trial was a cluster-randomized, double-blind trial in children <19 months who received PHiD-CV10 in 52 clusters or hepatitis B/A vaccine as control in 26 clusters according to 3+1 or 2+1 schedules (infants < 7 months) or catch-up schedules (children 7-18 months). Outcome data were collected using Finnish routine health-care registers, consisting of THL National Infectious Diseases Register, THL Care register, and Benefits Register of Social Insurance Institution of Finland. Blinded follow-up lasted from the date of first vaccination (trial enrolment Feb-2009 through Aug-2010) to January 31, 2012 for Invasive Pneumococcal Disease (IPD) and to end of December 2011 for four other outcomes: non-laboratory-confirmed IPD, hospital-diagnosed pneumonia, tympanostomy tube placements, and antimicrobial purchases. VPDI was estimated as difference in disease incidences between PHiD-CV10 clusters and control clusters. Altogether >47,000 children were enrolled. In 30,527 vaccinated infants <7 months at first dose, the VPDIs per 100,000 person-years were 75 for laboratory-confirmed IPD, 210 for non-laboratory-confirmed IPD, 271 for hospital-diagnosed pneumonia, 1143 for any tympanostomy tube placements and 11,381 for antimicrobial outpatient prescription, mainly due to otitis media. In a European developed-country setting, over 95% of the disease episode reductions in vaccinated children were seen in mild upper respiratory infections. The VPDIs of severe diseases are underestimated, because the majority of invasive disease goes undetected with routine blood-culture-based definitions. Evaluation of the absolute reduction achievable with vaccinations using sensitive case detection is essential for understanding the full disease burden, for valid cost-effectiveness analyses and for appropriate vaccination policy decisions. Registration: ClinicalTrials.gov, NCT00861380 and NCT00839254.

Long-term impact of 10-valent pneumococcal conjugate vaccination on invasive pneumococcal disease among children in Finland.

BACKGROUND: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. The impact of PCV10 vaccination against invasive pneumococcal disease (IPD) in vaccine-eligible children has been high. We evaluated the long-term impact of PCV10 vaccination against IPD in vaccine-eligible and older, unvaccinated children six years after PCV10 introduction with a special focus on cross-protection against PCV10-related serotypes (serotypes in the same serogroups as the PCV10 types). METHODS: We used data on IPD from the national, population-based surveillance. A target cohort of vaccine-eligible children (born June 2010 or later) was followed from 3 months of age until the end of 2016. For the indirect effect, another cohort of older PCV10-ineligible children was followed from 2012 through 2016. IPD rates were compared with those of season- and age-matched reference cohorts before NVP introduction. RESULTS: Among vaccine-eligible children, the incidence of all IPD decreased by 79% (95% CI 74-83%). There was a statistically significant reduction in the incidence of 6A IPD, but for 19A, the reduction was non-significant and the incidence of 19A increased towards the end of the study period in the older vaccine-eligible children. The increase in non-PCV10 related serotypes was non-significant. In the unvaccinated older children, the incidence of all IPD decreased by 33% (95% CI 8-52%) compared to the reference cohort, and there was no impact on serotype 6A or 19A IPD. CONCLUSION: Overall, the impact of PCV10 vaccination on IPD was high in vaccine-eligible children, with a major reduction in vaccine-type disease, and without notable replacement by other serotype groups. Our data suggest that PCV10 results in long-lasting direct cross-protection against 6A IPD. For 19A, no net reduction was observed six years after NVP introduction in the vaccine-eligible cohort. The indirect impact on IPD in unvaccinated children sustained.

Impact of National Ten-Valent Pneumococcal Conjugate Vaccine Program on Reducing Antimicrobial Use and Tympanostomy Tube Placements in Finland.

BACKGROUND: Otitis media in young children is associated with major resource use including antimicrobial consumption and tympanostomy tube placements (TTPs). We evaluated the impact of 10-valent pneumococcal conjugate vaccine (PCV10) introduction into the Finnish National Vaccination Programme (NVP) against these outcomes in vaccine-eligible children. METHODS: PCV10-NVP began September 2010 with a 2 + 1 schedule; uptake in 2012 was estimated at 92%. The relative and absolute reduction in the NVP-eligible target cohort was compared with a season and age-matched (3-54 months) cohort before NVP introduction. Outpatient antimicrobial purchase data were collected from the Social Insurance Institution register. Data on purchases of antimicrobials recommended for treatment of acute otitis media by the Finnish Current Care Guidelines (amoxicillin with/without enzyme inhibitor, cefuroxime, cefaclor, clarithromycin, azithromycin) were collected, but full data on penicillin and sulfadiazine/trimethoprim were not available. Data on all TTP procedures were obtained from national hospital discharge register and Social Insurance Institution benefits register. Generalized Cox regression was used in the analysis. RESULTS: The incidence rates of antimicrobial purchases in the reference and target cohorts were 1.09 and 0.89 per person-year, respectively. The relative rate reduction was 17.5% (95% confidence interval: 17.0-18.1) and the absolute rate reduction 0.20 per person-year. The rates of TTP in the reference and target cohorts were 5.41/100 and 4.56/100 person-years, respectively. The relative rate reduction was 14.8% (95% confidence interval: 13.1-16.5) and the absolute rate reduction 0.86/100 person-years. CONCLUSIONS: Use of antimicrobials and TTPs reduced after PCV10 was introduced into a routine vaccination program. This suggests considerable savings in health care resource use.

Population-level impact of infant 10-valent pneumococcal conjugate vaccination on adult pneumonia hospitalisations in Finland.

INTRODUCTION: Limited data are available on population-level herd effects of infant 10-valent pneumococcal conjugate vaccine (PCV10) programmes on pneumonia. We assessed national trends in pneumococcal and all-cause pneumonia hospitalisations in adults aged ≥18 years, before and after infant PCV10 introduction in 2010. METHODS: Monthly hospitalisation rates of International Statistical Classification of Diseases, 10th revision (ICD-10)-coded primary discharge diagnoses compatible with pneumonia from 2004-2005 to 2014-2015 were calculated with population denominators from the population register. Trends in pneumonia before and after PCV10 introduction were assessed with interrupted time-series analysis. Rates during the PCV10 period were estimated from adjusted negative binomial regression model and compared with those projected as continuation of the pre-PCV10 trend. All-cause hospitalisations were assessed for control purposes. RESULTS: Before PCV10, the all-cause pneumonia rate in adults aged ≥18 years increased annually by 2.4%, followed by a 4.7% annual decline during the PCV10 period. In 2014-2015, the overall all-cause pneumonia hospitalisation rate was 109.3/100 000 (95% CI 96.5 to 121.9) or 15.4% lower than the expected rate. A significant 6.7% decline was seen in persons aged ≥65 years (131.5/100 000), which translates to 1456 fewer pneumonia hospitalisations annually. In comparison, hospitalisations other than pneumonia decreased by 3.5% annually throughout the entire study period. CONCLUSION: These national data suggest that herd protection from infant PCV10 programme has reversed the increasing trend and substantially decreased all-cause pneumonia hospitalisations in adults, particularly the elderly.

Impact of ten-valent pneumococcal conjugate vaccine on pneumonia in Finnish children in a nation-wide population-based study.

BACKGROUND: The ten-valent pneumococcal conjugate vaccine (PCV10) was introduced into the Finnish National Vaccination Program (NVP) in September 2010 using a 2+1 schedule (3, 5, 12 months). We estimated the direct and indirect effects of PCV10 on pneumonia among children to evaluate the public health impact of the vaccine. METHODS: We conducted a nation-wide population-based, observational study comparing rates of pneumonia in children before and after the NVP introduction. For the total (direct and indirect) effect, the cohort of vaccine-eligible children (born June 1, 2010 or later) was followed until the end of 2013 (age range 3-42 months). For the indirect effect, a cohort of older children (age range 7-71 months) not eligible for the PCV vaccination was followed from 2011 to 2013. Both cohorts were compared with two season- and age-matched reference cohorts before NVP introduction. Hospitals' in- and outpatient discharge notifications with ICD-10 diagnoses compatible with pneumonia (J10.0, J11.0, J12-J18, J85.1 or J86) as set by the hospital pediatricians were collected from the national Care Register. The main outcome was hospital-treated primary pneumonia (HTPP), defined as primary diagnosis of pneumonia after in-patient hospitalization. We compared rates of pneumonia in the NVP target and reference cohorts by using Poisson regression models. RESULTS: The rate of HTPP episodes was 5.3/1000 person-years in the combined reference cohorts and 4.1/1000 person-years in the target cohort vaccine-eligible children. Compared with the reference cohort, the relative rate reduction in target cohort was 23% (95%CI 18-28) and the absolute reduction 1.3/1000 person-years. In the indirect effect evaluation, we observed continued increase in HTPP incidence until 2011 with a subsequent reduction of 18% (95%CI 10-25) during years 2012 to 2013. Number of empyema diagnoses remained low. CONCLUSIONS: A substantial decrease in pneumonia rates was observed both among vaccine-eligible children and among older, unvaccinated children after PCV10 introduction.

Effectiveness of the Ten-valent Pneumococcal Conjugate Vaccine Against Tympanostomy Tube Placements in a Cluster-randomized Trial.

BACKGROUND: We evaluated the impact of the new pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10, GSK Vaccines) on tympanostomy tube placements (TTPs). METHODS: Finnish Invasive Pneumococcal disease vaccine trial was a nationwide phase III/IV cluster-randomized, double-blind trial. Children younger than 19 months received PHiD-CV10 in two thirds of clusters (N = 52) or hepatitis B or A vaccine as control in 26 clusters according to 3 + 1 or 2 + 1 schedules (infants younger than 7 months) or catch-up schedules. A secondary objective of the trial was to assess vaccine effectiveness (VE) against TTPs in children who received at least one vaccine dose before or after 7 months of age. Blinded follow-up lasted from the date of first vaccination (from February 2009 through October 2010) to December 31, 2011. Outcome data were collected through the National Care register and Social Insurance Institution reimbursement register. RESULTS: More than 47,000 children were enrolled. In 30,527 infants younger than 7 months of age at enrolment, 4369 TTPs were reported in 3594 subjects. The incidence was 7.9 per 100 person-years in the infant control cohort. The VE estimate was 13% [95% confidence interval (CI): -2% to 26%] for combined PHiD-CV10 3 + 1 and 2 + 1 infant schedules. The VE estimates for the 3 + 1 and 2 + 1 infant schedules when estimated separately were similar. For the catch-up schedules, the VE was 11% (95% CI: -7% to 26%) for children enrolled at 7-11 months of age and -1% (95% CI: -21% to 16%) for children enrolled at 12-18 months of age. CONCLUSIONS: Our study results suggest that PHiD-CV10 immunization according to a 3 + 1 or 2 + 1 schedule initiated before 12 months of age may reduce the frequency of TTPs, although the primary analysis did not reach statistical significance.

Pneumococcal Conjugate Vaccine and Clinically Suspected Invasive Pneumococcal Disease.

OBJECTIVE: Ten-valent pneumococcal conjugate vaccine (PCV10) was earlier shown to reduce clinically suspected, non-laboratory-confirmed invasive pneumococcal disease (IPD) in a cluster-randomized trial (the Finnish Invasive Pneumococcal disease trial). PCV10 was introduced into the Finnish national vaccination program in September 2010 using a 3-dose schedule. We evaluated the impact of PCV10 on clinically suspected IPD among vaccine-eligible children in a population-based nationwide study. METHODS: The target cohort eligible for vaccination program (children born June 2010-September 2013) was compared with 2 season- and age-matched (ages 3-42 months) reference cohorts before PCV10 introduction. The trial period (January 2009-August 2010) was excluded. Hospitals' inpatient and outpatient discharge notifications with International Classification of Diseases, 10th Revision, diagnoses compatible with IPD (A40.3/B95.3/G00.1/M00.1) and unspecified sepsis (A40.9/A41.9/A49.9/G00/G00.9/I30.1/M00/M00.9/B95.5) were collected from the national Care Register. Laboratory-confirmed IPD cases were excluded. Rates of register-based non-laboratory-confirmed IPD (or unspecified sepsis) before and after PCV10 implementation were calculated. RESULTS: The rate of register-based non-laboratory-confirmed IPD episodes was 32 in 100 000 person-years in the vaccine-eligible target cohort and 94 in the combined reference cohorts. Relative rate reduction was 66% (95% confidence interval: 59-73) and absolute rate reduction 62 in 100 000 person-years. For the more sensitive case definition of register-based non-laboratory-confirmed IPD or unspecified sepsis, the relative rate reduction was 34% (95% confidence interval 29-39), but the absolute reduction was as high as 122 in 100 000 person-years. CONCLUSIONS: This is the first report demonstrating nationwide PCV impact on clinically suspected IPD during routine vaccination program. The large absolute rate reductions observed have major implications for cost-effectiveness of PCVs.