Esa Ruokokoski

Contribution of trends in survival and coronary-event rates to changes in coronary heart disease mortality : 10-year results from 37 WHO MONICA Project populations

Summary Background The WHO MONICA (monitoring trends and determinants in cardiovascular disease) Project monitored, from the early 1980s, trends over 10 years in coronary heart disease (CHD) across 37 populations in 21 countries. We aimed to validate trends in mortality, partitioning responsibility between changing coronary-event rates and changing survival. Methods Registers identified non-fatal definite myocardial infarction and definite, possible, or unclassifiable coronary deaths in men and women aged 35–64 years, followed up for 28 days in or out of hospital. We calculated rates from population denominators to estimate trends in age-standardised rates and case fatality (percentage of 28-day fatalities=[100-survival percentage]). Findings During 371 population-years, 166 000 events were registered. Official CHD mortality rates, based on death certification, fell (annual changes: men −4·0% [range −10·8 to 3·2]; women −4·0% [-12·7 to 3·0]). By MONICA criteria, CHD mortality rates were higher, but fell less (-2·7% [-8·0 to 4·2] and −2·1% [-8·5 to 4·1]). Changes in non-fatal rates were smaller (-2·1%, [-6·9 to 2·8] and −0·8% [-9·8 to 6·8]). MONICA coronary-event rates (fatal and non-fatal combined) fell more (-2·1% [-6·5 to 2·8] and −1·4% [-6·7 to 2·8]) than case fatality (-0·6% [-4·2 to 3·1] and −0·8% [-4·8 to 2·9]). Contribution to changing CHD mortality varied, but in populations in which mortality decreased, coronary-event rates contributed two thirds and case fatality one third. Interpretation Over the decade studied, the 37 populations in the WHO MONICA Project showed substantial contributions from changes in survival, but the major determinant of decline in CHD mortality is whatever drives changing coronary-event rates.

Effectiveness of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against invasive pneumococcal disease: a cluster randomised trial

BACKGROUND The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was designed to assess the effectiveness of a pneumococcal vaccine containing ten serotype-specific polysaccharides conjugated to Haemophilus influenzae protein D, tetanus toxoid, and diphtheria toxoid as the carrier proteins (PHiD-CV10) against invasive pneumococcal disease. METHODS In this cluster-randomised, double-blind trial, children aged younger than 19 months received PHiD-CV10 in 52 clusters or hepatitis vaccines as control in 26 clusters. Infants aged younger than 7 months at the first vaccination received either a 3+1 or a 2+1 vaccination schedule, children aged 7-11 months received a 2+1 schedule, and those 12-18 months of age received a two-dose schedule. The primary and secondary objectives were to assess vaccine effectiveness against culture-confirmed invasive pneumococcal disease due to any of the ten vaccine serotypes for the 3+1 and 2+1 schedules, respectively, in children who received at least one PHiD-CV10 dose before 7 months of age. Masked follow-up of pneumococcal disease lasted from the first vaccination (from February, 2009, to October, 2010) to January 31, 2012. Invasive disease data were retrieved from data accumulated in the national infectious diseases register. This trial and the nested acute otitis media trial are registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254, respectively. FINDINGS 47,369 children were enrolled from February, 2009, to October, 2010. 30,528 participants were assessed for the primary objective. 13 culture-confirmed vaccine-type cases of invasive pneumococcal disease were detected: none in the PHiD-CV10 3+1 group, one in the PHiD-CV10 2+1 group, and 12 in the control groups. The estimates for vaccine effectiveness were 100% (95% CI 83-100) for PHiD-CV10 3+1 and 92% (58-100) for PHiD-CV10 2+1 groups. Two cases of any culture-confirmed invasive disease irrespective of serotype were detected in combined PHiD-CV10 infant cohorts compared with 14 in the corresponding control cohorts (vaccine effectiveness 93%, 75-99). In catch-up cohorts, seven cases of invasive disease were reported, all in the control group: two cases in the children enrolled at 7-11 months of age; and five cases in children enrolled at 12-18 months of age (vaccine effectiveness 100%, 79-100). Non-fatal serious adverse events suspected to be vaccine-related were reported via routine post-immunisation safety surveillance in 18 children. INTERPRETATION This nationwide trial showed high PHiD-CV10 effectiveness against invasive pneumococcal disease when given in different schedules. For the first time, effectiveness of a 2+1 schedule in infants was confirmed in a clinical trial. FUNDING GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare, Finland.

Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial

BACKGROUND Antimicrobial drugs are frequently prescribed to children for respiratory tract infections such as otitis, tonsillitis, sinusitis, and pneumonia. We assessed the effect of the ten-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10; GlaxoSmithKline) on antimicrobial purchases. METHODS In this nationwide phase 3-4 cluster-randomised, double-blind trial, children younger than 19 months were randomly assigned to receive PHiD-CV10 in 52 of 78 clusters or hepatitis B or A vaccine as control in 26 clusters according to three plus one or two plus one schedules (infants younger than 7 months) or catch-up schedules (children aged 7-18 months). The main objective for the antimicrobial treatment outcome was to assess vaccine effectiveness against outpatient prescriptions of antimicrobial drugs recommended by national treatment guidelines for acute otitis media in Finland in children who received at least one dose of study vaccine before 7 months of age. Masked follow-up lasted from the date of first vaccination (from Feb 18, 2009, through Oct 5, 2010) to Dec 31, 2011. We obtained data on all purchased antimicrobial prescriptions through the benefits register of the Social Insurance Institution of Finland. This and the nested acute otitis media trial are registered at ClinicalTrials.gov, numbers NCT00861380 and NCT00839254. FINDINGS More than 47,000 children were enrolled. In 30,527 infants younger than 7 months at enrollment, 98,436 outpatient antimicrobial purchases were reported with incidence of 1.69 per person-year in the control clusters. Analysis of the main objective included 91% of all antimicrobial purchases: 31,982 in the control and 57,964 in the PHiD-CV10 clusters. Vaccine effectiveness was 8% (95% CI 1-14) and the incidence rate difference 0.12 per person-year corresponding to the number needed to vaccinate of five (95% CI 3-67) to prevent one purchase during the 2 year follow-up for combined PHiD-CV10 three plus one and two plus one infant schedules. The vaccine effectiveness was identical for the two infant schedules. In the catch-up schedules, the vaccine effectiveness was 3% (95% CI -4 to 10). INTERPRETATION Despite low relative rate reductions the absolute rate reductions were substantial because of the high incidence of the outcome. This reduction would lead to over 12,000 fewer antimicrobial purchases per year in children younger than 24 months in Finland (birth cohort of 60,000 children).

Vaccine effectiveness of the pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) against clinically suspected invasive pneumococcal disease: a cluster-randomised trial

BACKGROUND Vaccine effectiveness of pneumococcal conjugate vaccines against culture-confirmed invasive pneumococcal disease has been well documented. In the Finnish Invasive Pneumococcal disease (FinIP) trial, we reported vaccine effectiveness and absolute rate reduction against laboratory-confirmed invasive pneumococcal disease (confirmation by culture or antigen or DNA detection irrespective of serotype). Here, we assessed vaccine effectiveness of PHiD-CV10 against clinically suspected invasive pneumococcal disease in children by use of diagnoses coded in hospital discharge registers. METHODS For this phase 3/4 cluster-randomised, double-blind trial, undertaken between Feb 18, 2009, and Dec 31, 2011, in municipal health-care centres and the Tampere University Vaccine Research Centre (Finland), we randomly assigned (2:2:1:1) 78 clusters into PHiD-CV10 three plus one, PHiD-CV10 two plus one, control three plus one, control two plus one groups (26:26:13:13 clusters) to give PHiD-CV10 in either three plus one or two plus one schedule (if enrolled before 7 months of age; infant schedules), two plus one (if enrolled between 7 and 11 months; catch-up schedules), and two doses at least 6 months apart (if enrolled between 12 and 18 months; catch-up schedules). Children were eligible if they had not received and were not anticipated to receive any of the study vaccines and had no general contraindications to vaccinations. We collected all inpatient and outpatient discharge notifications from the national hospital discharge register with International Classification of Diseases (ICD) 10 diagnoses compatible with invasive pneumococcal disease or unspecified sepsis, and verified data with patient files. We excluded invasive pneumococcal disease cases confirmed by positive culture or DNA/RNA detection from normally sterile body fluid. The primary objective was to estimate vaccine effectiveness against all register-based non-laboratory-confirmed invasive pneumococcal disease or unspecified sepsis and patient-file verified non-laboratory-confirmed invasive pneumococcal disease in infants younger than 7 months at enrolment. Masked follow-up lasted from the date of the first vaccination to Dec 31, 2011. Vaccine effectiveness was calculated against all episodes. This trial is registered with ClinicalTrials.gov, numbers NCT00861380 and NCT00839254. FINDINGS We enrolled 47,366 children. On the basis of ICD-10 diagnoses, we recorded 264 episodes of register-based non-laboratory-confirmed invasive pneumococcal disease or unspecified sepsis, of which 102 were patient-file verified non-laboratory-confirmed invasive pneumococcal disease. The vaccine effectiveness was 50% (95% CI 32-63) in the 30,527 infants with three plus one and two plus one schedules combined and the absolute incidence rate reduction was 207 episodes per 100,000 person-years (95% CI 127-286). The vaccine effectiveness against the patient-file verified non-laboratory-confirmed invasive pneumococcal disease was 71% (95% CI 52-83) in infant three plus one and two plus one schedules combined. The absolute rate reduction was 142 episodes per 100,000 person-years (95% CI 91-191) in infant cohorts. INTERPRETATION This vaccine-probe analysis is the first report showing the effect of pneumococcal conjugate vaccines on clinically suspected invasive pneumococcal disease. The absolute rate reduction was markedly higher compared with laboratory-confirmed invasive pneumococcal disease, which implies low sensitivity of the laboratory-based case definitions and subsequently higher public health effect of pneumococcal conjugate vaccines against invasive pneumococcal disease than previously estimated. FUNDING GlaxoSmithKline Biologicals SA and National Institute for Health and Welfare (THL), Finland.

Survival of Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis Frozen in Skim Milk- Tryptone-Glucose-Glycerol Medium

ABSTRACT In STGG (skim milk, tryptone, glucose, glycerol) medium at −80°C, Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis isolates survived for at least 3 years, and the same species have survived in nasopharyngeal swabs for at least 1.5 years. At −20°C, S. pneumoniae and M. catarrhalis survived for 1.5 years, but H. influenzae survived for only 2 months.

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.

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.

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.

Incidence rates of Guillain Barré (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002–2012

Background In Finland a vaccination programme against human papillomavirus (HPV) was introduced in November 2013 for girls aged 11–12 years with a catchup for girls 13–15 years. Allegations that HPV vaccine is causing Guillain Barré syndrome (GBS) and non-specific diagnostic entities, such as chronic fatigue syndrome/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS), continue to surface. We examined population register-based incidence rates of CFS/SEID, GBS and POTS to provide baseline data for future HPV vaccine safety evaluations. Methods First diagnosis of CFS/SEID, GBS and POTS in girls aged 11–15 years were obtained from the National Hospital Discharge Register during 2002–2012. We considered the following ICD-10 codes: G93.3 for CFS; G61.0 for GBS and G90.9, G90.8, G93.3, I49.8 for POTS. We calculated incidence rates per 100,000 person-years with 95% confidence intervals (CI). Results In total, 9 CFS/SEID, 19 GBS and 72 POTS cases were identified. The overall incidence rate was 0.53/100,000 (95% CI; 0.27–1.01) for CFS/SEID, 1.11 (95% CI; 0.71–1.74) for GBS and 4.21 (95%CI; 3.34–5.30) for POTS. Significant relative increase in annual incidence rate with a peak in 2012 was observed in CFS/SEID (33% (95% CI; 3.0–70.3: p=0.029) and POTS (16.5% (95% CI; 7.8–25.9: p<0.05), but not in GBS (5.4% (95% CI; −8.4–21.3: p=0.460). Conclusions Our findings provide baseline estimates of CFS/SEID, GBS and POTS incidences in Finland. However, rates based on register data should be interpreted with caution, especially for non-specific diagnostic entities for which internationally and even nationally agreed criteria are still being discussed. To assess the associations with HPV vaccine, methods using register linkage for cohort and self-controlled case series should be explored in addition to factors contributing to patients seeking care, treating physicians setting the diagnoses, and their preference of using of codes for these clinical entities.

Similar antibody levels in 3-year old children vaccinated against measles mumps and rubella at the age of 12 months or 18 months

BACKGROUND Measles-mumps-rubella (MMR) vaccinations have been offered to Finnish children at 14-18 months and 6 years of age. In May 2011, the recommended age for the first vaccine dose was lowered to 12 months because of the European measles epidemic. METHODS Fingertip capillary blood samples were collected from 3-year-old Finnish children vaccinated once with MMR vaccine at 11-19 months of age. The immunoglobulin G (IgG) antibodies to all 3 MMR antigens were measured with enzyme-linked immunosorbent assay. Neutralizing antibodies and the avidity of antibodies were measured for measles virus. RESULTS From April through October 2013, 187 children were enrolled. Equally high proportions of the samples were seropositive for measles virus, mumps virus, or rubella virus antibodies, and there were no significant differences in the IgG antibody concentrations in children vaccinated at 11-13 months of age, compared with those vaccinated at 17-19 months of age. However, among children vaccinated at 11-13 months of age, boys had lower antibody concentrations than girls. Neutralizing measles virus antibody titers were above the threshold for protective immunity in all 78 samples analyzed. The measles virus antibody avidity indexes were high for all children. CONCLUSIONS MMR induces similar antibody responses in 12-month-old children as compared to 18-month-old children, but in boys increasing age appears to improve the antibody responses.