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.

Association between anti-capsular IgG levels at birth and risk of invasive group B streptococcus disease in Finnish newborns: a retrospective case-control study.

BACKGROUND: Group B streptococcus is a major cause of neonatal disease. Natural history studies have linked maternally transferred anti-group B streptococcus capsular polysaccharide antibodies with protection against infant group B streptococcus disease. Previous studies of capsular polysaccharide antibody concentration in European populations have used maternal (not infant) sera and a non-standardised assay. This study aimed to evaluate anti-capsular polysaccharide IgG concentrations associated with protection against invasive group B streptococcus disease in Finnish infants. METHODS: In this retrospective case-control study, we used cord sera from the Finnish DIPP study repository, which was obtained between Jan 1, 1995, and Dec 31, 2017. We included infants aged 6 months or younger with group B streptococcus infection (cases) and healthy infants (controls). We enrolled infants with invasive neonatal group B streptococcus (55 cases) and matched controls (229 controls) aged 6 months or younger after identification from Finnish health registers. We measured anti-capsular polysaccharide IgG (serotypes Ia-V) concentration using a standardised immunoassay and we estimated its relationship to disease risk using a Bayesian model. We used the derived risk-concentration curve to predict potential efficacy of six-valent group B streptococcus capsular polysaccharide vaccine (GBS6) based on previously reported immunogenicity data. FINDINGS: Most (32 [58%] of 55 cases) group B streptococcus cases were due to serotype III and anti-serotype III streptococcus capsular IgG concentrations were higher in serotype III-matched controls than in cases (p<0·001). 0·120-0·266 µg/mL serotype III-specific IgG was estimated to confer 75-90% risk reduction against serotype III disease. A universal risk-concentration curve, aggregating results across all six serotypes, yielded similar results. Application of this curve to GBS6 immunogenicity data predicted maternal immunisation to be more than 80% efficacious for prevention of infant group B streptococcus disease. INTERPRETATION: Higher neonatal anti-capsular polysaccharide serum IgG concentration at birth correlated with reduced risk of infant group B streptococcus disease in Finland. Based on these results, a maternal group B streptococcus capsular conjugate vaccine currently in development is predicted to be efficacious. FUNDING: Pfizer.

Hybrid Immunity Improves the Immune Response after the Fourth COVID-19 Vaccine Dose in Individuals with Medical Conditions Predisposing to Severe COVID-19.

Data on immune responses following COVID-19 booster vaccinations and subsequent infections in the immunocompromised are limited. We studied antibody responses after the fourth dose and subsequent infections to define patient groups benefiting most from boosters. Fourth vaccine (booster) doses were, in Finland, first recommended for severely immunocompromised individuals, whom we invited to participate in our study in 2022. We assessed spike protein-specific IgG and neutralizing antibodies (NAb) against the ancestral and Omicron BA.1 strains one month after the fourth dose from 488 adult participants and compared them to the levels of 35 healthy controls after three doses. We used Bayesian generalized linear modeling to assess factors explaining antibody levels and assessed vaccine-induced and hybrid immunity six months after the last vaccine dose. Chronic kidney disease (CKD) and immunosuppressive therapy (IT) were identified as factors explaining sub-optimal antibody responses. The proportion of participants with a normal antibody response and NAbs was significantly lower regarding CKD patients compared to the controls. By the 6-month sampling point, one-third of the participants became infected (documented by serology and/or molecular tests), which notably enhanced antibody levels in most immunocompromised participants. Impaired antibody responses, especially NAbs against the Omicron lineage, suggest limited protection in individuals with CKD and highlight the need for alternative pharmaceutical preventive strategies. Vaccination strategies should take into account the development of robust hybrid immunity responses also among the immunocompromised.

Changes in SARS-CoV-2 seroprevalence and population immunity in Finland, 2020-2022.

Studying the prevalence of SARS-CoV-2 specific antibodies (seroprevalence) allows for assessing the impact of epidemic containment measures and vaccinations and estimating the number of infections regardless of viral testing. We assessed antibody-mediated immunity to SARS-CoV-2 induced by infections and vaccinations from April 2020 to December 2022 in Finland by measuring serum IgG to SARS-CoV-2 nucleoprotein (N-IgG) and spike glycoprotein from randomly selected 18-85-year-old subjects (n = 9794). N-IgG seroprevalence remained at <7% until the last quartile (Q) of 2021. After the emergence of the Omicron variant, N-IgG seroprevalence increased rapidly and was 31% in Q1/2022 and 54% in Q4/2022. Seroprevalence was highest in the youngest age groups from Q2/2022 onwards. We did not observe regional differences in seroprevalence in 2022. We estimated that 51% of the Finnish 18-85-year-old population had antibody-mediated hybrid immunity induced by a combination of vaccinations and infections by the end of 2022. In conclusion, major shifts in the COVID-19 pandemic and resulting population immunity could be observed by serological testing.

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.

Cohort Profile: Childhood morbidity and potential non-specific effects of the childhood vaccination programmes in the Nordic countries (NONSEnse): register-based cohort of children born 1990-2017/2018.

PURPOSE: The aim of the NONSEnse project is to investigate the non-specific effects of vaccines and immunisation programmes on the overall health of children by using information from the extensive nationwide registers on health and sociodemographic factors in Denmark, Finland, Norway and Sweden. PARTICIPANTS: The cohort covers 9 072 420 children aged 0-17 years, born 1990-2017/2018 and living in Denmark, Finland, Norway or Sweden. All countries use a unique identification number for its permanent residents, which makes it possible to link individual-level information from different registers. FINDINGS TO DATE: Data collection and harmonisation according to a common data model was completed in March 2022. As a prerequisite for comparing the effects of childhood vaccinations on the overall health of children across the Nordic countries, we have identified indicators measuring similar levels of infectious disease morbidity across these settings. So far, studies pertaining to non-specific effects of vaccines are limited to investigations that could be undertaken using aggregated data sets that were available before the NONSEnse cohort with individual-level information was completely set up. FUTURE PLANS: We are currently performing several studies of the effects on non-targeted infectious disease morbidity across the countries following vaccination against measles, mumps, rubella, diphtheria, tetanus, pertussis, human papillomavirus, rotavirus and influenza. Multiple studies are planned within the next years using different study designs to facilitate triangulation of results and enhance causal inference. REGISTRATION: No clinical trials will be conducted within the NONSEnse project.

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.

A retrospective nationwide register-based study to evaluate the non-specific effects of first MMR vaccination among children in Finland.

BACKGROUND: According to earlier studies, live vaccines like measles-mumps-rubella (MMR) vaccine could reduce also other infections than only the infections they are targeted against. This non-specific effect has been seen especially in studies in low-income countries and results from high-income countries have not been unambiguous. In 2011 Finland changed the recommended schedule for the first MMR vaccination from 18 months to 12 months of age. This change created a natural experiment for evaluating the potential non-specific effects. METHODS: This is a retrospective nationwide register-based cohort study of Finnish children born between 2008 and 2012. Children were divided into two cohorts by age at MMR vaccination: children administered early MMR vaccination (11 through 12 months of age) and late MMR vaccination (18 through 19 months of age). Morbidity was evaluated during the main follow-up period (from 13 to 17 months of age) and before any MMR vaccination (3 to 10 months) and after all were vaccinated with MMR (20 to 35 months) as control follow-up periods. We analyzed all infections and did additional analyzes for urinary tract infections (UTI) and bronchitis. Injuries were analyzed as a control outcome. RESULTS: Early MMR vaccinated children (N = 79949) had fewer infections compared to late MMR vaccinated (N = 60965) during the main follow-up period. The incidence rate ratio (IRR) was 0.84 (95 % confidence interval (95 % CI) 0.81-0.87). However, similar differences were also observed during the control follow-up periods. MMR vaccinated children had less UTI in the main follow-up period (IRR 0.73, 0.60-0.89) but not in the control follow-up periods. When stratified by sex, the difference was observed among girls but not in boys. CONCLUSION: No clear evidence was found for non-specific effects in infectious diseases morbidity. However, there could be a nonspecific effect on UTI. Confirmation is needed from other studies, especially from high-income countries.

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.

Strong Neutralizing Antibody Responses to SARS-CoV-2 Variants Following a Single Vaccine Dose in Subjects With Previous SARS-CoV-2 Infection.

Background: Previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primes the immune system; thus individuals who have recovered from infection have enhanced immune responses to subsequent vaccination (hybrid immunity). However, it remains unclear how well hybrid immunity induced by severe or mild infection can cross-neutralize emerging variants. We aimed to compare the strength and breadth of antibody responses in vaccinated recovered and uninfected subjects. Methods: We measured spike-specific immunoglobulin (Ig)G and neutralizing antibodies (NAbs) from vaccinated subjects including 320 with hybrid immunity and 20 without previous infection. From 29 subjects with a previous severe or mild infection, we also measured NAb responses against Alpha (B.1.1.7), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529/BA.1) variants following vaccination. Results: A single vaccine dose induced 2-fold higher anti-spike IgG concentrations and up to 4-fold higher neutralizing potency of antibodies in subjects with a previous infection compared with vaccinated subjects without a previous infection. Hybrid immunity was more enhanced after a severe than a mild infection, with sequentially decreasing NAb titers against Alpha, Beta, Delta, and Omicron variants. We found similar IgG concentrations in subjects with a previous infection after 1 or 2 vaccine doses. Conclusions: Hybrid immunity induced strong IgG responses, particularly after severe infection. However, the NAb titers were low against heterologous variants, especially against Omicron.

High vaccine effectiveness against severe COVID-19 in the elderly in Finland before and after the emergence of Omicron.

BACKGROUND: The elderly are highly vulnerable to severe COVID-19. Waning immunity and emergence of Omicron have caused concerns about reduced effectiveness of COVID-19 vaccines. The objective was to estimate vaccine effectiveness (VE) against severe COVID-19 among the elderly. METHODS: This nationwide, register-based cohort analysis included all residents aged 70 years and over in Finland. The follow-up started on December 27, 2020, and ended on March 31, 2022. The outcomes of interest were COVID-19-related hospitalization and intensive care unit (ICU) admission timely associated with SARS-CoV-2 infection. VE was estimated as one minus the hazard ratio comparing the vaccinated and unvaccinated and taking into account time since vaccination. Omicron-specific VE was evaluated as the effectiveness observed since January 1, 2022. RESULTS: The cohort included 896,220 individuals. Comirnaty (BioNTech/Pfizer) VE against COVID-19-related hospitalization was 93% (95% CI 89-95%) and 85% (95% CI 82-87%) 14-90 and 91-180 days after the second dose; VE increased to 95% (95% CI 94-96%) 14-60 days after the third dose. VE of other homologous and heterologous three dose series was similar. Protection against severe COVID-19 requiring ICU treatment was even better. Since January 1, 2022, Comirnaty VE was 98% (95% CI 92-99%) and 92% (95% CI 87-95%) 14-90 and 91-180 days after the second and 98% (95% CI 95-99%) 14-60 days after the third dose. CONCLUSIONS: VE against severe COVID-19 is high among the elderly. It waned slightly after two doses, but a third restored the protection. VE against severe COVID-19 remained high even after the emergence of Omicron.

Time and labour costs of preventive health care, including vaccinations, in Finnish child health clinics.

In Finland all children are entitled to regular health check-up visits at child health clinics (CHC). During the visits public health nurses and physicians follow-up the growth and development of the child, evaluate the welfare of the family, give health counselling and vaccinate the children. The aim of this study was to measure the time used by the nurses and physicians for different tasks during the visits and evaluate the costs of preventive health care procedures. Special emphasis was on time and costs used for administering vaccinations. The study was conducted in four CHCs. Trained observers measured the time used for predefined tasks with a stopwatch application operating on a tablet computer. Labour costs of visits and vaccinations were evaluated by using the gross average salary costs of health care personnel. Time used for vaccine logistics and other administrative tasks was obtained by interviewing the nurses in charge of the vaccine logistics at each CHC. Altogether 325 CHC visits of children <13 months were followed. Public health nurse used for a visit in average 49 (range 12-101) minutes, and the corresponding labour costs were 17 (4-35) Euros. Vaccines were administered at 183 visits. Children got on average 2.4 (1-4) vaccine doses per visit. The observed time used for vaccinations was 10.2 (1.6-25) minutes and the costs 3.58 (0.57-8.62) Euros per visit. The observed time included guidance, preparation, administration, and documentation of vaccinations. Adding one dose into a visit increased the time spent on vaccination on average 2.8 minutes (0.99 Euros). The mean non-observed time used for vaccine logistics outside the visits was 3.4 minutes and cost 1.19 Euros per dose. Administering of the vaccines of the Finnish vaccination programme is relatively simple and inexpensive because Finnish children have regular scheduled visits to CHCs.

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

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

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.

High secondary attack rate and persistence of SARS-CoV-2 antibodies in household transmission study participants, Finland 2020-2021.

Background: Household transmission studies offer the opportunity to assess both secondary attack rate (SAR) and persistence of SARS-CoV-2 antibodies over time. Methods: In Spring 2020, we invited confirmed COVID-19 cases and their household members to four visits, where we collected nasopharyngeal and serum samples over 28 days after index case onset. We calculated SAR based on the presence of SARS-CoV-2 neutralizing antibodies (NAb) and assessed the persistence of NAb and IgG antibodies (Ab) against SARS-CoV-2 spike glycoprotein and nucleoprotein. Results: SAR was 45% (39/87), including 35 symptomatic secondary cases. During the initial 28-day follow-up, 62% (80/129) of participants developed NAb. Of those that seroconverted, 90% (63/70), 85% (63/74), and 78% (45/58) still had NAb to early B-lineage SARS-CoV-2 3, 6, and 12 months after the onset of the index case. Anti-spike IgG Ab persisted in 100% (69/69), 97% (72/74), and 93% (55/59) of seroconverted participants after 3, 6, and 12 months, while anti-nucleoprotein IgG Ab levels waned faster, persisting in 99% (68/69), 78% (58/74), and 55% (39/71) of participants, respectively. Conclusion: Following detection of a COVID-19 case in a household, other members had a high risk of becoming infected. NAb to early B-lineage SARS-CoV-2 persisted for at least a year in most cases.

Trends in Antibiotic Use in Danish, Finnish, Norwegian and Swedish Children.

Objective: To compare the use of antibiotics in children in four Northern European countries. Methods: We conducted a register-based study based on individual-level prescription data from national prescription registers. We identified all redeemed outpatient prescriptions for systemic antibiotics in children aged 0-14 years from July 2006 to June 2017 in Denmark, Finland, Norway, and Sweden. We computed incidence rates and incidence rate ratios of treatment episodes with any antibiotic and different antibiotic classes. Results: In 2016/2017, the rates of antibiotic treatment episodes per 1000 person-years in children aged 0-14 years were 429, 284, 219, and 184 in Finland, Denmark, Sweden, and Norway, respectively, and the rate ratios (95% confidence intervals) compared with Norway were 2.33 (2.33-2.34), 1.54 (1.54-1.55), and 1.19 (1.19-1.20) in Finland, Denmark, and Sweden, respectively. The rate of antibiotic treatment episodes declined over time in all countries. The relative reductions in 2016/2017 compared with 2006/2007 were 36% in Finland, 40% in Denmark, 49% in Sweden, and 29% in Norway. Treatment episodes peaked between age 12 and 18 months. The most used antibiotic class was beta-lactamase sensitive penicillins among all children in Norway and Sweden and among children above two years in Denmark, while penicillins with extended spectrum were most used in Finland and among the youngest children in Denmark. Conclusion: In all countries, the use of antibiotics in children declined between 2006 and 2017. However, there were still considerable differences in antibiotic use between otherwise quite similar Nordic countries, with a more than 2-fold difference between the countries with the lowest and highest rates. Interventions to reduce the number of antibiotic treatment episodes in the countries with higher rates could reduce the total antibiotic use.

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.

Analysis of Thromboembolic and Thrombocytopenic Events After the AZD1222, BNT162b2, and MRNA-1273 COVID-19 Vaccines in 3 Nordic Countries.

Importance: Vaccinations are paramount to halt the COVID-19 pandemic, and safety data are essential to determine the risk-benefit ratio of each COVID-19 vaccine. Objective: To evaluate the association between the AZD1222, BNT162b2, and mRNA-1273 vaccines and subsequent thromboembolic and thrombocytopenic events. Design, Setting, and Participants: This self-controlled case series used individual-level data from national registries in Norway, Finland, and Denmark. Participants included individuals with hospital contacts because of coronary artery disease, coagulation disorders, or cerebrovascular disease between January 1, 2020, and May 16, 2021. Exposures: AZD1222, BNT162b2, or mRNA-1273 vaccine. Main Outcomes and Measure: Relative rate (RR) of hospital contacts for coronary artery disease, coagulation disorders, or cerebrovascular disease in a 28-day period following vaccination compared with the control period prior to vaccination. Results: We found 265 339 hospital contacts, of whom 112 984 [43%] were for female patients, 246 092 [93%] were for patients born in 1971 or earlier, 116 931 [44%] were for coronary artery disease, 55 445 [21%] were for coagulation disorders, and 92 963 [35%] were for cerebrovascular disease. In the 28-day period following vaccination, there was an increased rate of coronary artery disease following mRNA-1273 vaccination (RR, 1.13 [95% CI, 1.02-1.25]), but not following AZD1222 vaccination (RR, 0.92 [95% CI, 0.82-1.03]) or BNT162b2 vaccination (RR, 0.96 [95% CI, 0.92-0.99]). There was an observed increased rate of coagulation disorders following all 3 vaccines (AZD1222: RR, 2.01 [95% CI, 1.75-2.31]; BNT162b2: RR, 1.12 [95% CI, 1.07-1.19]; and mRNA-1273: RR, 1.26 [95% CI, 1.07-1.47]). There was also an observed increased rate of cerebrovascular disease following all 3 vaccines (AZD1222: RR, 1.32 [95% CI, 1.16-1.52]; BNT162b2: RR, 1.09 [95% CI, 1.05-1.13]; and mRNA-1273: RR, 1.21 [95% CI, 1.09-1.35]). For individual diseases within the main outcomes, 2 notably high rates were observed: 12.04 (95% CI, 5.37-26.99) for cerebral venous thrombosis and 4.29 (95% CI, 2.96-6.20) for thrombocytopenia, corresponding to 1.6 (95% CI, 0.6-2.6) and 4.9 (95% CI, 2.9-6.9) excess events per 100 000 doses, respectively, following AZD1222 vaccination. Conclusions and Relevance: In this self-controlled case series, there was an increased rate of hospital contacts because of coagulation disorders and cerebrovascular disease, especially for thrombocytopenia and cerebral venous thrombosis, following vaccination with AZD1222. Although increased rates of several thromboembolic and thrombocytopenic outcomes following BNT162b2 and mRNA-1273 vaccination were observed, these increases were less than the rates observed after AZD1222, and sensitivity analyses were not consistent. Confirmatory analysis on the 2 mRNA vaccines by other methods are warranted.

Hospital Contacts for Infectious Diseases Among Children in Denmark, Finland, Norway, and Sweden, 2008-2017.

Purpose: Comparing rates of childhood infectious disease hospitalisations across countries may uncover areas for improvement in the prevention of severe childhood infections. We compared rates of childhood infectious disease hospital contacts across Denmark, Finland, Norway, and Sweden with the overall objective to elucidate potential differences in burden of disease and in organisational and registration practices. Methods: Using national registries, we estimated incidence rates for infectious disease hospital contacts between 2008 and 2017 among children aged 0-14 years. We investigated the rates for different types of contacts (inpatient or outpatient including emergency room), duration of admission, and by sex. Results: During the study period, the rate of all hospital contacts per 1000 person-years was highest in Sweden (125.2) followed by Finland (87.1), Denmark (79.0), and Norway (62.1). The rates aligned for inpatient contacts with overnight stays; 19.3 (Denmark), 16.6 (Finland), 16.3 (Norway), and 13.0 (Sweden); these were highest in early infancy in all countries. A peak around 1 year of age was seen in all countries except in Sweden. The rates were higher among boys compared with girls in early childhood, after 13 years of age the rates among girls surpassed the boys. Conclusion: Large cross-country differences were observed for outpatient and short-term hospital contacts for infectious diseases, affected by differences in organisational structures and coding practices across and within countries over time. Inpatient contacts requiring overnight stays reflected more comparable levels of severe infections across countries. Childhood infectious disease morbidity was greatest among boys and before 2 years of age.

Neutralizing antibodies to SARS-CoV-2 Omicron variant after third mRNA vaccination in health care workers and elderly subjects.

The emergence of SARS-CoV-2 Omicron variant (B.1.1.529) with major spike protein mutations has raised concern over potential neutralization escape and breakthrough infections among vaccinated and previously SARS-CoV-2-infected subjects. We measured cross-protective antibodies against variants in health care workers (HCW, n = 20) and nursing home residents (n = 9) from samples collected at 1-2 months, following the booster (3rd) dose. We also assessed the antibody responses in subjects infected before the Omicron era (n = 38) with subsequent administration of a single mRNA vaccine dose. Following booster vaccination, HCWs had high IgG antibody concentrations to the spike protein and neutralizing antibodies (NAb) were detectable against all variants. IgG concentrations among the elderly remained lower, and some lacked NAbs against the Beta and Omicron variants. NAb titers were significantly reduced against Delta, Beta, and Omicron compared to WT virus regardless of age. Vaccination induced high IgG concentrations and variable titers of cross-reactive NAbs in previously infected subjects, whereas NAb titers against Omicron were barely detectable 1 month postinfection. High IgG concentrations with cross-protective neutralizing activity were detected after three Coronavirus Disease 2019 (COVID-19) vaccine doses in HCWs. However, lower NAb titers seen in the frail elderly suggest inadequate protection against Omicron breakthrough infections, yet protection against severe COVID-19 is expected.