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.

Lower incidence of hospital-treated infections in infants under 3 months of age vaccinated with BCG.

BACKGROUND: Live vaccines potentially have non-specific effects that protect against other infections than those the vaccines are targeted against. The national vaccination program (NVP) in Finland was changed on September 1st, 2006: before BCG vaccine was given to all newborn babies and afterwards to babies in risk groups only. We used this natural experiment to study the non-specific effects of BCG in the frame of NVP using before-after design. METHODS: We compared the incidence of several outcomes obtained from Finnish health registers between children born between July 1st, 2004, and June 30th, 2006 (BCG-eligible) and an age- and season-matched reference cohort born between July 1st, 2007, and June 30th, 2009 (BCG-non-eligible) using Poisson regression. These cohorts were restricted to full-term children whose parents were born in Finland. Follow-up began at birth and lasted 3 months, which is the scheduled age for DTaP-IPV-Hib vaccination, and from 4 months until first birthday. The outcomes included all infections, pneumonia and injuries as a negative control outcome. RESULTS: The incidence rate ratio (IRR) of the BCG-eligible cohort (N = 93,658) compared to BCG-non-eligible cohort (N = 94,712) for hospital-diagnosed infections was 0.89 (95 %Cl 0.86-0.93) for the 3-month follow-up. The decrease was mainly caused by respiratory infections. In 4-12 months follow-up the BCG-eligible had slightly more infections than BCG-non-eligible children (IRR 1.03, 1.01-1.06). CONCLUSIONS: BCG vaccination was associated with a lower incidence of all hospital-diagnosed infections during the first three months of life. The difference cannot be attributed to lung tuberculosis, since only few paediatric cases occurred in Finland during 2000s. The disappearance of non-specific effect after administration of an inactivated vaccine is compatible with previous studies.

Effectiveness of trivalent influenza vaccines against hospitalizations due to laboratory-confirmed influenza a in the elderly: Comparison of test-negative design with register-based designs.

INTRODUCTION: Measuring influenza vaccine effectiveness (IVE) seasonally is important and has been conducted utilizing several observational study designs. The active test-negative design has been most widely used and the validity of passive register-based studies has been debated. We aimed to explore the potential differences, advantages, and weaknesses of different study designs in estimating influenza vaccine effectiveness. METHODS: We compared three study designs in estimating IVE against hospitalization in the elderly aged 65 years or more over three influenza seasons 2015/16, 2016/17 and 2017/18. Designs compared were active test-negative design (TND), register-based cohort design and register-based case-control design with different selection criteria for cases and controls. RESULTS: Adjusted IVE estimates for the three consecutive seasons 2015-18 in active test-negative design were 82% (95% confidence interval 26, 96), 21% (-179, 77), 15% (-113, 66). For case-control design, estimates from different analyses ranged in 2015/16 from 47% (-16, 76) to 52% (-48, 84), in 2016/17 from 10% (-42, 43) to 29% (-20, 58), and in 2017/18 from -27% (-91, 15) to 1% (-40, 30). In the cohort design, the adjusted IVE estimates were 48% (-9, 75), 29% (1, 49), 13% (-21, 37) for the three seasons. CONCLUSIONS: The register-based cohort design produced results more concordant with the active test-negative design than the case-control design. Furthermore, the register-based cohort design yielded most precise estimates with narrower confidence intervals. In Finland with the availability of near real-time nationwide register data, the register-based cohort design is the method of choice to continue the annual surveillance of influenza vaccine effectiveness.

Clinical characteristics and population-based attack rates of respiratory syncytial virus versus influenza hospitalizations among adults-An observational study.

BACKGROUND: The clinical significance of respiratory syncytial virus (RSV) among adults remains underinvestigated. We compared the characteristics and population-based attack rates of RSV and influenza hospitalizations. METHODS: During 2018-2020, we recruited hospitalized adults with respiratory infection to our prospective substudy at a tertiary care hospital in Finland and compared the characteristics of RSV and influenza patients. In our retrospective substudy, we calculated the attack rates of all RSV and influenza hospitalizations among adults in the same geographic area during 2016-2020. RESULTS: Of the 537 prospective substudy patients, 31 (6%) had RSV, and 106 (20%) had influenza. Duration of hospitalization, need for intensive care or outcome did not differ significantly between RSV and influenza patients. RSV was more often missed or its diagnosis omitted from medical record (13% vs 1% p = 0.016 and 48% vs 15%, p > 0.001). In the retrospective substudy, the mean attack rates of RSV, influenza A, and influenza B hospitalizations rose with age from 4.1 (range by season 1.9-5.9), 15.4 (12.3-23.3), and 4.7 (0.5-16.2) per 100,000 persons among 18- to 64-year-olds to 58.3 (19.3-117.6), 204.1 (31.0-345.0), and 60.4 (0.0-231.0) per 100,000 persons among 65+-year-olds and varied considerably between seasons. DISCUSSION: While the attack rates of influenza hospitalizations were higher compared with RSV, RSV and influenza hospitalizations were similar in severity. Missing or underreporting of RSV infections may lead to underestimating its disease burden. Both RSV and influenza caused a substantial amount of hospitalizations among the elderly, stressing the need for more effective interventions.

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.

Comparison of the clinical characteristics and outcomes of hospitalized adult COVID-19 and influenza patients - a prospective observational study.

BACKGROUND: We compared the clinical characteristics, findings, and outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) or influenza to detect relevant differences. METHODS: From December 2019 to April 2020, we recruited all eligible hospitalized adults with respiratory infection to a prospective observational study at a tertiary care hospital in Finland. Influenza and SARS-CoV-2 infections were confirmed by RT-PCR. Follow-up lasted for 3 months from admission. RESULTS: We included 61 patients, of whom 28 were COVID-19 and 33 influenza patients with median ages of 53 and 56 years. Majority of both COVID-19 and influenza patients were men (61% vs. 67%) and had at least one comorbidity (68% vs. 85%). Pulmonary diseases and current smoking were less common among COVID-19 than influenza patients (5 [18%] vs. 15 [45%], p=.03 and 1 [4%] vs. 10 [30%], p=.008). In chest X-ray at admission, ground-glass opacities (GGOs) and consolidations were more frequent among COVID-19 than influenza patients (19 [68%] and 7 [21%], p<.001). Severe disease and intensive care unit (ICU) admission occurred more often among COVID-19 than influenza patients (26 [93%] vs. 19 [58%], p=.003 and 8 [29%] vs. 2 [6%], p=.034). COVID-19 patients were hospitalized longer than influenza patients (six days [IQR 4-21] vs. 3 [2-4], p<.001). CONCLUSIONS: Bilateral GGOs and consolidations in chest X-ray may help to differentiate COVID-19 from influenza. Hospitalized COVID-19 patients had more severe disease, required longer hospitalization and were admitted to ICU more often than influenza patients, which has important implications for public health policies.

Vaccine effectiveness against influenza A(H3N2) and B among laboratory-confirmed, hospitalised older adults, Europe, 2017-18: A season of B lineage mismatched to the trivalent vaccine.

BACKGROUND: Influenza A(H3N2), A(H1N1)pdm09 and B viruses co-circulated in Europe in 2017-18, predominated by influenza B. WHO-recommended, trivalent vaccine components were lineage-mismatched for B. The I-MOVE hospital network measured 2017-18 seasonal influenza vaccine effectiveness (IVE) against influenza A(H3N2) and B among hospitalised patients (≥65 years) in Europe. METHODS: Following the same generic protocol for test-negative design, hospital teams in nine countries swabbed patients ≥65 years with recent onset (≤7 days) severe acute respiratory infection (SARI), collecting information on demographics, vaccination status and underlying conditions. Cases were RT-PCR positive for influenza A(H3N2) or B; controls: negative for any influenza. "Vaccinated" patients had SARI onset >14 days after vaccination. We measured pooled IVE against influenza, adjusted for study site, age, sex, onset date and chronic conditions. RESULTS: We included 3483 patients: 376 influenza A(H3N2) and 928 B cases, and 2028 controls. Most (>99%) vaccinated patients received the B lineage-mismatched trivalent vaccine. IVE against influenza A(H3N2) was 24% (95% CI: 2 to 40); 35% (95% CI: 6 to 55) in 65- to 79-year-olds and 14% (95% CI: -22 to 39) in ≥80-year-olds. Against influenza B, IVE was 30% (95% CI: 16 to 41); 37% (95% CI: 19 to 51) in 65- to 79-year-olds and 19% (95% CI: -7 to 38) in ≥80-year-olds. CONCLUSIONS: IVE against influenza B was similar to A(H3N2) in hospitalised older adults, despite trivalent vaccine and circulating B lineage mismatch, suggesting some cross-protection. IVE was lower in those ≥80 than 65-79 years. We reinforce the importance of influenza vaccination in older adults as, even with a poorly matched vaccine, it still protects one in three to four of this population from severe influenza.

Pandemic influenza A(H1N1pdm09) vaccine induced high levels of influenza-specific IgG and IgM antibodies as analyzed by enzyme immunoassay and dual-mode multiplex microarray immunoassay methods.

Influenza A viruses continue to circulate throughout the world as yearly epidemics or occasional pandemics. Influenza infections can be prevented by seasonal multivalent or monovalent pandemic vaccines. In the present study, we describe a novel multiplex microarray immunoassay (MAIA) for simultaneous measurement of virus-specific IgG and IgM antibodies using Pandemrix-vaccinated adult sera collected at day 0 and 28 and 180 days after vaccination as the study material. MAIA showed excellent correlation with a conventional enzyme immunoassay (EIA) in both IgG and IgM anti-influenza A antibodies and good correlation with hemagglutination inhibition (HI) test. Pandemrix vaccine induced 5-30 fold increases in anti-H1N1pdm09 influenza antibodies as measured by HI, EIA or MAIA. A clear increase in virus-specific IgG antibodies was found in 93-97% of vaccinees by MAIA and EIA. Virus-specific IgM antibodies were found in 90-92% of vaccinees by MAIA and EIA, respectively and IgM antibodies persisted for up to 6 months after vaccination in 55-62% of the vaccinees. Pandemic influenza vaccine induced strong anti-influenza A IgG and IgM responses that persisted several months after vaccination. MAIA was demonstrated to be an excellent method for simultaneous measurement of antiviral IgG and IgM antibodies against multiple virus antigens. Thus the method is well suitable for large scale epidemiological and vaccine immunity studies.

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.

The prevalence of otitis media in 2-3 year old Cameroonian children estimated by tympanometry.

BACKGROUND: Acute otitis media is a common illness in children under-five years of age and associated with major health care resources in high-income countries. However, there is paucity of data on its epidemiology and clinical presentation in low-income countries. We estimated the prevalence of otitis media and assessed risk factors among children in Cameroon. METHODS: A community-based cross-sectional prevalence study of otitis media (OM) was performed on randomly selected children aged 2-3 years in Yaoundé, Cameroon from March to June 2013. OM was assessed by clinical inspection for chronic suppurative otitis media (CSOM) and tympanometry for otitis media with effusion (OME). CSOM was defined as draining of the middle ear with duration of more than two weeks and OME was defined as a flat 'type B' tympanogram. RESULTS: Out of 529 children enrolled in the study, 433 (56% males) subjects with available tympanograms were evaluated. Altogether, 9.7% (42/433) of children met the case definition of CSOM, OME or its complications. This consisted of 3 (0.7%) children identified with unilateral CSOM; 7 (1.6%) children with bilateral OME; 31 (7.2%) with unilateral OME and 1 (0.2%) subject with unilateral dry tympanic membrane perforation. Logistic regression analyses showed statistically significant association between OM and parental reporting of "current symptoms of upper respiratory tract infections", Prevalence Odds Ratio (POR) = 3.71; 95% CI = 1.69-8.14). CONCLUSION: As many as two out of a hundred children between the ages of 2-3 years were affected by significant middle ear disease i.e. CSOM or bilateral OME. These data could be useful as a baseline for estimating the impact of pneumococcal conjugate vaccines (PCV13) introduced in July 2011 for infants in Cameroon.

Low 2016/17 season vaccine effectiveness against hospitalised influenza A(H3N2) among elderly: awareness warranted for 2017/18 season.

In a multicentre European hospital study we measured influenza vaccine effectiveness (IVE) against A(H3N2) in 2016/17. Adjusted IVE was 17% (95% confidence interval (CI): 1 to 31) overall; 25% (95% CI: 2 to 43) among 65-79-year-olds and 13% (95% CI: -15 to 30) among those ≥ 80 years. As the A(H3N2) vaccine component has not changed for 2017/18, physicians and public health experts should be aware that IVE could be low where A(H3N2) viruses predominate.

2015/16 seasonal vaccine effectiveness against hospitalisation with influenza A(H1N1)pdm09 and B among elderly people in Europe: results from the I-MOVE+ project.

We conducted a multicentre test-negative case-control study in 27 hospitals of 11 European countries to measure 2015/16 influenza vaccine effectiveness (IVE) against hospitalised influenza A(H1N1)pdm09 and B among people aged ≥ 65 years. Patients swabbed within 7 days after onset of symptoms compatible with severe acute respiratory infection were included. Information on demographics, vaccination and underlying conditions was collected. Using logistic regression, we measured IVE adjusted for potential confounders. We included 355 influenza A(H1N1)pdm09 cases, 110 influenza B cases, and 1,274 controls. Adjusted IVE against influenza A(H1N1)pdm09 was 42% (95% confidence interval (CI): 22 to 57). It was 59% (95% CI: 23 to 78), 48% (95% CI: 5 to 71), 43% (95% CI: 8 to 65) and 39% (95% CI: 7 to 60) in patients with diabetes mellitus, cancer, lung and heart disease, respectively. Adjusted IVE against influenza B was 52% (95% CI: 24 to 70). It was 62% (95% CI: 5 to 85), 60% (95% CI: 18 to 80) and 36% (95% CI: -23 to 67) in patients with diabetes mellitus, lung and heart disease, respectively. 2015/16 IVE estimates against hospitalised influenza in elderly people was moderate against influenza A(H1N1)pdm09 and B, including among those with diabetes mellitus, cancer, lung or heart diseases.

Repeated seasonal influenza vaccination among elderly in Europe: Effects on laboratory confirmed hospitalised influenza.

In Europe, annual influenza vaccination is recommended to elderly. From 2011 to 2014 and in 2015-16, we conducted a multicentre test negative case control study in hospitals of 11 European countries to measure influenza vaccine effectiveness (IVE) against laboratory confirmed hospitalised influenza among people aged ≥65years. We pooled four seasons data to measure IVE by past exposures to influenza vaccination. We swabbed patients admitted for clinical conditions related to influenza with onset of severe acute respiratory infection ≤7days before admission. Cases were patients RT-PCR positive for influenza virus and controls those negative for any influenza virus. We documented seasonal vaccination status for the current season and the two previous seasons. We recruited 5295 patients over the four seasons, including 465A(H1N1)pdm09, 642A(H3N2), 278 B case-patients and 3910 controls. Among patients unvaccinated in both previous two seasons, current seasonal IVE (pooled across seasons) was 30% (95%CI: -35 to 64), 8% (95%CI: -94 to 56) and 33% (95%CI: -43 to 68) against influenza A(H1N1)pdm09, A(H3N2) and B respectively. Among patients vaccinated in both previous seasons, current seasonal IVE (pooled across seasons) was -1% (95%CI: -80 to 43), 37% (95%CI: 7-57) and 43% (95%CI: 1-68) against influenza A(H1N1)pdm09, A(H3N2) and B respectively. Our results suggest that, regardless of patients' recent vaccination history, current seasonal vaccine conferred some protection to vaccinated patients against hospitalisation with influenza A(H3N2) and B. Vaccination of patients already vaccinated in both the past two seasons did not seem to be effective against A(H1N1)pdm09. To better understand the effect of repeated vaccination, engaging in large cohort studies documenting exposures to vaccine and natural infection is needed.

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.

Effectiveness of the live attenuated and the inactivated influenza vaccine in two-year-olds - a nationwide cohort study Finland, influenza season 2015/16.

Although widely recommended, influenza vaccination of children is part of the national vaccination programme only in few countries. In addition to Canada and the United States (US), in Europe Finland and the United Kingdom have introduced live attenuated influenza vaccine (LAIV) for healthy children in their programmes. On 22 June 2016, the US Advisory Committee on Immunizations Practices, voted against further use of LAIV due to no observed vaccine effectiveness (VE) over three consecutive influenza seasons (2013/14 to 2015/16). We summarise the results of a nationwide, register-based cohort study (N=55,258 of whom 8,086 received LAIV and 4,297 TIV); all outcome (laboratory-confirmed influenza), exposure (vaccination) and confounding variable data were retrieved from four computerised national health registers, which were linked via a unique personal identity code assigned to all permanent Finnish residents regardless of nationality. Our study provides evidence of moderate effectiveness against any laboratory-confirmed influenza of the quadrivalent LAIV vaccine (VE: 51%; 95% confidence interval (CI): 28-66%) as well as the inactivated trivalent vaccine (VE: 61%; 95% CI: 31-78%) among two-year-olds during the influenza season 2015/16 in Finland. Based on these data, Finland will continue using LAIV for young children in its National Immunisation Programme this coming influenza season.

New Pneumococcal Carriage Acquired in Association with Acute Respiratory Infection Is Prone to Cause Otitis Media.

For considering vaccine-prevention of pneumococcal acute otitis media (PncAOM), relationships between pneumococcal carriage, respiratory infection and PncAOM need to be understood. We analyzed nasopharyngeal samples collected from 329 unvaccinated Finnish children aged 2-24 months at scheduled visits and at visits during respiratory infection in 1994-97. We assessed temporal associations of respiratory infection with pneumococcal acquisition and whether PncAOM hazard depends on the relative timing of acquisition and the infection onset. The data comprised 607 person-years of risk-time for acquisition, 245 person-months of concurrent respiratory infection and carriage, and 119 episodes of PncAOM. The acquisition hazard was 3-fold in the month preceding respiratory sickness (hazard ratio, HR 3.5, 90% credible interval CI 2.9, 4.1) as compared to acquisition in healthy children. Moreover, the PncAOM hazard was markedly higher (HR 3.7, 90% CI 2.4, 5.3) during the first month of carriage acquired around the acute phase of respiratory infection (between 1 month before and 1 week after the sickness onset), as compared to carriage acquired later during sickness. The high proportion (76%) of PncAOM events occurring within 1 month of acquisition was due to frequent acquisition being associated with respiratory infection as well as the susceptibility of such acquisition to cause otitis media.

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.

Health benefit for the child and promotion of the common good were the two most important reasons for participation in the FinIP vaccine trial.

BACKGROUND AND AIMS: The Finnish Invasive Pneumococcal disease (FinIP) vaccine trial was a nationwide cluster-randomised double-blind trial designed to demonstrate the effectiveness of pneumococcal conjugate vaccine in vaccinated children and indirect effects in unvaccinated populations. Together with the parallel carriage/AOM trial, over 47,000 children were enrolled, 52% of the initial target. We conducted a questionnaire study to find out which factors affected parents' decision on their child's study participation. METHODS: A questionnaire designed to evaluate parents' attitudes to vaccine trial participation in general and the FinIP trial in particular was mailed after the trial enrolment period had ended to parents of randomly selected children: 1484 who participated in the trial and 1485 who did not participate. RESULTS: Altogether 1438 parents (48%) responded to the questionnaire. The response rate was higher among FinIP participants (65%, 965/1484) than among FinIP non-participants (32%, 473/1485). The two most important reasons for giving consent to the FinIP trial were the potential benefit of immunisation against pneumococcal diseases (75% of consenters) and the promotion of the common good and public health (11%). The reasons reported as most important for declining consent were suspicions of vaccine safety (36%) and the double-blind trial design (12%). Up to 65% of the non-consenters declared that drug and vaccine trials should not be conducted in children at all. CONCLUSIONS: The expected health benefit for the child was by far the most important reason for consenting to the vaccine trial. Safety concern was the main reason for decline. Importance and necessity of clinical drug and vaccine trials among children and the rationale of the blinded studies should be thoroughly explained to the public. This may increase participation in future vaccine trials.

Effectiveness of pandemic and seasonal influenza vaccines in preventing laboratory-confirmed influenza in adults: a clinical cohort study during epidemic seasons 2009-2010 and 2010-2011 in Finland.

BACKGROUND: One dose of pandemic influenza vaccine Pandemrix (GlaxoSmithKline) was offered to the entire population of Finland in 2009-10. We conducted a prospective clinical cohort study to determine the vaccine effectiveness in preventing febrile laboratory-confirmed influenza infection during the influenza season 2009-10 and continued the study in 2010-11. METHODS: In total, 3,518 community dwelling adults aged 18-75 years living in Tampere city were enrolled. The participants were not assigned to any vaccination regimen, but they could participate in the study regardless of their vaccination status or intention to be vaccinated with the pandemic or seasonal influenza vaccine. They were asked to report if they received Pandemrix in 2009-10 and/or trivalent influenza vaccine in 2010-11. Vaccinations were verified from medical records. The participants were instructed to report all acute symptoms of respiratory tract infection with fever (at least 38°C) and pneumonias to the study staff. Nasal and oral swabs were obtained within 5-7 days after symptom onset and influenza-specific RNA was identified by reverse transcription polymerase chain reaction. RESULTS: In 2009-10, the estimated vaccine effectiveness was 81% (95%CI 30-97). However, the vaccine effectiveness could not be estimated reliably, because only persons in prioritized groups were vaccinated before/during the first pandemic wave and many participants were enrolled when they already had the symptoms of A(H1N1)pdm09 influenza infection. In 2010-11, 2,276 participants continued the follow-up. The vaccine effectiveness, adjusted for potential confounding factors was 81% (95%CI 41-96) for Pandemrix only and 88% (95%CI 63-97) for either Pandemrix or trivalent influenza vaccine 2010-11 or both, respectively. CONCLUSION: Vaccination with an AS03-adjuvanted pandemic vaccine in 2009-10 was still effective in preventing A(H1N1)pdm09 influenza during the following epidemic season in 2010-11. TRIAL REGISTRATION: ClinicalTrials.gov NCT01024725. NCT01206114.

No serological evidence of influenza A H1N1pdm09 virus infection as a contributing factor in childhood narcolepsy after Pandemrix vaccination campaign in Finland.

BACKGROUND: Narcolepsy cataplexy syndrome, characterised by excessive daytime sleepiness and cataplexy, is strongly associated with a genetic marker, human leukocyte antigen (HLA) DQB1*06:02. A sudden increase in the incidence of childhood narcolepsy was observed after vaccination with AS03-adjuvanted Pandemrix influenza vaccine in Finland at the beginning of 2010. Here, we analysed whether the coinciding influenza A H1N1pdm pandemic contributed, together with the Pandemrix vaccination, to the increased incidence of childhood narcolepsy in 2010. The analysis was based on the presence or absence of antibody response against non-structural protein 1 (NS1) from H1N1pdm09 virus, which was not a component of Pandemrix vaccine. METHODS: Non-structural (NS) 1 proteins from recombinant influenza A/Udorn/72 (H3N2) and influenza A/Finland/554/09 (H1N1pdm09) viruses were purified and used in Western blot analysis to determine specific antibody responses in human sera. The sera were obtained from 45 patients who fell ill with narcolepsy after vaccination with AS03-adjuvanted Pandemrix at the end of 2009, and from controls. FINDINGS: Based on quantitative Western blot analysis, only two of the 45 (4.4%) Pandemrix-vaccinated narcoleptic patients showed specific antibody response against the NS1 protein from the H1N1pdm09 virus, indicating past infection with the H1N1pdm09 virus. Instead, paired serum samples from patients, who suffered from a laboratory confirmed H1N1pdm09 infection, showed high levels or diagnostic rises (96%) in H1N1pdm virus NS1-specific antibodies and very high cross-reactivity to H3N2 subtype influenza A virus NS1 protein. CONCLUSION: Based on our findings, it is unlikely that H1N1pdm09 virus infection contributed to a sudden increase in the incidence of childhood narcolepsy observed in Finland in 2010 after AS03-adjuvanted Pandemrix vaccination.