High-Dose Quadrivalent Influenza Vaccine for Prevention of Cardiovascular and Respiratory Hospitalizations in Older Adults.

BACKGROUND: We assessed the relative vaccine effectiveness (rVE) of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) in preventing respiratory or cardiovascular hospitalizations in older adults. METHODS: FinFluHD was a phase 3b/4 modified double-blind, randomized pragmatic trial. Enrolment of 121,000 adults ≥65 years was planned over three influenza seasons (October to December 2019-2021). Participants received a single injection of QIV-HD or QIV-SD. The primary endpoint was first occurrence of an unscheduled acute respiratory or cardiovascular hospitalization (ICD-10 primary discharge J/I codes), from ≥14 days post-vaccination until May 31. The study was terminated after one season due to COVID-19; follow-up data for 2019-2020 are presented. RESULTS: 33,093 participants were vaccinated (QIV-HD, n = 16,549; QIV-SD, n = 16,544); 529 respiratory or cardiovascular hospitalizations (QIV-HD, n = 257; QIV-SD, n = 272) were recorded. The rVE of QIV-HD versus QIV-SD to prevent respiratory/cardiovascular hospitalizations was 5.5% (95% CI, -12.4 to 20.7). When prevention of respiratory and cardiovascular hospitalizations were considered separately, rVE estimates of QIV-HD versus QIV-SD were 5.4% (95% CI, -28.0 to 30.1) and 7.1% (95% CI, -15.0 to 25.0), respectively. Serious adverse reactions were <0.01% in both groups. CONCLUSIONS: Despite insufficient statistical power due to the impact of COVID-19, rVE point estimates demonstrated a trend toward a benefit of QIV-HD over QIV-SD. QIV-HD was associated with lower respiratory or cardiovascular hospitalization rates than QIV-SD, with a comparable safety profile. Adequately powered studies conducted over multiple influenza seasons are needed to determine statistical significance of QIV-HD compared with QIV-SD against preventing respiratory and cardiovascular hospitalizations. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT04137887.

Underreporting of SARS-CoV-2 infections during the first wave of the 2020 COVID-19 epidemic in Finland-Bayesian inference based on a series of serological surveys.

In Finland, the first wave of the COVID-19 epidemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) took place from March to June 2020, with the majority of COVID-19 cases diagnosed in the Helsinki-Uusimaa region. The magnitude and trend in the incidence of COVID-19 is one way to monitor the course of the epidemic. The diagnosed COVID-19 cases are a subset of the infections and therefore the COVID-19 incidence underestimates the SARS-CoV-2 incidence. The likelihood that an individual with SARS-CoV-2 infection is diagnosed with COVID-19 depends on the clinical manifestation as well as the infection testing policy and capacity. These factors may fluctuate over time and the underreporting of infections changes accordingly. Quantifying the extent of underreporting allows the assessment of the true incidence of infection. To obtain information on the incidence of SARS-CoV-2 infection in Finland, a series of serological surveys was initiated in April 2020. We develop a Bayesian inference approach and apply it to data from the serological surveys, registered COVID-19 cases, and external data on antibody development, to estimate the time-dependent underreporting of SARS-Cov-2 infections during the first wave of the COVID-19 epidemic in Finland. During the entire first wave, there were 1 to 5 (95% probability) SARS-CoV-2 infections for every COVID-19 case. The underreporting was highest before April when there were 4 to 17 (95% probability) infections for every COVID-19 case. It is likely that between 0.5%-1.0% (50% probability) and no more than 1.5% (95% probability) of the adult population in the Helsinki-Uusimaa region were infected with SARS-CoV-2 by the beginning of July 2020.

Incidence of sinus thrombosis with thrombocytopenia-A nation-wide register study.

Safe vaccination is essential for mitigation of the COVID-19 pandemic. Two adenoviral vector vaccines, ChAdOx1 nCov-19 (AstraZeneca) and Ad26.COV2.S (Johnson&Johnson/Janssen) have shown to be effective and they are distributed globally, but reports on serious cerebral venous sinus thrombosis (CVST) associated with thrombocytopenia, have emerged. Our objective was to evaluate the background incidence of CVST with thrombocytopenia and to compare it to incidences following COVID-19 vaccines. We conducted a register-based nation-wide cohort study in Finland, including all 5.5 million individuals alive in Finland, 1 Jan 2020. COVID-19 vaccinations registered in the National Vaccination Register served as the exposure. We detected CVST admissions or hospital visits recorded in the hospital discharge register from Jan 1, 2020 through April 2, 2021. We confirmed the diagnosis of CVST and thrombocytopenia (platelet count <150,000 per cubic millimeter) using radiology reports and laboratory data. By Poisson regression, we compared the baseline incidences to the risks within four weeks after COVID-19 vaccinations. Out of the 167 CVST episodes identified in the registers, 117 were confirmed as CVST, 18 of which coincided with thrombocytopenia (baseline incidence 0.18 per 28 days per million persons). We found 2 episodes of CVST with thrombocytopenia within 28 days of the first ChAdOx1 nCov-19 vaccination (among 200,397 vaccinated, aged 16 or above). No cases were found following the first mRNA vaccine dose among 782,604 vaccinated. The background incidence of CVST combined with thrombocytopenia was minuscule compared to the incidence during the weeks following the ChAdOx1 nCov-19 vaccination. Accurate estimation of the baseline incidence is essential in the critical appraisal of the benefit-risk of any vaccination program.

Pneumococcal vaccine schedules (PVS) study: a cluster-randomised, non-inferiority trial of an alternative versus standard schedule for pneumococcal conjugate vaccination-statistical analysis plan.

RATIONALE: The effectiveness of universal immunisation with pneumococcal conjugate vaccine (PCV) has been evident in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in several countries. Reducing the cost of PCV programmes may facilitate vaccine introduction in some countries and improve the sustainability of PCV in EPIs in low-income countries when they transition away from subsidised vaccine supply. METHODS AND DESIGN: PVS is a real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative '1+1' schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard '3+0' schedule). Delivery of the interventions began in late 2019 in 68 geographic clusters and will continue for 4 years. The primary endpoint is the prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2-260 weeks with clinical pneumonia in year 4. Secondary endpoints are the prevalence of vaccine-type pneumococcal carriage among all ages in year 4 and the incidence of radiological pneumonia in children enrolled to receive the interventions. Additional disease and carriage endpoints are included. PURPOSE: This statistical analysis plan (SAP) describes the cohorts and populations, and follow-up criteria, to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe how analyses will account for the effect of clustering and stratified randomisation. The SAP defines the approach to non-inferiority and other analyses. Defining the SAP early in the trial will avoid bias in analyses that may arise from prior knowledge of trial findings.

A cluster-randomised, non-inferiority trial of the impact of a two-dose compared to three-dose schedule of pneumococcal conjugate vaccination in rural Gambia: the PVS trial.

BACKGROUND: Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by the cost of PCV. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where PCV has been introduced with good disease control but where transmission of vaccine-type pneumococci persists. We are conducting a large cluster-randomised, non-inferiority, field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. METHODS: PVS is a prospective, cluster-randomised, non-inferiority, real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative '1 + 1' schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard '3 + 0' schedule). The intervention will be delivered for 4 years. The primary endpoint is the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2 weeks to 59 months with clinical pneumonia in year 4 of the trial. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoint will be masked. Sixty-eight geographic population clusters have been randomly allocated, in a 1:1 ratio, to each schedule and all resident infants are eligible for enrolment. All resident children less than 5 years of age are under continuous surveillance for clinical safety endpoints measured at 11 health facilities; invasive pneumococcal disease, radiological pneumonia, clinical pneumonia, and hospitalisations. Secondary endpoints include the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in years 2 and 4 and vaccine-type carriage prevalence in unimmunised infants aged 6-12 weeks in year 4. The trial includes components of mathematical modelling, health economics, and health systems research. DISCUSSION: Analysis will account for potential non-independence of measurements by cluster, comparing the population-level impact of the two schedules with interpretation at the individual level. The non-inferiority margin is informed by the 'acceptable loss of effect' of the alternative compared to the standard schedule. The secondary endpoints will provide substantial evidence to support the interpretation of the primary endpoint. PVS will evaluate the effect of transition from a standard 3+ 0 schedule to an alternative 1 + 1 schedule in a setting of high pneumococcal transmission. The results of PVS will inform global decision-making concerning the use of reduced-dose PCV schedules. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number 15056916 . Registered on 15 November 2018.

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.

Effectiveness of the quadrivalent high-dose influenza vaccine for prevention of cardiovascular and respiratory events in people aged 65 years and above: Rationale and design of a real-world pragmatic randomized clinical trial.

BACKGROUND: Influenza has been an acknowledged cause of respiratory disease for decades. However, considerable related, and often unappreciated, disease burden stems from cardiovascular complications, exacerbations of underlying medical conditions and secondary respiratory complications, with the highest burden in the elderly. This novel study combines the gold standard method of a randomized controlled trial with real-world data collection through national registries, to assess the relative effectiveness of high-dose (QIV-HD) vs standard-dose quadrivalent influenza vaccine (QIV-SD) in preventing cardio-respiratory hospitalizations in a large cohort of adults aged ≥65 years. METHODS AND RESULTS: This trial (NCT04137887) is a Phase III/IV, modified double-blinded, randomized, registry-based trial, conducted by the Finnish Institute for Health and Welfare (THL). Participants (n>120 000) are being enrolled over multiple influenza seasons and randomized (1:1) to receive QIV-HD or QIV-SD. Participant follow-up is based on data collection up to 11 months post-vaccination using Finnish national health registries. The primary objective is to demonstrate the relative superior effectiveness of QIV-HD over QIV-SD in preventing cardio-respiratory hospitalizations up to 6 months post-vaccination. Safety will be assessed using automated online tools throughout the study, with causality assessed using statistical and probabilistic methods; serious adverse reactions and adverse events of special interest will be investigated individually. CONCLUSION: This large, real-world, randomized study will provide valuable insight into the contribution of influenza in causing severe cardio-respiratory events, and the role of vaccination with QIV-HD in reducing these outcomes compared to the current standard of care. FUNDING: Sanofi Pasteur.

Cohort study design for estimating the effectiveness of seasonal influenza vaccines in real time based on register data: The Finnish example.

This paper presents the principles of implementing register-based cohort studies as currently applied for real-time estimation of influenza vaccine effectiveness in Finland. All required information is retrieved from computerised national registers and deterministically linked via the unique personal identity code assigned to each Finnish resident. The study cohorts comprise large subpopulations eligible for a free seasonal influenza vaccination as part of the National Vaccination Programme. The primary outcome is laboratory-confirmed influenza. Each study subject is taken to be at risk of experiencing the outcome from the onset of the influenza season until the first of the following three events occurs: outcome, loss to follow up or end of season. Seasonal influenza vaccination is viewed as time-dependent exposure. Accordingly, each subject may contribute unvaccinated and vaccinated person-time during their time at risk. The vaccine effectiveness is estimated as one minus the influenza incidence rate ratio comparing the vaccinated with the unvaccinated within the study cohorts. Data collection in register-based research is an almost fully automated process. The effort, resources and the time spent in the field are relatively small compared to other observational study designs. This advantage is pivotal when vaccine effectiveness estimates are needed in real time. The paper outlines possible limitations of register-based cohort studies. It also addresses the need to explore how national and subnational registers available in the Nordic countries and elsewhere can be utilised in vaccine effectiveness research to guide decision making and to improve individual health as well as public health.

Culture of all sputum samples irrespective of quality adds value to the diagnosis of pneumococcal community-acquired pneumonia in the elderly.

Culture of expectorated sputum in the microbiological diagnosis of community-acquired pneumonia (CAP) is considered valid only if high-quality (HQ) samples are obtained, but evidence regarding pneumococcal etiology specifically is lacking. We studied 323 radiologically confirmed CAP cases in patients aged ≥ 65 years. Sputum samples were assessed for quality microscopically and cultured. Two quality criteria sets were applied to delineate HQ from low-quality (LQ) sputa: leukocytes/epithelial cells ratio > 5 and ≤ 2.5 epithelial cells/400× magnification field (HQ1), or leukocytes/epithelial cells ratio > 1 (HQ2). A sputum sample was obtained and the quality assessed in 224 cases; 47% were HQ1 and 76% HQ2. Encapsulated pneumococci (EPnc) were cultured in 25 (24%), 14 (12%), 35 (21%), and 4 (7%) of the HQ1-, LQ1-, HQ2-, and LQ2-samples, respectively. If another pneumococcal test (blood culture, urine antigen, or ≥ twofold increase in CbpA or PsaA antibodies) was positive, EPnc were cultured at similar proportions in HQ1- and LQ1-sputa; if the other test was negative, EPnc were cultured less often in LQ1- than HQ1-sputa. EPnc were found less often in LQ2- than in HQ2-sputa. Our results suggest similar specificity in LQ- and HQ-sputum cultures. All sputum samples add value to the pneumococcal CAP-diagnosis in the elderly.

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.

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.

Testing Pneumonia Vaccines in the Elderly: Determining a Case Definition for Pneumococcal Pneumonia in the Absence of a Gold Standard.

Clinical assessments of vaccines to prevent pneumococcal community-acquired pneumonia (CAP) require sensitive and specific case definitions, but there is no gold standard diagnostic test. To develop a new case definition suitable for vaccine efficacy studies, we applied latent class analysis (LCA) to the results from 7 diagnostic tests for pneumococcal etiology on clinical specimens from 323 elderly persons with radiologically confirmed pneumonia enrolled in the Finnish Community-Acquired Pneumonia Epidemiology study during 2005-2007. Compared with the conventional use of LCA, which is mainly to determine sensitivities and specificities of different tests, we instead used LCA as an appropriate instrument to predict the probability of pneumococcal etiology for each CAP case based on individual test profiles, and we used the predictions to minimize the sample size that would be needed for a vaccine efficacy trial. When compared with the conventional laboratory criteria of encapsulated pneumococci in culture, in blood culture or high-quality sputum culture, or urine antigen positivity, our optimized case definition for pneumococcal CAP resulted in a trial sample size that was almost 20,000 subjects smaller. We believe that the novel application of LCA detailed here to determine a case definition for pneumococcal CAP could also be similarly applied to other diseases without a gold standard.

lytA Quantitative PCR on Sputum and Nasopharyngeal Swab Samples for Detection of Pneumococcal Pneumonia among the Elderly.

Real-time quantitative PCR (qPCR) assay of sputum or nasopharyngeal specimens has shown promising results in the detection of pneumococcal community-acquired pneumonia (PncCAP). We applied qPCR for the autolysin gene (lytA) and compared sputum and nasopharyngeal swab (NPS) pneumococcal loads in elderly patients with community-acquired pneumonia (CAP), and specifically in patients with PncCAP, to those in patient groups with other respiratory diseases. We studied patients aged ≥65 years with radiologically confirmed CAP, clinical CAP not retrospectively radiologically confirmed, other acute respiratory infections, or stable chronic lung disease. Pneumococcal etiology of CAP was ascertained by using a combination of multiple diagnostic methods. We analyzed sputum and NPS specimens by lytA qPCR with 104 pneumococcal genome equivalents (GE)/ml as a cutoff for positivity. Among PncCAP patients, lytA qPCR detected pneumococci in 94% of the sputum samples and in large quantities (mean, 6.82 ± 1.02 log10 GE/ml) but less frequently in NPS (44%) and in smaller quantities (5.55 ± 0.92 log10 GE/ml). In all other patient groups, ≤10% of the sputum samples and <5% of the NPS samples were lytA qPCR positive; but when they were positive, the sputum pneumococcal loads were similar to those in the PncCAP patients, suggesting a pneumococcal etiology in these patients. This was supported by other pneumococcal assay results. Overall, sputum lytA qPCR positivity was more common in PncCAP patients than in the other patient groups, but the quantitative results were mainly similar. NPS lytA qPCR was less sensitive than sputum lytA qPCR in detecting PncCAP.

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.

The MATEX cohort - a Finnish population register birth cohort to study health effects of prenatal exposures.

BACKGROUND: The prevalence of chronic diseases, such as immune, neurobehavioral, and metabolic disorders has increased in recent decades. According to the concept of Developmental Origin of Health and Disease (DOHaD), developmental factors associated with environmental exposures and maternal lifestyle choices may partly explain the observed increase. Register-based epidemiology is a prime tool to investigate the effects of prenatal exposures over the whole life course. Our aim is to establish a Finnish register-based birth cohort, which can be used to investigate various (prenatal) exposures and their effects during the whole life course with first analyses focusing on maternal smoking and air pollution. In this paper we (i) review previous studies to identify knowledge gaps and overlaps available for cross-validation, (ii) lay out the MATEX study plan for register linkages, and (iii) analyse the study power of the baseline MATEX cohort for selected endpoints identified from the international literature. METHODS/DESIGN: The MATEX cohort is a fully register-based cohort identified from the Finnish Medical Birth Register (MBR) (1987-2015). Information from the MBR will be linked with other Finnish health registers and the population register to link the cohort with air quality data. Epidemiological analyses will be conducted for maternal smoking and air pollution and a range of health endpoints. DISCUSSION: The MATEX cohort consists of 1.75 million mother-child pairs with a maximum follow up time of 29 years. This makes the cohort big enough to reach sufficient statistical power to investigate rare outcomes, such as birth anomalies, childhood cancers, and sudden infant death syndrome (SIDS). The linkage between different registers allows for an extension of the scope of the cohort and a follow up from the prenatal period to decades later in life.

Direct and Indirect Effectiveness of the 10-Valent Pneumococcal Conjugate Vaccine Against Carriage in a Cluster Randomized Trial.

Finnish invasive pneumococcal disease (FinIP) vaccine trial was designed to evaluate effectiveness of 10-valent pneumococcal conjugate vaccine (PHiD-CV10; GSK; Rixensart, Belgium). We conducted 2 satellite studies to evaluate ten-valent Pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) effectiveness against pneumococcal carriage in FinIP-vaccinated children (long-term direct and indirect effectiveness combined) and in their unvaccinated siblings (indirect effectiveness within the family). FinIP was a cluster randomized trial, where >47,000 children <19 months of age were recruited in 2009-2010. Children received PHiD-CV10 in 2/3, and control vaccine in 1/3 of clusters according to age-specific infant and catch-up schedules. We obtained nasopharyngeal samples from subgroups of FinIP-vaccinated children at 3-5 years of age in 2013 and their unvaccinated older siblings in 2011 and 2013, and compared carriage in PHiD-CV10 clusters to control clusters in parallel. National Vaccination Programme with PHiD-CV10 for all 3-month-old children started in 2010 resulting in 92% vaccination coverage. To investigate indirect effects, over 2200 nasopharyngeal swabs were obtained during each round from unvaccinated older siblings. In 2011, we observed a 29% (95% confidence interval: 6-47) reduction in vaccine-type carriage in siblings of PHiD-CV10 participants vaccinated according to infant schedules. Vaccine-type carriage prevalences were low with no differences observed in 2013, 3 years after PHiD-CV10 introduction. For estimation of combined direct and indirect effectiveness, 1550 swabs from FinIP-vaccinated children were obtained in 2013. We observed a reduction of 54% (95% confidence interval: 34-68) in vaccine-type carriage in PHiD-CV10-vaccinated children. This study was the first randomized trial to show the indirect effect of extended valency pneumococcal conjugate vaccination on carriage. Also, long-term effectiveness against vaccine-type carriage was demonstrated in vaccinated children.

Establishing and maintaining the National Vaccination Register in Finland.

Computerised, population-based vaccination registers are valuable tools for assessing the vaccine uptake and impact in populations. However, reliable impact assessment is only possible if the data quality can be reviewed and monitored continuously. This report describes the establishment and maintenance of the National Vaccination Register (NVR) in Finland. Currently, the NVR covers nationwide records of vaccinations given within the frame of the National Vaccination Programme since 2009. All vaccinations registered in the NVR contain a record of the personal identity code, the administered vaccine, and the date of vaccination. The vaccine lot number is the key component for recording and identifying vaccinations, because of its broad availability across patient information systems and its importance in vaccine safety monitoring. Vaccination records are accumulated and updated daily into the NVR, and their completeness is monitored monthly to assess deficiencies in data entry and data collection. Additionally, an alert system reports unexpected changes in data accumulation prompting the validation of observed changes in vaccination coverage. The presented process documentation may serve as basis to improve the design and quality of other vaccination or healthcare registers and aims to inspire the set-up of vaccination registers in those countries which still do not have one.

Rotavirus Vaccination and the Risk of Celiac Disease or Type 1 Diabetes in Finnish Children at Early Life.

BACKGROUND: Rotavirus infection has been suggested as a trigger of type 1 diabetes (T1D)-related autoimmunity and celiac disease (CD)-related autoimmunity. METHODS: We carried out a nationwide, population-based cohort study evaluating whether prevention of rotavirus infection with vaccination affects the risk of CD and T1D diagnosed during 2009-2014 in Finnish children by comparing vaccinated and unvaccinated children in a cohort born in 2009-2010. Nationwide rotavirus vaccination records were collected from healthcare databases during 2009-2011 and validated for a sample of 495 children born from July 2009 to December 2009. Incident diagnoses of CD and T1D during 2009-2014 in the cohort were identified in the National Care Register. RESULTS: The adjusted relative risks (with 95% confidence intervals) were 0.91 (0.69-1.20) for T1D and 0.87 (0.65-1.17) for CD in vaccinated children compared with unvaccinated, suggesting that oral rotavirus vaccination does not alter the risk of CD or T1D during 4-6 years follow-up after vaccination. CONCLUSIONS: Our results suggest that oral rotavirus vaccination is considered safe in the individuals at risk of CD and T1D.