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Infection with Influenza A virus (IAV) causes the well-known symptoms of the flu, including fever, loss of appetite, and excessive sleepiness. These responses, mediated by the brain, will normally disappear once the virus is cleared from the system, but a severe respiratory virus infection may cause long-lasting neurological disturbances. These include encephalitis lethargica and narcolepsy. The mechanisms behind such long lasting changes are unknown. The hypothalamus is a central regulator of the homeostatic response during a viral challenge. To gain insight into the neuronal and non-neuronal molecular changes during an IAV infection, we intranasally infected mice with an H1N1 virus and extracted the brain at different time points. Using single-nucleus RNA sequencing (snRNA-seq) of the hypothalamus, we identify transcriptional effects in all identified cell populations. The snRNA-seq data showed the most pronounced transcriptional response at 3 days past infection, with a strong downregulation of genes across all cell types. General immune processes were mainly impacted in microglia, the brain resident immune cells, where we found increased numbers of cells expressing pro-inflammatory gene networks. In addition, we found that most neuronal cell populations downregulated genes contributing to the energy homeostasis in mitochondria and protein translation in the cytosol, indicating potential reduced cellular and neuronal activity. This might be a preventive mechanism in neuronal cells to avoid intracellular viral replication and attack by phagocytosing cells. The change of microglia gene activity suggest that this is complemented by a shift in microglia activity to provide increased surveillance of their surroundings.

The world has seen numerous infectious disease outbreaks in the past decade. In many cases these outbreaks have had considerable perinatal health consequences including increased risk of preterm delivery (e.g., influenza, measles, and COVID-19), and the delivery of low birth weight or small for gestational age babies (e.g., influenza, COVID-19). Furthermore, severe perinatal outcomes including perinatal and infant death are a known consequence of multiple infectious diseases (e.g., Ebola virus disease, Zika virus disease, pertussis, and measles). In addition to vaccination during pregnancy (where possible), pregnant women, are provided some level of protection from the adverse effects of infection through community-level application of evidence-based transmission-control methods. This review demonstrates that it takes almost 2 years for the perinatal impacts of an infectious disease outbreak to be reported. However, many infectious disease outbreaks between 2010 and 2020 have no associated pregnancy data reported in the scientific literature, or pregnancy data is reported in the form of case-studies only. This lack of systematic data collection and reporting has a negative impact on our understanding of these diseases and the implications they may have for pregnant women and their unborn infants. Monitoring perinatal health is an essential aspect of national and global healthcare strategies as perinatal life has a critical impact on early life mortality as well as possible effects on later life health. The unpredictable nature of emerging infections and the potential for adverse perinatal outcomes necessitate that we thoroughly assess pregnancy and perinatal health implications of disease outbreaks and their public health interventions in tandem with outbreak response efforts. Disease surveillance programs should incorporate perinatal health monitoring and health systems around the world should endeavor to continuously collect perinatal health data in order to qu

The world has seen numerous infectious disease outbreaks in the past decade. In many cases these outbreaks have had considerable perinatal health consequences including increased risk of preterm delivery (e.g., influenza, measles, and COVID-19), and the delivery of low birth weight or small for gestational age babies (e.g., influenza, COVID-19). Furthermore, severe perinatal outcomes including perinatal and infant death are a known consequence of multiple infectious diseases (e.g., Ebola virus disease, Zika virus disease, pertussis, and measles). In addition to vaccination during pregnancy (where possible), pregnant women, are provided some level of protection from the adverse effects of infection through community-level application of evidence-based transmission-control methods. This review demonstrates that it takes almost 2 years for the perinatal impacts of an infectious disease outbreak to be reported. However, many infectious disease outbreaks between 2010 and 2020 have no associated pregnancy data reported in the scientific literature, or pregnancy data is reported in the form of case-studies only. This lack of systematic data collection and reporting has a negative impact on our understanding of these diseases and the implications they may have for pregnant women and their unborn infants. Monitoring perinatal health is an essential aspect of national and global healthcare strategies as perinatal life has a critical impact on early life mortality as well as possible effects on later life health. The unpredictable nature of emerging infections and the potential for adverse perinatal outcomes necessitate that we thoroughly assess pregnancy and perinatal health implications of disease outbreaks and their public health interventions in tandem with outbreak response efforts. Disease surveillance programs should incorporate perinatal health monitoring and health systems around the world should endeavor to continuously collect perinatal health data in order to qu

Introduction: Seasonal inactivated influenza vaccine (IIV) is routinely recommended during pregnancy to protect both mothers and infants from complications following influenza infection. While previous studies have evaluated the risk of major structural birth defects in infants associated with prenatal administration of monovalent pandemic IIV, fewer studies have evaluated the risk associated with prenatal seasonal IIV. Methods: We conducted a population-based cohort study of 125,866 singleton births between 2012 and 2016 in Western Australia. Birth registrations were linked to the state's registers for congenital anomalies and a state prenatal vaccination database. We estimated prevalence ratios (PR) of any major structural birth defect and defects by organ system. Vaccinated pregnancies were defined as those with a record of IIV in the first trimester. Inverse probability treatment weighting factored for baseline probability for vaccination. A Bonferroni correction was applied to account for multiple comparisons. Results: About 3.9% of births had a major structural birth defect. Seasonal IIV exposure during the first trimester was not associated with diagnosis of any major structural birth defect diagnosed within 1 month of birth (PR 0.98, 95% CI: 0.77, 1.28) or within 6 years of life (PR 1.02, 95% CI: 0.78, 1.35). We identified no increased risk in specific birth defects associated with seasonal IIV. Conclusion: Based on registry data for up to 6 years of follow-up, results suggest there is no association between maternal influenza vaccination and risk of major structural birth defects. These results support the safety of seasonal IIV administration during pregnancy.

Objective To assess whether clinical and/or laboratory-confirmed diagnosis of maternal influenza during pregnancy increases the risk of seizures in early childhood. Design Analysis of prospectively collected registry data for children born between 2009 and 2013 in three high-income countries. We used Cox regression to estimate country-level adjusted HRs (aHRs); fixed-effects meta-analyses were used to pool adjusted estimates. Setting Population-based. Participants 1 360 629 children born between 1 January 2009 and 31 December 2013 in Norway, Australia (New South Wales) and Canada (Ontario). Exposure Clinical and/or laboratory-confirmed diagnosis of maternal influenza infection during pregnancy. Main outcome measures We extracted data on recorded seizure diagnosis in secondary/specialist healthcare between birth and up to 7 years of age; additional analyses were performed for the specific seizure outcomes epilepsy' and febrile seizures'. Results Among 1 360 629 children in the study population, 14 280 (1.0%) were exposed to maternal influenza in utero. Exposed children were at increased risk of seizures (aHR 1.17, 95% CI 1.07 to 1.28), and also febrile seizures (aHR 1.20, 95% CI 1.07 to 1.34). There was no strong evidence of an increased risk of epilepsy (aHR 1.07, 95% CI 0.81 to 1.41). Risk estimates for seizures were higher after influenza infection during the second and third trimester than for first trimester. Conclusions In this large international study, prenatal exposure to influenza infection was associated with increased risk of childhood seizures.

Background Influenza is a major cause of morbidity, mortality and exacerbation of extant chronic disease worldwide. Influenza vaccination is thus fundamental to reduce the burden of disease. In this study, we describe the trend of influenza vaccination coverage in the seasons 2010/11-2020/21 among children aged < 2, 2-4 and 5-8 in Italy. Methods We analyzed the trend of influenza vaccination coverage in the pediatric population in Italy from the 2010/11 to the 2020/21 season at national and regional level and observed the incidence of influenza-like illness (ILI) in the pediatric population between 2010/11 and 2020/21. Results In the period 2010/11-2019/20 the highest value of coverage (4.5%) was reached in the age group 2-4 and 5-8 (season 2010/11 and 2011/12, respectively), while the lowest belonged to the < 2 group (1.1% in the season 2015/16). In the season 2020/2021 all the age groups reported a substantial increase of coverage compared with the previous season. The highest value (19.0%) was reported in the age group 2-4, followed by the group 5-8 and < 2 (13.1 and 9.2%, respectively). Considering the rates of annual ILI cases, the highest value for the 0-4 age group was 18.5% in the 2011/12 season; for the 5-14 age group, the highest value was 27.7% in the 2010/11 season. Conclusions Over the past 11 years pediatric influenza vaccination coverage in Italy has been low, with relevant differences across regions and seasons, albeit a general increase in coverage has been observed in the 2020/21 season. Universal influenza vaccination for children should be considered as a priority for the high incidence in this age group. Further research is needed to improve knowledge and comparability of coverage rates, and to identify the best practices for organizational models of delivery which can support the improvement of trends, the acceptability and accessibility by parents and awareness in stakeholders and decision makers.

type:Text, Plastic bronchitis (PB) is a severe acute respiratory disease that develops as a result of the formation of branching mucus plugs in the bronchial tree. PB is known as a complication of influenza A virus infection, but some cases have been associated with influenza B virus infections. This patient was a 3-year-old boy with no history of allergic disease who developed PB requiring ventilator management after influenza B virus infection. He was hospitalized and managed with ventilator support because of acute respiratory failure. Influenza B virus infection was diagnosed via rapid antigen test and real-time reverse-transcription polymerase chain reaction (RT-PCR). A bronchoscopy performed after a chest X-ray and computed tomography confirmed the presence of extensive atelectasis in the right lung field and mucus plugs in the right bronchus. The patient's respiratory condition improved rapidly after removal of the plugs. Quantitative real-time RT-PCR performed with nasal and aspirated sputum samples obtained at hospitalization revealed a higher viral RNA load in the upper rather than in the lower respiratory tract. Viral replication in the lower respiratory was not found to be a major contributor toward mucus plug formation. The finding of increased serum IgE in the absence of a history of allergic disease suggests that an allergic reaction contributed to the formation of mucus plugs.

INTRODUCTION: The COVID-19 pandemic has emerged as a global health problem, associated with high morbidity and mortality rates. The aim of this study was to compare the outcomes of hospitalized patients with COVID-19 or with seasonal influenza in a teaching hospital in Belgium. METHODS: In this retrospective, single-center cohort study, 1384 patients with COVID-19 and 226 patients with influenza were matched using a propensity score with a ratio of 3:1. Primary outcomes included admission to intensive care unit (ICU), intubation rates, hospital length of stay, readmissions within 30 days and in-hospital mortality. Secondary outcomes included pulmonary bacterial superinfection, cardiovascular complications and ECMO. RESULTS: Based on the analysis of the matched sample, patients with influenza had an increased risk of readmission within 30 days (Risk Difference (RD): 0.07, 95% CI: 0.03 to 0.11) and admission to intensive care unit (RD: 0.09, 95% CI: 0.03 to 0.15) compared with those with COVID-19. Patients with influenza had also more pulmonary bacterial superinfections (46.2% vs 7.4%) and more cardiovascular complications (32% vs 3.9%) than patients with COVID-19.However, a two-fold increased risk of mortality (RD: -0.10, 95% CI: 0.15 to -0.05) was observed in COVID-19 compared to influenza. ECMO was also more required among the COVID-19 patients who died than among influenza patients (5% vs 0%). CONCLUSIONS: COVID-19 is associated with a higher in-hospital mortality compared to influenza infection, despite a high rate of ICU admission in the influenza group. These findings highlighted that the severity of hospitalized patients with influenza should not be underestimated.

Seasonal epidemics of influenza and the respiratory syncytial virus (RSV) are the cause of substantial morbidity and mortality among children. During the global coronavirus disease 2019 (COVID-19) pandemic, the epidemiology of these viruses seems to have changed dramatically. In Australia and New Zealand, a significant decrease in both influenza and bronchiolitis have been noticed during usual peak seasons. Data from early months of winter seasons in Europe are showing similar trends. This current scenario imposes a reconsideration of the paradigm that toddlers and young schoolchildren are the main drivers of seasonal RSV outbreaks and respiratory epidemics in general. In this article, we summarize current literature, address current knowledge or role of adults in the RSV epidemiology, describe the lessons learned from pertussis epidemics and call the international community to better understand the community transmission dynamics of respiratory infections in all age groups. This can allow the establishment of better and more affordable preventive measures in the whole population level, which can ultimately save millions of child lives.

Background. The elderly, commonly defined as subjects aged ≥65 years, are among the at-risk subjects recommended for annual influenza vaccination in European countries. Currently, two new vaccines are available for this population: the MF59-adjuvanted quadrivalent influenza vaccine (aQIV) and the high-dose quadrivalent influenza vaccine (hdQIV). Their multidimensional assessment might maximize the results in terms of achievable health benefits. Therefore, we carried out a Health Technology Assessment (HTA) of the aQIV by adopting a multidisciplinary policy-oriented approach to evaluate clinical, economic, organizational, and ethical implications for the Italian elderly. Methods. A HTA was conducted in 2020 to analyze influenza burden; characteristics, efficacy, and safety of aQIV and other available vaccines for the elderly; cost-effectiveness of aQIV; and related organizational and ethical implications. Comprehensive literature reviews/analyses were performed, and a transmission model was developed in order to address the above issues. Results. In Italy, the influenza burden on the elderly is high and from 77.7% to 96.1% of influenza-related deaths occur in the elderly. All available vaccines are effective and safe; however, aQIV, such as the adjuvanted trivalent influenza vaccine (aTIV), has proved more immunogenic and effective in the elderly. From the third payer’s perspective, but also from the societal one, the use of aQIV in comparison with egg-based standard QIV (eQIV) in the elderly population is cost-effective. The appropriateness of the use of available vaccines as well as citizens’ knowledge and attitudes remain a challenge for a successful vaccination campaign. Conclusions. The results of this project provide decision-makers with important evidence on the aQIV and support with scientific evidence on the appropriate use of vaccines in the elderly.

BACKGROUND: The severity of influenza disease can range from mild symptoms to severe respiratory failure and can partly be explained by host genetic factors that predisposes the host to severe influenza. Here, we aimed to summarize the current state of evidence that host genetic variants play a role in the susceptibility to severe influenza infection by conducting a systematic review and performing a meta-analysis for all markers with at least three or more data entries. RESULTS: A total of 34 primary human genetic association studies were identified that investigated a total of 20 different genes. The only significant pooled ORs were retrieved for the rs12252 polymorphism: an overall OR of 1.52 (95% CI [1.06-2.17]) for the rs12252-C allele compared to the rs12252-T allele. A stratified analysis by ethnicity revealed opposite effects in different populations. CONCLUSION: With exception for the rs12252 polymorphism, we could not identify specific genetic polymorphisms to be associated with severe influenza infection in a pooled meta-analysis. This advocates for the use of large, hypothesis-free, genome-wide association studies that account for the polygenic nature and the interactions with other host, pathogen and environmental factors.

BackgroundSeasonal influenza-like illness (ILI) affects millions of people yearly. Severe acute respiratory infections (SARI), mainly influenza, are a leading cause of hospitalisation and mortality. Increasing evidence indicates that non-influenza respiratory viruses (NIRV) also contribute to the burden of SARI. In Belgium, SARI surveillance by a network of sentinel hospitals has been ongoing since 2011.AimWe report the results of using in-house multiplex qPCR for the detection of a flexible panel of viruses in respiratory ILI and SARI samples and the estimated incidence rates of SARI associated with each virus.MethodsWe defined ILI as an illness with onset of fever and cough or dyspnoea. SARI was defined as an illness requiring hospitalisation with onset of fever and cough or dyspnoea within the previous 10 days. Samples were collected in four winter seasons and tested by multiplex qPCR for influenza virus and NIRV. Using catchment population estimates, we calculated incidence rates of SARI associated with each virus.ResultsOne third of the SARI cases were positive for NIRV, reaching 49.4% among children younger than 15 years. In children younger than 5 years, incidence rates of NIRV-associated SARI were twice that of influenza (103.5 vs 57.6/100,000 person-months); co-infections with several NIRV, respiratory syncytial viruses, human metapneumoviruses and picornaviruses contributed most (33.1, 13.6, 15.8 and 18.2/100,000 person-months, respectively).ConclusionEarly testing for NIRV could be beneficial to clinical management of SARI patients, especially in children younger than 5 years, for whom the burden of NIRV-associated disease exceeds that of influenza.

Influenza vaccination is the most commonly recommended immune prevention strategy. However, data on influenza vaccination in patients with congenital heart disease (CHD) are scarce. In this study, our goals were to: (1) measure vaccination coverage rates (VCRs) for influenza in a large cohort of children, adolescents, and adults with CHD; (2) identify patient characteristics as predictors for vaccination; and (3) investigate the effect of influenza vaccination on hospitalization. A nationwide cohort study in Belgium included 16,778 patients, representing 134,782 vaccination years, from the Belgian Congenital Heart Disease Database Combining Administrative and Clinical Data (BELCODAC). Data over 9 vaccination years (2006-2015) were used, and patients were stratified into 5 age cohorts: 6 months to 4 years; 5-17 years; 18-49 years; 50-64 years; and 65 years and older. In the respective age cohorts, the VCR was estimated to be 6.6%, 8.0%, 23.9%, 46.6%, and 72.8%. There was a steep increase in VCRs as of the age of 40 years. Multivariable logistic regression showed that higher anatomical complexity of CHD, older age, presence of genetic syndromes, and previous cardiac interventions were associated with significantly higher VCRs. Among adults, men had lower and pregnant women had higher VCRs. The association between influenza vaccination and all-cause hospitalization was not significant in this study. The influenza VCR in people with CHD is low, especially in children and adolescents. Older patients, particularly those with complex CHD, are well covered. Our findings should inform vaccination promotion strategies in populations with CHD.

Il vaccino antinfluenzale Fluenz Tetra® (vaccino vivo attenuato quadrivalente, spray nasale, in sospensione) sarà disponibile in Italia per la prevenzione e il controllo dell’influenza per la stagione influenzale 2021-2022. Tale vaccino è indicato per la profilassi dell’influenza in bambini e adolescenti di età compresa tra i 24 mesi e i 18 anni [1]. I decision makers dovranno, quindi, presto valutarne l’utilizzo. Questa decisione potrebbe essere supportata dalla disponibilità di uno specifico rapporto di Health Technology Assessment (HTA). Infatti, l’HTA rappresenta oggi l’approccio valutativo più utile per i decision makers per prendere le più appropriate decisioni in ambito sanitario in base alle prove scientifiche disponibili. Anche il Piano Nazionale Prevenzione Vaccinale 2017-2019 (PNPV 2017-2019) conferma il ruolo rilevante dell’HTA ai fini della valutazione delle potenzialità e dei limiti di un vaccino e auspica un sempre maggiore utilizzo di questa metodologia per favorire le decisioni basate sulle evidenze, in un’ottica di corretto utilizzo delle limitate risorse disponibili [2]. In ambito vaccinale l’HTA si esplica nella valutazione dell’epidemiologia della specifica infezione e delle malattie correlate nella popolazione target, del disease burden della patologia, delle attuali misure preventive e terapeutiche disponibili contro l'infezione e le malattie esaminate, dell’efficacia e sicurezza del vaccino oggetto di studio e degli eventuali altri vaccini disponibili, delle valutazioni economiche, e infine degli aspetti etici, legali, sociali e organizzativi correlati all’introduzione di tale vaccino [3]. Pertanto, tutte le evidenze scientifiche disponibili su questi aspetti dovrebbero essere raccolte e esaminate criticamente all’interno di un rapporto di HTA al fine di eseguire una valutazione completa. Particolare attenzione va posta sul fatto che questa metodologia di valutazione si applica non solo per la valutazione dell’introduzione di nuovi vaccini (c

BACKGROUND: The severity of an influenza infection is influenced by both host and viral characteristics. This study aims to assess the relevance of viral genomic data for the prediction of severe influenza A(H3N2) infections among patients hospitalized for severe acute respiratory infection (SARI), in view of risk assessment and patient management. METHODS: 160 A(H3N2) influenza positive samples from the 2016-2017 season originating from the Belgian SARI surveillance were selected for whole genome sequencing. Predictor variables for severity were selected using a penalized elastic net logistic regression model from a combined host and genomic dataset, including patient information and nucleotide mutations identified in the viral genome. The goodness-of-fit of the model combining host and genomic data was compared using a likelihood-ratio test with the model including host data only. Internal validation of model discrimination was conducted by calculating the optimism-adjusted area under the Receiver Operating Characteristic curve (AUC) for both models. RESULTS: The model including viral mutations in addition to the host characteristics had an improved fit ([Formula: see text]=12.03, df = 3, p = 0.007). The optimism-adjusted AUC increased from 0.671 to 0.732. CONCLUSIONS: Adding genomic data (selected season-specific mutations in the viral genome) to the model containing host characteristics improved the prediction of severe influenza infection among hospitalized SARI patients, thereby offering the potential for translation into a prospective strategy to perform early season risk assessment or to guide individual patient management.

In order to reduce the burden on healthcare systems and to support differential diagnosis with COVID-19, influenza and pneumococcal vaccinations were strongly recommended during the COVID-19 pandemic, especially in vulnerable groups. However, no univocal and conclusive evidence on the relationship between influenza and pneumococcal vaccinations and COVID‐19 outcomes exists. We evaluated the association between such vaccinations, COVID-19 hospitalization, intensive care unit admissions and deaths in a cohort (N = 741) of COVID-19 patients who had access to the emergency room of a large Italian University hospital between March 1, 2020 and June 1, 2020. Results show that influenza and pneumococcal vaccinations did not affect hospitalization, intensive care unit admission and deaths in COVID-19 patients in the overall sample and in those ≥65 years. The same pattern of results was confirmed considering timing of influenza vaccine administration, vaccination type, and number of uptakes in the last five vaccination campaigns. In conclusion, our study does not support an impact of influenza and pneumococcal vaccinations on COVID-19 outcomes.

Objectives: During a pandemic, healthcare workers (HCWs) are essential to the health system response. Based on our knowledge, little information is available regarding the psychosocial impact on HCWs or interventions for supporting them during pandemics. Therefore, the study aimed to assess available literature on perceived stress and psychological responses to influenza pandemics in HCWs and identify implications for healthcare practice and future research. Methods: This is a rapid review of the literature. The review was conducted according to the Preferred Reporting Items for Systematic Review and Meta-Analysis. Results: Across all the studies—both qualitative and quantitative—HCWs working during the epidemic reported frequent concerns regarding their own health and the fear of infecting their families, friends and colleagues. Moreover, social isolation, uncertainty, fears of stigmatization and reluctance to work or considering absenteeism were frequently reported. Moreover, many studies highlighted a high prevalence of high levels of stress, anxiety and depression symptoms, which could have long-term psychological implications in HCWs. Conclusions: This rapid review offers an overview of the major concerns regarding HCWs’ psychosocial well-being and possible preventive strategies, which could be useful for the current COVID-19 outbreak and similar future pandemics. Studies suggested to invest on preventive psychological, social, family and physical support and to guaranteeing reasonable work conditions and others in order to protect HCWs from the long-lasting psychological effect of the COVID-19 pandemic.

BACKGROUND Respiratory syncytial virus (RSV) is a common cause of severe respiratory illness in young children (< 5 years old) and older adults (≥ 65 years old) leading the World Health Organization (WHO) to recommend the implementation of a dedicated surveillance in countries. AIM We tested the capacity of the severe acute respiratory infection (SARI) hospital network to contribute to RSV surveillance in Belgium. METHODS During the 2018/19 influenza season, we started the SARI surveillance for influenza in Belgium in week 40, earlier than in the past, to follow RSV activity, which usually precedes influenza virus circulation. While the WHO SARI case definition for influenza normally used by the SARI hospital network was employed, flexibility over the fever criterion was allowed, so patients without fever but meeting the other case definition criteria could be included in the surveillance. RESULTS Between weeks 40 2018 and 2 2019, we received 508 samples from SARI patients. We found an overall RSV detection rate of 62.4% (317/508), with rates varying depending on the age group: 77.6% in children aged < 5 years (253/326) and 34.4% in adults aged ≥ 65 years (44/128). Over 90% of the RSV-positive samples also positive for another tested respiratory virus (80/85) were from children aged < 5 years. Differences were also noted between age groups for symptoms, comorbidities and complications. CONCLUSION With only marginal modifications in the case definition and the period of surveillance, the Belgian SARI network would be able to substantially contribute to RSV surveillance and burden evaluation in children and older adults, the two groups of particular interest for WHO.

Background: Influenza infection is a serious event for patients with heart failure (HF). Little knowledge exists about the association between influenza vaccination and outcome in patients with HF. This study sought to determine whether influenza vaccination is associated with improved long-term survival in patients with newly diagnosed HF. Methods: We performed a nationwide cohort study including all patients who were >18 years of age and diagnosed with HF in Denmark in the period of January 1, 2003, to June 1, 2015 (n=134 048). We collected linked data using nationwide registries. Vaccination status, number, and frequency during follow-up were treated as time-varying covariates in time-dependent Cox regression. Results: Follow-up was 99.8% with a median follow-up time of 3.7 years (interquartile range, 1.7-6.8 years). The vaccination coverage of the study cohort ranged from 16% to 54% during the study period. In unadjusted analysis, receiving ≥1 vaccinations during follow-up was associated with a higher risk of death. After adjustment for inclusion date, comorbidities, medications, household income, and education level, receiving ≥1 vaccinations was associated with an 18% reduced risk of death (all-cause: hazard ratio, 0.82; 95% CI, 0.81-0.84; P<0.001; cardiovascular causes: hazard ratio, 0.82; 95% CI, 0.81-0.84; P<0.001). Annual vaccination, vaccination early in the year (September to October), and greater cumulative number of vaccinations were associated with larger reductions in the risk of death compared with intermittent vaccination. Conclusions: In patients with HF, influenza vaccination was associated with a reduced risk of both all-cause and cardiovascular death after extensive adjustment for confounders. Frequent vaccination and vaccination earlier in the year were associated with larger reductions in the risk of death compared with intermittent and late vaccination.

We analysed the impact of several strategies aimed at increasing influenza immunisation rates among Medical Residents (MRs) of an Italian teaching Hospital. During the 2015–16 and 2016–17 influenza seasons we carried out several interventions: ambulatory doubling where vaccination was offered, ambulatory opening hour extension, email invitations, informative materials, forum theatre and vaccination campaign conference. In addition, during the 2016–17 the OSV was carried out: MRs who go to specific wards where they perform influenza immunisation counselling and eventually vaccinate the personnel. 99/1041 (9.5%) and 184/1013 (18.2%) MRs received the vaccine in 2015–16 and in 2016–17 respectively (p < 0.0001). Significant difference was found among three specialisation areas (medicine, surgery, “services”; p < 0.001) and among years of residency (p < 0.001). The highest coverage was found among Infectious Diseases, Paediatrics, Haematology and Hygiene MRs (80%, 67%, 52% and 52% respectively) in 2016–2017 season. The highest coverage increase was found among MRs in Pneumology and Geriatrics (566% and 268%, respectively). The coverage rate has increased even though important differences among specialties persist. The study shows a significant increase in immunisation rate among MRs after the implementation of these strategies.

Flu vaccination, as well as being effective to prevent seasonal influenza, decreases staff illness and absenteeism and reduces costs resulting from loss of productivity. Despite the effectiveness of flu vaccination, the seasonal coverage among healthcare workers is usually low. The aim of this retrospective observational study was to analyze the vaccination coverage rate among all employees (healthcare workers and administrative staff) of a large teaching hospital in Rome during the 2017-2018 influenza season, to perform a cost-consequence analysis of influenza vaccination (by evaluating the absenteeism due to illness in the epidemic period), and to assess the impact of vaccination in terms of both costs and sick days. The flu vaccination coverage rate was 9.8% among 4631 healthcare workers and 852 administrative employees. The human capital approach estimated a loss of productivity equal to 297.06 € for each vaccinated worker and 517.22 € for each unvaccinated worker (cost-outcome ratio: 120.07 €/sick day). Applying the friction cost method, a loss of productivity equal to 237.65 € for each vaccinated worker and 413.78 € for each unvaccinated worker (cost-outcome ratio: 104.19 €/sick day) was found. These results confirm the benefits of the flu vaccination for the society and the company. This allowed the management to grant one hour of permission to the flu-vaccinated workers in the following annual vaccination campaign (2018-2019).

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Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and pigs, respectively. There is no robust in vitro model for assessing the infectivity of emerging viruses in humans. Based on a recently established method, we generated long-term expanding 3D human airway organoids which accommodate four types of airway epithelial cells: ciliated, goblet, club, and basal cells. We report differentiation conditions which increase ciliated cell numbers to a nearly physiological level with synchronously beating cilia readily discernible in every organoid. In addition, the differentiation conditions induce elevated levels of serine proteases, which are essential for productive infection of human influenza viruses and low-pathogenic avian influenza viruses. We also established improved 2D monolayer culture conditions for the differentiated airway organoids. To demonstrate the ability of differentiated airway organoids to identify human-infective virus, 3D and 2D differentiated airway organoids are applied to evaluate two pairs of viruses with known distinct infectivity in humans, H7N9/Ah versus H7N2 and H1N1pdm versus an H1N1 strain isolated from swine (H1N1sw). The human-infective H7N9/Ah virus replicated more robustly than the poorly human-infective H7N2 virus; the highly human-infective H1N1pdm virus replicated to a higher titer than the counterpart H1N1sw. Collectively, we developed differentiated human airway organoids which can morphologically and functionally simulate human airway epithelium. These differentiated airway organoids can be applied for rapid assessment of the infectivity of emerging respiratory viruses to human.

Dear Editor, Influenza affects between two and three million people worldwide each year, with complications responsible for a significant number of excess hospitalizations in intensive care units (ICUs) [1]. Since the newsworthy 2009 A(H1N1) pandemic (pdm), publications about influenza in ICUs remain scarce, with crucial outstanding issues on prognosis factors including the timing of antiviral treatments [2, 3, 4, 5]. Here, we present a multicenter prospective study of critically ill influenza-infected patients aimed to identify prognosis factors associated with death. [...]

Background. Seasonal influenza can cause a significant public health burden. Vaccination is proposed as the most effective measure to prevent influenza and related undesired outcomes. Objective. To estimate the efficiency of influenza vaccination. Methods. A literature review of economic evaluations of influenza vaccinations, published over the last 5 years, was performed using MEDLINE (through PubMed), Web of Science and Scopus. Results. 935 papers were identified and 30 were selected, including studies performed in different population subgroups: general population, children, adults, elderly, pregnant women and high risk patients. Twenty-one studies were performed in Europe and in US. The majority of the studies were carried out on elderly patients and children. All except one were cost-effectiveness analyses and reported influenza vaccination as a cost-saving or cost-effective intervention. Conclusions. Vaccination strategies are economically favourable in a range of countries and sub-groups of patients.

Novel reassortant avian influenza H7N9 virus and pandemic 2009 H1N1 (H1N1pdm) virus cause human infections, while avian H7N2 and swine H1N1 virus mainly infect birds and pigs, respectively. There is no robust in vitro model for assessing the infectivity of emerging viruses in humans. Based on a recently established method, we generated long-term expanding 3D human airway organoids which accommodate four types of airway epithelial cells: ciliated, goblet, club, and basal cells. We report differentiation conditions which increase ciliated cell numbers to a nearly physiological level with synchronously beating cilia readily discernible in every organoid. In addition, the differentiation conditions induce elevated levels of serine proteases, which are essential for productive infection of human influenza viruses and low-pathogenic avian influenza viruses. We also established improved 2D monolayer culture conditions for the differentiated airway organoids. To demonstrate the ability of differentiated airway organoids to identify human-infective virus, 3D and 2D differentiated airway organoids are applied to evaluate two pairs of viruses with known distinct infectivity in humans, H7N9/Ah versus H7N2 and H1N1pdm versus an H1N1 strain isolated from swine (H1N1sw). The human-infective H7N9/Ah virus replicated more robustly than the poorly human-infective H7N2 virus; the highly human-infective H1N1pdm virus replicated to a higher titer than the counterpart H1N1sw. Collectively, we developed differentiated human airway organoids which can morphologically and functionally simulate human airway epithelium. These differentiated airway organoids can be applied for rapid assessment of the infectivity of emerging respiratory viruses to human.

In this study we describe the immunogenicity results from a subset of older people (N = 5187) who participated in a Phase 3 randomized, observer-blinded trial of AS03-TIV versus TIV (Fluarix™) (ClinicalTrials.gov, NCT00753272). Participants received one dose of AS03-TIV or TIV in each study year and antibody titers against the vaccine strains were assessed using hemagglutination-inhibition (HI) assay at 21 d and 180 d post-vaccination in each vaccine group in the 2008/09 (Year 1) and 2009/10 (Year 2) influenza seasons. Manufacturing consistency of 3 lots of AS03-TIV for HI antibody responses in Year 1 was a co-primary objective. In a post-hoc analysis, a statistical regression model included 4830 subjects in whom immunogenicity and laboratory-confirmed attack rate data were available; the analysis was performed to assess HI antibody titers against A/H3N2 as a correlate of protection for laboratory-confirmed A/H3N2 influenza. AS03-TIV and TIV elicited strong HI antibody responses against each vaccine strain 21 d post-vaccination in both years. The manufacturing consistency of 3 lots of AS03-TIV was demonstrated. In both years and each vaccine group, HI antibody responses were lower for A/H1N1 than the other vaccine strains. Day 180 seroconversion rates (proportion with ≥4-fold increase in titer compared with pre-vaccination titer) in Year 1 in the AS03-TIV and TIV groups, respectively, were 87.7% and 74.1% for A/H3N2, 69.7% and 59.6% for influenza B, and 58.3% and 47.4% for A/H1N1. The post-hoc statistical model based on A/H3N2 attack rates and HI antibody titers estimated that a 4-fold increase in post-vaccination titers against A/H3N2 was associated with a 2-fold decrease in the odds of A/H3N2 infection.

BACKGROUND: Quantitative estimates of the global burden of the 1957 influenza pandemic are lacking. Here we fill this gap by modeling historical mortality statistics.METHODS: We used annual rates of age- and cause-specific deaths to estimate pandemic-related mortality in excess of background levels in 39 countries in Europe, the Asia-Pacific region, and the Americas. We modeled the relationship between excess mortality and development indicators to extrapolate the global burden of the pandemic.RESULTS: The pandemic-associated excess respiratory mortality rate was 1.9/10,000 population (95% confidence interval [CI], 1.2-2.6 cases/10,000 population) on average during 1957-1959. Excess mortality rates varied 70-fold across countries; Europe and Latin America experienced the lowest and highest rates, respectively. Excess mortality was delayed by 1-2 years in 18 countries (46%). Increases in the mortality rate relative to baseline were greatest in school-aged children and young adults, with no evidence that elderly population was spared from excess mortality. Development indicators were moderate predictors of excess mortality, explaining 35%-77% of the variance. Overall, we attribute 1.1 million excess deaths (95% CI, .7 million-1.5 million excess deaths) globally to the 1957-1959 pandemic.CONCLUSIONS: The global mortality rate of the 1957-1959 influenza pandemic was moderate relative to that of the 1918 pandemic but was approximately 10-fold greater than that of the 2009 pandemic. The impact of the pandemic on mortality was delayed in several countries, pointing to a window of opportunity for vaccination in a future pandemic.

The prompt availability of reliable epidemiological information on emerging pandemics is crucial for public health policy-makers. Early in 2013, a possible new H1N1 epidemic notified by an intensive care unit (ICU) to GiViTI, the Italian ICU network, prompted the re-activation of the real-time monitoring system developed during the 2009-2010 pandemic. Based on data from 216 ICUs, we were able to detect and monitor an outbreak of severe H1N1 infection, and to compare the situation with previous years. The timely and correct assessment of the severity of an epidemic can be obtained by investigating ICU admissions, especially when historical comparisons can be made.

While influenza vaccines aim to decrease the incidence of severe influenza among high-risk groups, evidence of influenza vaccine effectiveness (IVE) among the influenza vaccine target population is sparse. We conducted a multicentre test-negative case–control study to estimate IVE against hospitalised laboratoryconfirmed influenza in the target population in 18 hospitals in France, Italy, Lithuania and the Navarre and Valencia regions in Spain. All hospitalised patients aged ≥18 years, belonging to the target population presenting with influenza-like illness symptom onset within seven days were swabbed. Patients positive by reverse transcription polymerase chain reaction for influenza virus were cases and those negative were controls. Using logistic regression, we calculated IVE for each influenza virus subtype and adjusted it for month of symptom onset, study site, age and chronic conditions. Of the 1,972 patients included, 116 were positive for influenza A(H1N1)pdm09, 58 for A(H3N2) and 232 for influenza B. Adjusted IVE was 21.3% (95% confidence interval (CI): -25.2 to 50.6; n=1,628), 61.8% (95% CI: 26.8 to 80.0; n=557) and 43.1% (95% CI: 21.2 to 58.9; n=1,526) against influenza A(H1N1) pdm09, A(H3N2) and B respectively. Our results suggest that the 2012/13 IVE was moderate against influenza A(H3N2) and B and low against influenza A(H1N1) pdm09.

1-9, Dynamic transmission models are essential to design and evaluate control strategies for airborne infections. Our objective was to develop a dynamic transmission model for seasonal influenza allowing to evaluate the impact of vaccinating specific age groups on the incidence of infection, disease and mortality. Projections based on such models heavily rely on assumed ‘input’ parameter values. In previous seasonal influenza models, these parameter values were commonly chosen ad hoc, ignoring between-season variability and without formal model validation or sensitivity analyses. We propose to directly estimate the parameters by fitting the model to age-specific influenza-like illness (ILI) incidence data over multiple influenza seasons. We used a weighted least squares (WLS) criterion to assess model fit and applied our method to Belgian ILI data over six influenza seasons. After exploring parameter importance using symbolic regression, we evaluated a set of candidate models of differing complexity according to the number of season-specific parameters. The transmission parameters (average R0, seasonal amplitude and timing of the seasonal peak), waning rates and the scale factor used for WLS optimization, influenced the fit to the observed ILI incidence the most. Our results demonstrate the importance of between-season variability in influenza transmission and our estimates are in line with the classification of influenza seasons according to intensity and vaccine matching.

BACKGROUND: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients.METHODS AND FINDINGS: Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A (H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1-3) and 6 days (IQR 4-10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4-7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5-26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons.CONCLUSIONS: Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of season

BACKGROUND: Data from prospectively planned cohort studies on risk of major clinical outcomes and prognostic factors for patients with influenza A(H1N1)pdm09 virus are limited. In 2009, in order to assess outcomes and evaluate risk factors for progression of illness, two cohort studies were initiated: FLU 002 in outpatients and FLU 003 in hospitalized patients.METHODS AND FINDINGS: Between October 2009 and December 2012, adults with influenza-like illness (ILI) were enrolled; outpatients were followed for 14 days and inpatients for 60 days. Disease progression was defined as hospitalization and/or death for outpatients, and hospitalization for >28 days, transfer to intensive care unit (ICU) if enrolled from general ward, and/or death for inpatients. Infection was confirmed by RT-PCR. 590 FLU 002 and 392 FLU 003 patients with influenza A (H1N1)pdm09 were enrolled from 81 sites in 17 countries at 2 days (IQR 1-3) and 6 days (IQR 4-10) following ILI onset, respectively. Disease progression was experienced by 29 (1 death) outpatients (5.1%; 95% CI: 3.4-7.2%) and 80 inpatients [death (32), hospitalization >28 days (43) or ICU transfer (20)] (21.6%; 95% CI: 17.5-26.2%). Disease progression (death) for hospitalized patients was 53.1% (26.6%) and 12.8% (3.8%), respectively, for those enrolled in the ICU and general ward. In pooled analyses for both studies, predictors of disease progression were age, longer duration of symptoms at enrollment and immunosuppression. Patients hospitalized during the pandemic period had a poorer prognosis than in subsequent seasons.CONCLUSIONS: Patients with influenza A(H1N1)pdm09, particularly when requiring hospital admission, are at high risk for disease progression, especially if they are older, immunodeficient, or admitted late in infection. These data reinforce the need for international trials of novel treatment strategies for influenza infection and serve as a reminder of the need to monitor the severity of season

INTRODUCTION Health authorities find thresholds useful to gauge the start and severity of influenza seasons. We explored a method for deriving thresholds proposed in an influenza surveillance manual published by the World Health Organization (WHO). METHODS For 2002-2011, we analysed two routine influenza-like-illness (ILI) datasets, general practice sentinel surveillance and a locum medical service sentinel surveillance, plus laboratory data and hospital admissions for influenza. For each sentinel dataset, we created two composite variables from the product of weekly ILI data and the relevant laboratory data, indicating the proportion of tested specimens that were positive. For all datasets, including the composite datasets, we aligned data on the median week of peak influenza or ILI activity and assigned three threshold levels: seasonal threshold, determined by inspection; and two intensity thresholds termed average and alert thresholds, determined by calculations of means, medians, confidence intervals (CI) and percentiles. From the thresholds, we compared the seasonal onset, end and intensity across all datasets from 2002-2011. Correlation between datasets was assessed using the mean correlation coefficient. RESULTS The median week of peak activity was week 34 for all datasets, except hospital data (week 35). Means and medians were comparable and the 90% upper CIs were similar to the 95(th) percentiles. Comparison of thresholds revealed variations in defining the start of a season but good agreement in describing the end and intensity of influenza seasons, except in hospital admissions data after the pandemic year of 2009. The composite variables improved the agreements between the ILI and other datasets. Datasets were well correlated, with mean correlation coefficients of >0.75 for a range of combinations. CONCLUSIONS Thresholds for influenza surveillance are easily derived from historical surveillance and laboratory data using the approach proposed by WHO. Use

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29).CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.

Prospective studies establishing the temporal relationship between the degree of inflammation and human influenza disease progression are scarce. To assess predictors of disease progression among patients with influenza A(H1N1)pdm09 infection, 25 inflammatory biomarkers measured at enrollment were analyzed in two international observational cohort studies.

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29).CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29).CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.

BACKGROUND: Pregnant women were suspected to be at particular risk when H1N1pnd09 influenza became pandemic in 2009. Our primary objective was to compare the immune responses conferred by MF59®-adjuvanted vaccine (Focetria®) in H1N1pnd09-naïve pregnant and non-pregnant women. The secondary aims were to compare influences of dose and adjuvant on the immune response.METHODS: The study was nested in the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) pregnancy cohort in 2009-2010 and conducted as a single-blinded block-randomised [1∶1∶1] controlled clinical trial in pregnant women after gestational week 20: (1) 7.5 µg H1N1pnd09 antigen with MF59-adjuvant (Pa7.5 µg); (2) 3.75 µg antigen half MF59-adjuvanted (Pa3.75 µg); (3) 15 µg antigen unadjuvanted (P15 µg); and in non-pregnant women receiving (4) 7.5 µg antigen full adjuvanted (NPa7.5 µg). Blood samples were collected at baseline, 3 weeks, 3 and 10 months after vaccination, adverse events were recorded prospectively.RESULTS: 58 pregnant women were allocated to Pa7.5 µg and 149 non-pregnant women were recruited to NPa7.5 µg. The sero-conversion rate was significantly increased in non-pregnant (NPa7.5 µg) compared with pregnant (Pa7.5 µg) women (OR = 2.48 [1.03-5.95], p = 0.04) and geometric mean titers trended towards being higher, but this difference was not statistically significant (ratio 1.27 [0.85-1.93], p = 0.23). The significant titer increase rate showed no difference between pregnant (Pa7.5 µg) and non-pregnant (NPa7.5 µg) groups (OR = 0.49 [0.13-1.85], p = 0.29).CONCLUSION: Our study suggests the immune response to the 7.5 µg MF59-adjuvanted Focetria® H1N1pnd09 vaccine in pregnant women may be diminished compared with non-pregnant women.TRIAL REGISTRATION: ClinicalTrials.gov NCT01012557.

BACKGROUND: This study aims to evaluate the length of time elapsed between reports of the same incidents related to avian flu and H1N1 outbreaks published by the WHO and ProMED-mail, the two major global health surveillance systems, before and after the amendment of the International Health Regulations in 2005 (IHR 2005) and to explore the association between country transparency and this timeliness gap. METHODS: We recorded the initial release dates of each report related to avian flu or H1N1 listed on the WHO Disease Outbreak News site and the matching outbreak report from ProMED-mail, a non-governmental program for monitoring emerging diseases, from 2003 to the end of June 2009. The timeliness gap was calculated as the difference in days between the report release dates of the matching outbreaks in the WHO and ProMED-mail systems. Civil liberties scores were collected as indicators of the transparency of each country. The Human Development Index and data indicating the density of physicians and nurses were collected to reflect countries' development and health workforce statuses. Then, logistic regression was performed to determine the correlation between the timeliness gap and civil liberties, human development, and health workforce status, controlling for year. RESULTS: The reporting timeliness gap for avian flu and H1N1 outbreaks significantly decreased after 2003. On average, reports were posted 4.09 (SD = 7.99) days earlier by ProMED-mail than by the WHO. Countries with partly free (OR = 5.77) and free civil liberties scores (OR = 10.57) had significantly higher likelihoods of longer timeliness gaps than non-free countries. Similarly, countries with very high human development status had significantly higher likelihoods of longer timeliness gaps than countries with middle or low human development status (OR = 5.30). However, no association between the timeliness gap and health workforce density was found. CONCLUSION: The study found that the adoption of IHR

Swine generate reassortant influenza viruses because they can be simultaneously infected with avian and human influenza; however, the features that restrict influenza reassortment in swine and human hosts are not fully understood. Type I and III interferons (IFNs) act as the first line of defense against influenza virus infection of respiratory epithelium. To determine if human and swine have different capacities to mount an antiviral response the expression of IFN and IFN-stimulated genes (ISG) in normal human bronchial epithelial (NHBE) cells and normal swine bronchial epithelial (NSBE) cells was evaluated following infection with human (H3N2), swine (H1N1), and avian (H5N3, H5N2, H5N1) influenza A viruses. Expression of IFNλ and ISGs were substantially higher in NHBE cells compared to NSBE cells following H5 avian influenza virus infection compared to human or swine influenza virus infection. This effect was associated with reduced H5 avian influenza virus replication in human cells at late times post infection. Further, RIG-I expression was lower in NSBE cells compared to NHBE cells suggesting reduced virus sensing. Together, these studies identify key differences in the antiviral response between human and swine respiratory epithelium alluding to differences that may govern influenza reassortment.

28 p., Ill., FOREWORD 1 -- ABSTRACT 2 -- SYNTHESIS 4 -- 1. INFLUENZA DISEASE AND VACCINES 6 -- 1.1. INFLUENZA, A COMMON DISEASE BUT A COMPLEX VIRUS 6 -- 1.2. INFLUENZA VACCINES AND POLICIES IN BELGIUM 6 -- 1.3. WHY VACCINATING CHILDREN AGAINST SEASONAL INFLUENZA? 7 -- 1.4. RESEARCH QUESTIONS 7 -- 2. METHODS 8 -- 2.1. VACCINATION OPTIONS 8 -- 2.2. MODELS 8 -- 2.2.1. Dynamic model 9 -- 2.2.2. Static model 9 -- 2.3. ECONOMIC ANALYSIS 9 -- 3. MODEL PARAMETERS AND ASSUMPTIONS 10 -- 3.1. DISEASE BURDEN AND TRANSMISSION 10 -- 3.2. INFLUENZA VACCINES, SAFETY AND IMMUNITY 11 -- 4. COST-EFFECTIVENESS OF SEASONAL INFLUENZA VACCINATION 15 -- 4.1. VACCINATING CHILDREN ONLY 15 -- 4.2. MODIFYING VACCINATION COVERAGE IN ADULTS ONLY 17 -- 4.2.1. By age group 17 -- 4.2.2. In specific target groups 19 -- 4.3. VACCINATING CHILDREN AND MODIFYING COVERAGE IN ADULTS 20 -- 5. DISCUSSION 21 -- 5.1. VACCINATING CHILDREN 21 -- 5.2. CHANGING COVERAGE IN ADULTS WITH OR WITHOUT CHILDHOOD VACCINATION 22 -- 5.3. LIMITATIONS OF THE STUDY 23 -- 5.4. FUTURE PERSPECTIVES 23 -- 6. CONCLUSIONS 24 -- REFERENCES 26 -- RECOMMENDATIONS 28

30 p., Ill., PRÉFACE 1 -- RÉSUMÉ 2 -- SYNTHÈSE 4 -- 1. LA GRIPPE ET LES VACCINS ANTIGRIPPAUX 6 -- 1.1. LA GRIPPE, UNE MALADIE COURANTE, MAIS UN VIRUS COMPLEXE 6 -- 1.2. POLITIQUES ET VACCINS ANTIGRIPPAUX EN BELGIQUE 6 -- 1.3. POURQUOI VACCINER LES ENFANTS CONTRE LA GRIPPE SAISONNIÈRE? 7 -- 1.4. QUESTIONS DE RECHERCHE 8 -- 2. MÉTHODES 8 -- 2.1. OPTIONS DE VACCINATION 8 -- 2.2. MODÈLES 9 -- 2.2.1. Modèle dynamique 9 -- 2.2.2. Modèle statique 9 -- 2.3. ANALYSE ÉCONOMIQUE 9 -- 3. HYPOTHÈSES ET PARAMÈTRES DU MODÈLE 11 -- 3.1. CHARGE DE MORBIDITÉ ET TRANSMISSION 11 -- 3.2. VACCINS ANTIGRIPPAUX, SÉCURITÉ ET IMMUNITÉ 12 -- 4. RAPPORT COÛT-EFFICACITÉ DE LA VACCINATION CONTRE LA GRIPPE SAISONNIÈRE 16 -- 4.1. VACCINATION DES ENFANTS UNIQUEMENT 16 -- 4.2. MODIFICATION DE LA COUVERTURE VACCINALE DES ADULTES UNIQUEMENT 18 -- 4.2.1. Par groupe d'âge 18 -- 4.2.2. Parmi les groupes cibles spécifiques 20 -- 4.3. VACCINATION DES ENFANTS ET MODIFICATION DE LA COUVERTURE DES ADULTES 21 -- 5. DISCUSSION 22 -- 5.1. VACCINATION DES ENFANTS 22 -- 5.2. MODIFIER LA COUVERTURE ADULTE, AVEC OU SANS VACCINATION DES ENFANTS 24 -- 5.3. LIMITATIONS DE L'ÉTUDE 24 -- 5.4. PERSPECTIVES FUTURES 25 -- 6. CONCLUSIONS 26 -- RÉFÉRENCES 27 -- RECOMMANDATIONS 29

29 p., Ill., 5. STATIC MODEL: ADDITIONAL RESULTS 3 -- 5.1. HCW WITHOUT MARGINAL ADMINISTRATION COSTS 3 -- 5.1.1. HCW aged 20-29 years 3 -- 5.1.2. HCW aged 30-49 years 4 -- 5.1.3. HCW aged 50-65 years 5 -- 5.2. HCW WITH MARGINAL ADMINISTRATION COSTS 14 -- 5.2.1. HCW aged 20-29 years 14 -- 5.2.2. HCW aged 30-49 years 15 -- 5.2.3. HCW aged 50-65 years 16

30 p., Ill., VOORWOORD 1 -- SAMENVATTING 2 -- SYNTHESE 4 -- 1. INFLUENZA, ZIEKTE EN VACCINS 6 -- 1.1. INFLUENZA, EEN VEEL VOORKOMENDE ZIEKTE MAAR EEN COMPLEX VIRUS 6 -- 1.2. INFLUENZAVACCINS EN BELEID IN BELGIË 6 -- 1.3. WAAROM VACCINEREN TEGEN SEIZOENSINFLUENZA? 7 -- 1.4. ONDERZOEKSVRAGEN 8 -- 2. METHODEN 8 -- 2.1. VACCINATIE-OPTIES 8 -- 2.2. MODELLEN 9 -- 2.2.1. Dynamisch model 9 -- 2.2.2. Statisch model 9 -- 2.3. ECONOMISCHE ANALYSE 10 -- 3. MODELPARAMETERS EN VERONDERSTELLINGEN 10 -- 3.1. ZIEKTELAST EN OVERDRACHT 10 -- 3.2. INFLUENZAVACCINS, VEILIGHEID EN IMMUNITEIT 12 -- 4. KOSTENEFFECTIVITEIT VAN VACCINATIE TEGEN SEIZOENSINFLUENZA 16 -- 4.1. ALLEEN KINDEREN VACCINEREN 16 -- 4.2. ALLEEN WIJZIGEN VAN DE VACCINATIEDEKKING BIJ VOLWASSENEN 18 -- 4.2.1. Per leeftijdsgroep 18 -- 4.2.2. In specifieke doelgroepen 19 -- 4.3. VACCINEREN VAN KINDEREN EN WIJZIGEN VAN DE VACCINATIEDEKKING BIJ -- VOLWASSENEN 21 -- 5. BESPREKING 22 -- 5.1. HET VACCINEREN VAN KINDEREN 22 -- 5.2. DE VACCINDEKKING BIJ VOLWASSENEN VERANDEREN MET OF ZONDER VACCINATIE VOOR -- KINDEREN 24 -- 5.3. BEPERKINGEN VAN HET ONDERZOEK 24 -- 5.4. TOEKOMSTIGE OVERWEGINGEN 25 -- 6. CONCLUSIES 26 -- REFERENCES 27 -- AANBEVELINGEN 29

247 p., Ill., SCIENTIFIC REPORT 16 -- 1 BACKGROUND 16 -- 2 OBJECTIVES 18 -- 3 EVIDENCE REVIEWS 18 -- 3.1 VACCINE EFFICACY AND EFFECTIVENESS 18 -- 3.1.1 Methods 18 -- 3.1.2 Influenza vaccine efficacy in children. 20 -- 3.1.3 Influenza vaccine efficacy in healthy adults 25 -- 3.1.4 Influenza vaccine efficacy/effectiveness in the elderly 26 -- 3.1.5 Influenza vaccine efficacy/effectiveness in the persons ≤65 years with co-morbidities 29 -- 3.2 VACCINE SAFETY 30 -- 3.2.1 Influenza vaccines safety in children 30 -- 3.2.2 Influenza vaccines safety in adults 31 -- 3.2.3 Special potential issues for influenza vaccine safety 33 -- 3.3 ECONOMIC EVALUATIONS 34 -- 3.3.1 Childhood vaccination options 34 -- 3.3.2 Adult vaccination options 40 -- 3.4 DYNAMIC TRANSMISSION MODELS 44 -- 3.4.1 Search strategy 44 -- 3.4.2 Results 45 -- 3.5 QUALITY OF LIFE 54 -- 3.5.1 Search strategy 54 -- 3.5.2 Results 54 -- 4 DATA COLLECTION AND INTERMEDIARY ANALYSES 59 -- 4.1 EPIDEMIOLOGICAL AND BURDEN OF DISEASE DATA 59 -- 4.1.1 ILI and influenza surveillance, hospitalization rates and deaths 59 -- 4.1.2 Estimation of influenza related admissions and deaths through regression analyses 59 -- 4.2 COST DATA 65 -- 4.2.1 Out of hospital costs for Influenza Like Illness (ILI) and clinically diagnosed influenza 65 -- 4.2.2 In-hospital costs for hospitalised influenza patients 76 -- 5 METHODS 80 -- 5.1 OPTIONS FOR VACCINATION 80 -- 5.1.1 Using the dynamic transmission model 80 -- 5.1.2 Using the static models 81 -- 5.2 DESCRIPTION OF THE DYNAMIC TRANSMISSION MODEL 81 -- 5.2.1 Model structure 81 -- 5.2.2 Fundamental differences between our and Vynnycky et al’s approach 87 -- 5.2.3 Dynamic model parameter imputation by fitting to past observations 89 -- 5.3 DESCRIPTION OF THE STATIC MODELS 97 -- 5.4 ANALYTICAL APPROACH TO ECONOMIC EVALUATION 97 -- 5.5 PARAMETER VALUES AND DISTRIBUTIONS 99 -- 5.5.1 Parameters for dynamic transmission model-based projections 99 -- 5.5.2 Parameters for static model-based projections 105