Estimates of Seasonal Influenza Burden That Could Be Averted by Improved Influenza Vaccines in the Australian Population Aged Under 65 Years, 2015-2019.

BACKGROUND: The interpretation of relative vaccine effectiveness (rVE) of improved influenza vaccines is complex. Estimation of burden averted is useful to contextualise their potential impact across different seasons. For the population aged under 65 years in Australia, this study estimated the additional morbidity and mortality that could be averted using improved influenza vaccines. METHODS: We used observed, season-specific (2015-2019) influenza notification and influenza-coded hospitalisation frequencies and published modelled estimates of influenza-associated hospitalisations and deaths that occurred under the prevailing influenza vaccination coverage scenario. After back-calculating to the estimated burden in the population without vaccination, we applied published standard influenza vaccine effectiveness and coverage estimates to calculate the burden potentially averted by standard and improved influenza vaccines. A plausible range of rVE values were used, assuming 50% coverage. RESULTS: The percentage point difference in absolute vaccine effectiveness (VE) of an improved vaccine compared to a standard vaccine is directly proportional to its rVE and inversely proportional to the effectiveness of the standard vaccine. The incremental burden averted by an improved vaccine is a function of both its difference in absolute VE and the severity of the influenza season. Assuming an rVE of 15% with 50% coverage, the improved vaccine was estimated to additionally avert 1517 to 12,641 influenza notifications, 287 to 1311 influenza-coded hospitalisations and 9 to 33 modelled all-cause influenza deaths per year compared to the standard vaccine. CONCLUSIONS: Improved vaccines can have substantial clinical and population impact, particularly when the effectiveness of standard vaccines is low, and burden is high.

The association between influenza vaccination uptake and influenza and pneumonia-associated deaths in the United States.

BACKGROUND: The influenza mortality burden has remained substantial in the United States (US) despite relatively high levels of influenza vaccine uptake. This has led to questions regarding the effectiveness of the program against this outcome, particularly in the elderly. The aim of this evaluation was to develop and explore a new approach to estimating the population-level effect of influenza vaccination uptake on pneumonia and influenza (P&I) associated deaths. METHODS: Using publicly available data we examined the association between state-level influenza vaccination and all-age P&I associated deaths in the US from the 2013-2014 influenza season to the 2018-2019 season. In the main model, we evaluated influenza vaccine uptake in all those age 6 months and older. We used a mixed-effects regression analysis with generalised least squares estimation to account for within state correlation in P&I mortality. RESULTS: From 2013-2014 through 2018-2019, the total number of all-age P&I related deaths during the influenza seasons was 480,111. The mean overall cumulative influenza vaccine uptake (age 6 months and older) across the states and years considered was 46.7%, with higher uptake (64.8%) observed in those aged ≥ 65 years. We found that overall influenza vaccine uptake (6 months and older) had a statistically significant protective association with the P&I death rate. This translated to a 0.33 (95% CI: 0.20, 0.47) per 100,000 population reduction in P&I deaths in the influenza season per 1% increase in overall influenza vaccine uptake. DISCUSSION: These results using a population-level statistical approach provide additional support for the overall effectiveness of the US influenza vaccination program. This reassurance is critical given the importance of ensuring confidence in this life saving program. Future research is needed to expand on our approach using more refined data.

Bayesian structural time series, an alternative to interrupted time series in the right circumstances.

OBJECTIVES: Compare two approaches to analyzing time series data-interrupted time series with segmented regression (ITS-SR) and Bayesian structural time series using the CausalImpact R package (BSTS-CI)-highlighting advantages, disadvantages, and implementation considerations. STUDY DESIGN AND SETTING: We analyzed electronic health records using each approach to estimate the antibiotic prescribing reduction associated with an educational program delivered to Australian primary care physicians between 2012 and 2017. Two outcomes were considered: antibiotics for upper respiratory tract infections (URTIs) and antibiotics of specified formulations. RESULTS: For URTI indication prescribing, average monthly prescriptions changes were estimated at -4,550; (95% confidence interval, -5,486 to -3,614) and -4,270; (95% credible interval, -5,934 to -2,626) for ITS-SR and BSTS-CI, respectively. Similarly for specified formulation prescribing, monthly average changes were estimated at -7,923; (95% confidence interval, -15,887 to 40) for ITS-SR and -20,269; (95% credible interval, -25,011 to -15,635) for BSTS-CI. CONCLUSION: Differing results between ITS-SR and BSTS-CI appear driven by divergent explanatory and outcome series trends. The BSTS-CI may be a suitable alternative to ITS-SR only if the explanatory series represent the secular trend of the outcome series before the intervention and are equally affected by exogenous or confounding factors. When appropriately applied, BSTS-CI provides an alternative to ITS with more readily interpretable Bayesian effect estimates.

Effectiveness of influenza vaccination in reducing influenza-like illness and related antibiotic prescriptions in adults from a primary care-based case-control study.

BACKGROUND: Evidence on the effectiveness of influenza vaccine in preventing antibiotic prescriptions for influenza-like illness (ILI) in adults is limited. METHODS: A primary care-based case-control study was conducted to estimate influenza vaccine effectiveness (VE) against influenza-like illness (ILI) and antibiotic prescribing for ILI in adults aged ≥40 years. Cases were patients diagnosed with ILI from 1st June to 30th September in each year, 2015-2018; a subset of those with ILI prescribed antibiotics was also defined. Controls were patients attending a practice who did not receive an ILI diagnosis. Generalised estimating equations were used to calculate adjusted VE overall, by age (<65 versus ≥65 years) and comorbidity status. RESULTS: The number of ILI cases varied from 558 in 2018 to 2901 in 2017 and controls from 86618 in 2015 to 136763 in 2017. Over 4 years the pooled estimate of VE was 24% (95%CI, 11% to 34%) against ILI and 15% (95%CI, -3% to 29%) against antibiotic prescription for ILI. Influenza vaccine was effective in reducing ILI with an associated antibiotic prescriptions in patients aged <65 years (VE=23%, 95%CI, 3% to 38%) and if no comorbidities were recorded (VE=22%, 95%CI, 1% to 39%) but not in other subgroups. CONCLUSIONS: Influenza vaccine reduced the likelihood of antibiotic prescriptions for ILI in low-risk adults (40-64 years and those without comorbidities).

Modelled estimates of hospitalisations attributable to respiratory syncytial virus and influenza in Australia, 2009-2017.

BACKGROUND: Respiratory syncytial virus (RSV) and influenza are important causes of disease in children and adults. In Australia, information on the burden of RSV in adults is particularly limited. METHODS: We used time series analysis to estimate respiratory, acute respiratory infection, pneumonia and influenza, and bronchiolitis hospitalisations attributable to RSV and influenza in Australia during 2009 through 2017. RSV and influenza-coded hospitalisations in <5-year-olds were used as proxies for relative weekly viral activity. RESULTS: From 2009 to 2017, the estimated all-age average annual rates of respiratory hospitalisations attributable to RSV and seasonal influenza (excluding 2009) were 54.8 (95% confidence interval [CI]: 20.1, 88.8) and 87.8 (95% CI: 74.5, 97.7) per 100,000, respectively. The highest estimated average annual RSV-attributable respiratory hospitalisation rate per 100,000 was 464.2 (95% CI: 285.9, 641.2) in <5-year-olds. For seasonal influenza, it was 521.6 (95% CI: 420.9, 600.0) in persons aged ≥75 years. In ≥75-year-olds, modelled estimates were approximately eight and two times the coded estimates for RSV and seasonal influenza, respectively. CONCLUSIONS: RSV and influenza are major causes of hospitalisation in young children and older adults in Australia, with morbidity underestimated by hospital diagnosis codes.

RSV Epidemiology in Australia Before and During COVID-19.

COVID-19 public health measures altered respiratory syncytial virus (RSV) epidemiology. We examined age-stratified trends in RSV-related disease in Australian children in 2020 compared with previous years.

Influenza-associated mortality in Australia, 2010 through 2019: High modelled estimates in 2017.

INTRODUCTION: In Australia, the 2017 and 2019 influenza seasons were severe. High-dose or adjuvanted vaccines were introduced for ≥65 year-olds in 2018. AIM: To compare influenza-associated mortality in 2017 and 2019 with the average for 2010-2019. METHODS: We used time series modelling to obtain estimates of influenza-associated death rates for influenza A(H1N1)pdm09, A(H3N2) and B in Australia, in persons of all ages and <65, 65-74 and ≥75 years. Estimates were made for pneumonia and influenza (P&I, 2010-2018), respiratory (2010-2018), and all-cause outcomes (2010-2019). RESULTS: During 2010 through 2018 (and 2019 for all-cause), influenza was estimated to be associated with an annual average of 2.1 (95% confidence interval (CI) 1.9, 2.4), 4.0 (95% CI 3.4, 4.6), and 11.6 (95% CI 8.4, 15.0) P&I, respiratory and all-cause deaths per 100,000 population, respectively. Influenza A(H1N1)pdm09 was estimated to be associated with less than one quarter of influenza-associated P&I and respiratory deaths, while A(H3N2) and B were each estimated to contribute approximately equally to the remaining influenza-associated deaths. In 2017, the respective rates were 7.8 (95% CI 7.1, 8.4), 12.3 (95% CI 10.9, 13.6) and 26.0 (95% CI 20.8, 32.0) per 100,000. In 2019, the all-cause estimate was 20.8 (95% CI 14.9, 26.7) per 100,000. CONCLUSIONS: Seasonal influenza continues to be associated with substantial mortality in Australia, with at least double the average occurring in 2017. Age-specific monitoring of vaccine effectiveness is needed in Australia to understand higher mortality seasons.

Evaluation of the Indonesian Early Warning Alert and Response System (EWARS) in West Papua, Indonesia.

Background: The Early Warning and Response System (EWARS) is Indonesia's national syndromic and early warning surveillance system for the rapid detection of infectious diseases and outbreaks. We evaluated EWARS in the remote West Papua province of Indonesia. Methods: Structured telephone interviews were conducted with 11 key informants from West Papuan health services. EWARS data were analysed for usefulness of reporting. Results: Most respondents reported that EWARS is important and useful in improving early detection of outbreaks. The system has led to increased disease control coordination among health jurisdictional levels in the province. However, respondents noted that the limited number of districts involved in the system affected representativeness, and some stated that only about 30-35% of districts in each regency were involved and trained in EWARS reporting, partly owing to lack of a mobile telephone network. Barriers to complete reporting and response to alerts included limited human and funding resources for surveillance, lack of epidemiological training, and technical limitations imposed by limited internet and mobile communication infrastructure in this remote region. Conclusion: Great progress has been made in integrating West Papua into a nationally consistent disease and outbreak detection system. Strategies for addressing barriers resulting from remoteness, constrained human, funding and laboratory resources, lack of training, and limited internet and communications infrastructure are needed if EWARS in West Papua is to advance.

Estimated hospitalisations attributable to seasonal and pandemic influenza in Australia: 2001- 2013.

BACKGROUND: Influenza continues to cause seasonal epidemics and pandemics in humans. The burden of influenza is underestimated by traditional laboratory-based surveillance, and modelled estimates are required for influenza-attributable morbidity and mortality. We aimed to estimate the influenza-attributable hospitalisation in Australia, by influenza type. METHODS: A generalised-additive regression model was used to estimate type- and age-specific influenza-attributable hospitalisation rates per 100,000 population by principal diagnosis in Australia, from 2001 through 2013. Weekly counts of laboratory-confirmed influenza notifications and by type, influenza A and B were used as covariates in the model. Main principal diagnosis categories of interest were influenza and pneumonia and respiratory admissions. A smoothing spline was used to control for unmeasured time varying factors. Results for 2009, in which the pandemic influenza A(H1N1)pdm09 virus circulated, were not included in annual averages and are reported separately. RESULTS: During the study period, the estimated annual average, all-age, annual respiratory hospitalisation rates attributable to seasonal influenza type A, B and total influenza were 45.4 (95% CI: 34.9, 55.9), 32.6 (95% CI: 22.8, 42.4), and 76.9 (95% CI: 73.6, 80.2) per 100,000 population, respectively. During 2009, the estimated total pandemic influenza-attributable, all-age, respiratory hospitalisation rate was 56.1 (95% CI: 47.4, 64.9) per 100,000. Older adults (≥85 years of age) experienced the highest influenza-attributable hospitalisation rates for both seasonal and 2009 pandemic influenza. Collinearity between influenza A and B time series in some years limited the ability of the model to resolve differences in influenza attribution between the two virus types. CONCLUSION: Both seasonal and pandemic influenza caused considerable morbidity in Australia during the years studied, particularly among older adults. The pandemic hospitalisation rate in 2009 was lower than the average overall annual rate for seasonal influenza, but young to middle aged adults experience a hospitalisation rate similar to that of severe seasonal influenza.

A model of influenza infection and vaccination in children aged under 5 years in Beijing, China.

BACKGROUND: Children aged under 5 years are particularly vulnerable to influenza infection. In this study, we aim to estimate the number and incidence of influenza among young children and estimate the impact of childhood vaccination in different scenarios from 2013/14 to 2016/17 seasons. METHODS: The number and incidence rate of influenza infections among children aged under 5 years in Beijing was estimated by scaling up observed surveillance data. Then, we used a susceptible-exposed-infected-recovery (SEIR) model to reproduce the weekly number of influenza infections estimated in Beijing during the study seasons, and to estimate the number and proportion of influenza-attributed medically attended acute respiratory infections (I-MAARI) averted by vaccination in each season. Finally, we evaluated the impact of alternative childhood vaccination programs with different coverage and speed of vaccine distribution. RESULTS: The estimated average annual incidence of influenza in children aged under 5 years was 33.9% (95% confidence interval (CI): 27.5%, 47.2%) during the study period. With the actual coverage during the included seasons at around 2.9%, an average of 3.9% (95%CI: 3.5%, 4.4%) I-MAARI was reduced compared to a no-vaccination scenario. Reaching 20%, 40%, 50%, 60%, 80% and 100% vaccine coverage would lead to an overall I-MAARI reduction of 25.3%, 42.7%, 51.9%, 57.0%, 65.3% and 71.2%. At 20% coverage scenario, an average of 28.8% I-MAARI will be prevented if intensive vaccination implemented in 2 months since the vaccine released. CONCLUSION: In Beijing, the introduction of a program for vaccinating young children, even at relatively low vaccine coverage rates, would considerably reduce I-MAARI, particularly if the vaccines can be quickly delivered.

Effect of overseas parental employment migration on healthcare seeking for common childhood illnesses and nutritional status among left-behind young children: A systematic review.

We aimed to examine the available evidence on the impact of overseas parental migration on healthcare seeking for common childhood illnesses and the nutritional status of children left-behind under five years of age. A systematic review of English language articles was conducted on PubMed, MEDLINE and EMBASE, supplemented by a manual search of grey literature and reference lists. There were no studies examining the association between overseas parental migration and healthcare seeking for common childhood illnesses. We found three cross-sectional surveys examining the association with an indicator of nutritional status. We observed mixed findings from the available studies. The results indicated that children left-behind may have positive, negative or null effects on their nutritional status. There was insufficient information available to draw conclusions on the magnitude and direction of the association between overseas parental migration and its effect on either healthcare seeking for common childhood illnesses or the nutritional status of left-behind children. The association, if any, may be context or country dependent. Prospective studies are needed to address this important knowledge gap.

Impact of seasonal influenza on polyclinic attendances for upper respiratory tract infections in Singapore.

PURPOSE: The burden of influenza on primary health-care services is not well established in tropical countries, where there are no clearly defined influenza seasons. We aimed to estimate the association between influenza infection activity and polyclinic attendance rates for upper respiratory tract infections (URTIs) in the Singapore population. METHODS: We used generalized additive time series models to estimate the association between the proportion of respiratory tests positive for influenza infection in Singapore reported to the World Health Organization every week, and the population rate of polyclinic attendances in Singapore for physician-diagnosed URTI, which includes influenza-like illness (ILI), for six years from 2012 through 2017. Where data were available, we controlled for other infections that can cause fever or respiratory symptoms. RESULTS: Influenza, dengue fever and chickenpox (varicella) were positively associated with acute URTI polyclinic attendances. The estimated URTI polyclinic attendance rates attributable to influenza, dengue fever and chickenpox were 618.9 (95% confidence interval [CI]: 501.6-736.3), 153.3 (95% CI: 16.5-290.2) and 1751.5 (95% CI: 1246.3-2256.8) per 100 000 population per year, respectively. CONCLUSION: Influenza poses a considerable burden on primary health-care services in Singapore. However, a substantial number of polyclinic attendances due to febrile infections such as dengue fever and chickenpox appear to be recorded as URTI in the polyclinic database. These associations require further investigation.

An indirect comparison meta-analysis of AS03 and MF59 adjuvants in pandemic influenza A(H1N1)pdm09 vaccines.

BACKGROUND: Although oil-in-water adjuvants improve pandemic influenza vaccine efficacy, AS03 versus MF59 adjuvant comparisons in A(H1N1)pdm09 pandemic vaccines are lacking. METHODS: We conducted an indirect-comparison meta-analysis extracting published data from randomised controlled trials in literature databases (01/01/2009-09/09/2018), evaluating immunogenicity and safety of AS03- or MF59-adjuvanted vaccines. We conducted comparisons of log-transformed haemagglutination inhibition geometric mean titre ratio (GMTR; primary outcome) of different regimens of each adjuvant versus unadjuvanted counterparts. Then via test of subgroup differences, we indirectly compared different AS03 versus MF59 regimens. RESULTS: We identified 22 publications with 10,734 participants. In adults, AS03-adjuvanted vaccines (3.75 µg haemagglutinin) achieved superior GMTR versus unadjuvanted vaccines (all four comparisons); MD = 0.56 (95%CI 0.33 to 0.80, p < 0.001) to 1.18 (95%CI 0.72 to 1.65, p < 0.001). MF59 (full-dose)-adjuvanted vaccines (7.5 µg haemagglutinin) were superior to unadjuvanted vaccines (three of four comparisons); MD = 0.47 (95%CI 0.19 to 0.75, p = 0.001) to 0.80 (95%CI 0.44 to 1.16, p < 0.001). Adult indirect comparisons favoured AS03 over MF59 (six of eight comparisons; p < 0.001 to p = 0.088). Paediatric indirect comparisons favoured MF59-adjuvanted vaccines (two of seven comparisons; p = 0.011, 0.079). However, unadjuvanted control group seroconversion rate was lower in MF59 than AS03 studies (p < 0.001 to p = 0.097). There was substantial heterogeneity, and adult AS03 studies had lower risk of bias. CONCLUSIONS: Despite limited studies, in adults, AS03-adjuvanted vaccines allow antigen sparing versus MF59-adjuvanted and unadjuvanted vaccines, with similar immunogenicity, but higher risk of pain and fatigue (secondary outcomes) than unadjuvanted vaccines. In children, adjuvanted vaccines are also superior, but the better adjuvant is uncertain.

Rapid mapping of the spatial and temporal intensity of influenza.

Surveillance of influenza epidemics is a priority for risk assessment and pandemic preparedness, yet representation of their spatiotemporal intensity remains limited. Using the epidemic of influenza type A in 2016 in Australia, we demonstrated a simple but statistically sound adaptive method of mapping epidemic evolution over space and time. Weekly counts of persons with laboratory confirmed influenza type A infections in Australia in 2016 were analysed by official national statistical region. Weekly standardised epidemic intensity was represented by a standard score (z-score) calculated using the standard deviation of below-median counts in the previous 52 weeks. A geographic information system (GIS) was used to present the epidemic progression. There were 79,628 notifications of influenza A infections included. Of these, 79,218 (99.5%) were allocated to a geographical area. The GIS maps indicated areas of elevated epidemic intensity across Australia by week and area that were consistent with the observed start, peak and decline of the epidemic when compared with counts aggregated at the state and territory level. This simple, adaptable approach could improve local level epidemic intelligence in a variety of settings and for other diseases. It may also facilitate increased understanding of geographic epidemic dynamics.

Redefining influenza seasonality at a global scale and aligning it to the influenza vaccine manufacturing cycle: A descriptive time series analysis.

OBJECTIVES: Annual seasonal influenza vaccine manufacturing cycles align with temperate country seasonality in each hemisphere, yet influenza seasonality is poorly defined for many countries. The study introduces a novel and universal approach to defining and classifying seasonality that can be used to classify any country's influenza vaccine cycle alignment. METHODS: Countries reporting to the World Health Organization's FluNet influenza virology database in 90% of weeks during 2011 through 2017 were included. A smoothed, standardised, average proportion of influenza occurring in each week of the year was used to determine degree of seasonality based on the range of average weekly variation. The proportion of activity occurring May through October was used to align influenza activity with a hemisphere's vaccine manufacturing cycle. RESULTS: From 84 included countries, there were 2,239,208 positive influenza results, of which 26% were influenza type B. Degree of seasonality was moderately positively correlated with absolute value of latitude (r = 0.69, p < 0.0001). Latitude was strongly negatively correlated with the proportion of influenza occurring during May through October (r = -0.83, p < 0.0001). Thirteen countries (12% of the included global population), mainly in tropical zones, had influenza occurrence aligned with the opposite hemisphere's influenza vaccine manufacturing cycle. In tropical zones, concordance in the degree of seasonality and vaccine cycle alignment within regions and between adjacent countries was limited. In temperate zones, on average, influenza B peaked four weeks later than A. CONCLUSIONS: Influenza activity in many countries aligns with the vaccine manufacturing cycle of the opposite hemisphere. In tropical regions, there is limited scope for grouping countries for vaccine distribution and administration.

Hospitalizations for Influenza-Associated Severe Acute Respiratory Infection, Beijing, China, 2014-2016.

We analyzed surveillance data for 2 sentinel hospitals to estimate the influenza-associated severe acute respiratory infection hospitalization rate in Beijing, China. The rate was 39 and 37 per 100,000 persons during the 2014-15 and 2015-16 influenza seasons, respectively. Rates were highest for children <5 years of age.

Preliminary results of official influenza and acute respiratory infection surveillance in two towns of Burkina Faso, 2013-2015.

BACKGROUND: In 2010, influenza, influenza-like illness (ILI) and acute respiratory infection (ARI) surveillance was established by the government of Burkina Faso. We provide preliminary descriptive results from this surveillance activity. METHODS: The study period was 2013 through 2015. Two primary healthcare facilities in Bobo-Dioulasso district reported ILI in outpatients. Influenza virology, using reverse transcription-polymerase chain reaction (rRT-PCR), was available for a proportion of ILI patients. One hospital, in the capital Ouagadougou, reported ARI in both outpatients and inpatients (hospitalized). Inpatients admitted with ARI were considered severe ARI (SARI). We estimated the proportion of primary care outpatient visits that were ILI, and the proportion of those that were due to influenza, by age. We estimated the proportion of hospital outpatient visits that were ARI and the proportion of those that were SARI, by age. RESULTS: Among combined outpatient visits in the Bobo-Dioulasso facilities, 19.6% were for ILI. One half (49.9%) of outpatient visits in infants and 30.9% in 1-4 year-olds were ILI. Among ILI outpatient visits 14.8% were due to influenza virus and, of these, 58.5% were type A and 41.5% type B. At the Ouagadougou hospital, 6.7% of outpatient visits were ARI, and 22.3% of those were SARI. The highest proportions of ARI were among infants (19.8%) and 1-4 year-olds (16.0%). The proportion of ARI that was SARI was highest among ≥15 year-olds (31.5%) followed by 1-4 year-olds (22.4%). Overall, 4.1% of SARI patients died. CONCLUSIONS: These preliminary data indicate the importance of respiratory infections among health care attendances in Burkina Faso, and influenza may be an important contributor to these.

Influenza illness averted by influenza vaccination among school year children in Beijing, 2013-2016.

BACKGROUND: The benefit of school-based influenza vaccination policy has not been fully addressed in Beijing. OBJECTIVES: To evaluate the benefit of school-based influenza vaccination policy launched in Beijing. METHODS: Using existing surveillance and immunization data, we developed a dynamic transmission model to assess the impact of influenza vaccination in school-going children. The outcome was defined as the averted number of medically attended influenza illnesses and the prevented disease fraction to all children aged 5-14 years for the 2013/14, 2014/15, and 2015/16 seasons. RESULTS: We estimated that during the three consecutive influenza seasons, the averted number of medically attended influenza illnesses among children aged 5-14 years was around 104 000 (95% CI: 101 000-106 000), 23 000 (95% CI: 22 000-23 000), and 21 000 (95% CI: 21 000-22 000), respectively. Corresponding prevented fractions to all children aged 5-14 years were 76.3%, 38.5%, and 43.9%. CONCLUSIONS: In Beijing, school-based vaccinations reduced a substantial number of medically attended influenza illnesses despite seasonal variation in the prevented fraction. This is strong supportive evidence for the continuation of school-based vaccination programs to reduce the influenza burden in this age group.

Economic burden of seasonal influenza in the United States.

BACKGROUND: Seasonal influenza is responsible for a large disease and economic burden. Despite the expanding recommendation of influenza vaccination, influenza has continued to be a major public health concern in the United States (U.S.). To evaluate influenza prevention strategies it is important that policy makers have current estimates of the economic burden of influenza. OBJECTIVE: To provide an updated estimate of the average annual economic burden of seasonal influenza in the U.S. population in the presence of vaccination efforts. METHODS: We evaluated estimates of age-specific influenza-attributable outcomes (ill-non medically attended, office-based outpatient visit, emergency department visits, hospitalizations and death) and associated productivity loss. Health outcome rates were applied to the 2015 U.S. population and multiplied by the relevant estimated unit costs for each outcome. We evaluated both direct healthcare costs and indirect costs (absenteeism from paid employment) reporting results from both a healthcare system and societal perspective. Results were presented in five age groups (<5 years, 5-17 years, 18-49 years, 50-64 years and ≥65 years of age). RESULTS: The estimated average annual total economic burden of influenza to the healthcare system and society was $11.2 billion ($6.3-$25.3 billion). Direct medical costs were estimated to be $3.2 billion ($1.5-$11.7 billion) and indirect costs $8.0 billion ($4.8-$13.6 billion). These total costs were based on the estimated average numbers of (1) ill-non medically attended patients (21.6 million), (2) office-based outpatient visits (3.7 million), (3) emergency department visit (0.65 million) (4) hospitalizations (247.0 thousand), (5) deaths (36.3 thousand) and (6) days of productivity lost (20.1 million). CONCLUSIONS: This study provides an updated estimate of the total economic burden of influenza in the U.S. Although we found a lower total cost than previously estimated, our results confirm that influenza is responsible for a substantial economic burden in the U.S.