Incidence of Influenza-Related Medical Encounters and the Associated Healthcare Resource Use and Complications Across Adult Age Groups in The United States During the 2015-2020 Influenza Seasons.

BACKGROUND: Research on influenza burden in adults has focused on crude subgroups with cut-points at 65-years, limiting insight into how burden varies with increasing age. This study describes the incidence of influenza-related outpatient visits, emergency room (ER) visits, and hospitalizations, along with healthcare resource use and complications in the aging adult population. METHODS: Individuals ≥18 years of age in the United States were evaluated retrospectively in five seasonal cohorts (2015-2020 seasons) in strata of age with 5-year increments. Person-level electronic medical records linked to pharmacy and medical claims were used to ascertain patient characteristics and outcomes. Influenza-related medical encounters were identified based on diagnostic codes (ICD-10 codes J09*-J11*). RESULTS: Incidence of influenza-related outpatient visits was highest among people aged 18-34 years and declined with increasing age. For ER visits, incidence tended to be elevated for people aged 18-34 years, relatively stable from 35 through 60, and increased rapidly after 60. Hospitalization incidence remained relatively stable until about 50 years of age and then increased with age. One in three patients was diagnosed with pneumonia after hospitalization, regardless of age. Across seasons, age groups, and clinical settings, on average, 40.8% of individuals were prescribed antivirals and 17.2% antibiotics. CONCLUSIONS: Incidence of influenza-related hospitalizations begins to increase around age 50 rather than the more common cut-point of 65, whereas incidence of outpatient visits was highest among younger adults. Influenza infections frequently led to antiviral and antibiotic prescriptions, underscoring the role influenza vaccination can play in combating antimicrobial resistance.

Influenza During the 2010-2020 Decade in the United States: Seasonal Outbreaks and Vaccine Interventions.

The 10 years between the last influenza pandemic and start of the severe acute respiratory syndrome coronavirus 2 pandemic have been marked by great advances in our ability to follow influenza occurrence and determine vaccine effectiveness (VE), largely based on widespread use of the polymerase chain reaction assay. We examine the results, focusing mainly on data from the United States and inactivated vaccines. Surveillance has expanded, resulting in increased ability to characterize circulating viruses and their impact. The surveillance has often confirmed previous observations on timing of outbreaks and age groups affected, which can now be examined in greater detail. Selection of strains for vaccines is now based on enhanced viral characterization using immunologic, virologic, and computational techniques not previously available. Vaccine coverage has been largely stable, but VE has remained modest and, in some years, very low. We discuss ways to improve VE based on existing technology while we work toward supraseasonal vaccines.

Postoperative acute kidney injury and renal replacement therapy after DCD lung transplantation.

Acute kidney injury (AKI) after lung transplantation (LTx) is a common complication. We aimed to assess whether donation after circulatory death (DCD) is associated with an increased risk of AKI and renal replacement therapy (RRT) in the early postoperative period compared to the donation after brain death (DBD). Retrospective data on a cohort (N = 95) of LTx patients (DCD n = 17, DBD n = 78) characterized by no use of ex-vivo lung perfusion were analyzed for the incidence of AKI within 30 postoperative days and incidence of RRT within 7 and 30 days. After optimal full matching, an imbalance remained between the DCD and DBD patients in respect to intraoperative use of cardiopulmonary bypass (CPB). Therefore, a further subset (n = 77) was defined that excluded CPB patients, and matching was repeated (DCD n = 13 vs. DBD n = 63) resulting in a fair balance on a range of preoperative characteristics and intraoperative use of ECMO. In both matched subsets, DCD was associated with around twice higher risk of AKI and RRT within 7 and 30 postoperative days. In conclusion, data suggest that DCD could be associated with worse early renal outcomes in a subset of LTx patients and justify further studies on the topic in order to refine further renal care pathways perioperatively.

Midterm outcomes of venovenous extracorporeal membrane oxygenation as a bridge to lung transplantation: Comparison with nonbridged recipients.

OBJECTIVES: Venovenous extracorporeal membrane oxygenation (VV-ECMO) is increasingly being used in acutely deteriorating patients with end-stage lung disease as a bridge to transplantation (BTT). It can allow critically ill recipients to remain eligible for lung transplants (LTx) while reducing pretransplant deconditioning. We analyzed early- and midterm postoperative outcomes of patients on VV-ECMO as a BTT and the impact of preoperative VV-ECMO on posttransplant survival outcomes. METHODS: All consecutive LTx performed at our institution between January 2012 and December 2018 were analyzed. After matching, BTT patients were compared with nonbridged LTx recipients. RESULTS: Out of 297 transplanted patients, 21 (7.1%) were placed on VV-ECMO as a BTT. After matching, we observed similar 30-day mortality between BTT and non-BTT patients (4.6% vs. 6.6%, p = .083) despite a higher incidence of early postoperative complications (need for ECMO, delayed chest closure, and acute kidney injury). Furthermore, preoperative VV-ECMO did not appear associated with 30-day or 1-year mortality in both frequentist and Bayesian analysis (odds ratio [OR]: 0.35, 95% confidence interval: 0.03-3.49, p = .369; OR: 0.27, 95% credible interval: 0.01-3.82, p = 84.7%, respectively). In sensitivity analysis, both subgroups were similar in respect to 30-day (7.8% vs. 6.5%, p = .048) and 1-year mortality (12.5% vs. 18%, p = .154). CONCLUSIONS: Patients with acute refractory respiratory failure while waiting for LTx represent a high-risk cohort of patients. VV-ECMO as a BTT is a reasonable strategy in adult patients with acceptable operative mortality and 1-year survival comparable to non-BTT patients.

Algorithms to guide ambulance clinicians in the management of emergencies in patients with implanted rotary left ventricular assist devices.

Advances in left ventricular assist device (LVAD) therapy have resulted in increasing numbers of adult LVAD recipients in the community. However, device failure, stroke, bleeding, LVAD thrombosis and systemic infection can be life-threatening emergencies. Currently, four LVAD systems are implanted in six UK transplant centres, each of which provides device-specific information to local emergency services. This has resulted in inconsistent availability and content of information with the risks of delayed or inappropriate decision-making. In order to improve patient safety, a consortium of UK healthcare professionals with expertise in LVADs developed universally applicable prehospital emergency algorithms. Guidance was framed as closely as possible on the standard ABCDE approach to the assessment of critically ill patients.

Co-Administration of Influenza and COVID-19 Vaccines: Policy Review and Vaccination Coverage Trends in the European Union, UK, US, and Canada between 2019 and 2023.

Recommending co-administration of influenza and COVID-19 vaccines has emerged as a strategy to enhance vaccination coverage. This study describes the policy on co-administration and uptake of influenza and COVID-19 vaccination in Europe, the United Kingdom, the United States, and Canada between 2019 and 2023. We collected co-administration policy data from governmental websites, national health organizations, and newspapers. Influenza vaccination coverage among persons ≥65 years and COVID-19 vaccination coverage rates among persons ≥60 years or the general population were collected using national databases, the ECDC database, or ourworldindata.org between 2019 and 2023. Descriptive analyses were used. We collected data from 30/32 (94%) countries on vaccination policy in seasons 2021-2022 and 2022-2023, with most countries (25/30 to 30/30) having policies recommending co-administration. For influenza vaccination coverage, we collected data from 29/32 (91%, 2019-2020), 28/32 (88%, 2020-2021), 27/32 (84%, 2021-2022), and 6/32 (19%, 2022-2023) countries. COVID-19 vaccination was collected from 32/32 (2020-2021), 31/32 (97%, 2021-2022), and 24/32 (75%, 2022-2023) countries. Influenza vaccination coverage increased from 2019-2020 to 2021-2022. COVID-19 vaccination coverage was higher among countries with higher influenza vaccination coverage. By 2022-2023, all countries included implemented a policy supporting co-administration. A positive correlation existed between higher influenza vaccination coverage and higher COVID-19 vaccination rates.

Influenza burden averted with a cell-based quadrivalent seasonal influenza vaccine compared with egg-based quadrivalent seasonal influenza vaccine.

BACKGROUND: Cell-based quadrivalent inactivated influenza vaccines (IIV4c) avoid egg-adaptive mutations found in egg-based production, improving vaccine effectiveness (VE). Studies demonstrate improved VE for IIV4c relative to egg-based quadrivalent inactivated influenza vaccines (IIV4). RESEARCH DESIGN AND METHODS: We built on a static compartmental model developed by the CDC to estimate the influenza burden in persons 0-64 years that would be additionally averted by vaccination with IIV4c vs. IIV4. Model inputs were based on published data from 2017-2018, 2018-2019, and 2019-2020 Northern Hemisphere influenza seasons for the US. RESULTS: Over 3 influenza seasons, relative to IIV4, IIV4c would avert 31-39% more symptomatic cases, 29-40% more outpatient visits, 29-38% more hospitalizations and ICU admissions, and 34-49% more deaths vs. IIV4. In a deterministic sensitivity analysis, the main drivers were the relative VE of IIV4c vs. IIV4 in the 2017-2018 season and influenza burden estimates for the 2018-2019 and 2019-2020 seasons. Probabilistic sensitivity analysis showed that the interquartile range of symptomatic cases was ± 13% of baseline in 2017-2018, ±8% in 2018-2019, and ± 7% in 2019-2020. CONCLUSIONS: IIV4c prevented significantly more symptomatic cases, outpatient visits, hospitalizations, and deaths than IIV4 in persons aged 0-64 years over 3 influenza seasons.

Number of Influenza Risk Factors Informs an Adult's Increased Potential of Severe Influenza Outcomes: A Multiseason Cohort Study From 2015 to 2020.

Background: While studies have evaluated factors influencing the risk of severe influenza outcomes, there is limited evidence on the additive impact of having multiple influenza risk factors and how this varies by age. Methods: Patients ≥18 years of age in the United States were evaluated retrospectively in 5 seasonal cohorts during the 2015-2020 influenza seasons. Patient-level electronic medical records linked to pharmacy and medical claims were used to ascertain covariates and outcomes. Multivariable logistic regression models were fitted for the overall population and by age subgroups to evaluate the association of demographic and clinical characteristics with odds of influenza-related medical encounters (ICD-10 codes J09*-J11*). The logistic regression models included sex, race/ethnicity, geographic region, baseline health care resource use, vaccination status, specific high-risk comorbidities, number of influenza risk factors, body mass index, and smoking status. Odds ratios from each of the 5 seasons were summarized via fixed effect meta-analysis. Results: Season cohort sizes ranged from 887 260 to 3 628 168 adults. Of all patient characteristics evaluated, an individual's cumulative number of high-risk influenza conditions, as defined per the Centers for Disease Control and Prevention, was the most predictive of an increased probability of having an influenza-related medical encounter overall and across age groups. For adults of any age, odds ratios for influenza hospitalization ranged from 1.8 (95% CI, 1.7-2.0) for 1 risk factor to 6.4 (95% CI, 5.8-7.0) for ≥4 risk factors. Conclusions: These results show that a simple measure such as the number of influenza risk factors can be highly informative of an adult's potential for severe influenza outcomes.

Relative Vaccine Effectiveness of Cell- vs Egg-Based Quadrivalent Influenza Vaccine Against Test-Confirmed Influenza Over 3 Seasons Between 2017 and 2020 in the United States.

Background: Influenza vaccine viruses grown in eggs may acquire egg-adaptive mutations that may reduce antigenic similarity between vaccine and circulating influenza viruses and decrease vaccine effectiveness. We compared cell- and egg-based quadrivalent influenza vaccines (QIVc and QIVe, respectively) for preventing test-confirmed influenza over 3 US influenza seasons (2017-2020). Methods: Using a retrospective test-negative design, we estimated the relative vaccine effectiveness (rVE) of QIVc vs QIVe among individuals aged 4 to 64 years who had an acute respiratory or febrile illness and were tested for influenza in routine outpatient care. Exposure, outcome, and covariate data were obtained from electronic health records linked to pharmacy and medical claims. Season-specific rVE was estimated by comparing the odds of testing positive for influenza among QIVc vs QIVe recipients. Models were adjusted for age, sex, geographic region, influenza test date, and additional unbalanced covariates. A doubly robust approach was used combining inverse probability of treatment weights with multivariable regression. Results: The study included 31 824, 33 388, and 34 398 patients in the 2017-2018, 2018-2019, and 2019-2020 seasons, respectively; ∼10% received QIVc and ∼90% received QIVe. QIVc demonstrated superior effectiveness vs QIVe in prevention of test-confirmed influenza: rVEs were 14.8% (95% CI, 7.0%-22.0%) in 2017-2018, 12.5% (95% CI, 4.7%-19.6%) in 2018-2019, and 10.0% (95% CI, 2.7%-16.7%) in 2019-2020. Conclusions: This study demonstrated consistently superior effectiveness of QIVc vs QIVe in preventing test-confirmed influenza over 3 seasons characterized by different circulating viruses and degrees of egg adaptation.

Global analysis of respiratory viral circulation and timing of epidemics in the pre-COVID-19 and COVID-19 pandemic eras, based on data from the Global Influenza Surveillance and Response System (GISRS).

OBJECTIVES: The COVID-19 pandemic significantly changed respiratory viruses' epidemiology due to non-pharmaceutical interventions and possible viral interactions. This study investigates whether the circulation patterns of respiratory viruses have returned to pre-pandemic norms by comparing their peak timing and duration during the first three SARS-CoV-2 seasons to pre-pandemic times. METHODS: Global Influenza Surveillance and Response System data from 194 countries (2014-2023) was analyzed for epidemic peak timing and duration, focusing on pre-pandemic and pandemic periods across both hemispheres and the intertropical belt. The analysis was restricted to countries meeting specific data thresholds to ensure robustness. RESULTS: In 2022/2023, the northern hemisphere experienced earlier influenza and respiratory syncytial virus (RSV) peaks by 1.9 months (P <0.001). The duration of influenza epidemics increased by 2.2 weeks (P <0.001), with RSV showing a similar trend. The southern hemisphere's influenza peak shift was not significant (P = 0.437). Intertropical regions presented no substantial change in peak timing but experienced a significant reduction in the duration for human metapneumovirus and adenovirus (7.2 and 6.5 weeks shorter, respectively, P <0.001). CONCLUSIONS: The pandemic altered the typical patterns of influenza and RSV, with earlier peaks in 2022 in temperate areas. These findings highlight the importance of robust surveillance data to inform public health strategies on evolving viral dynamics in the years to come.

Effectiveness of Cell-Based Quadrivalent Seasonal Influenza Vaccine: A Systematic Review and Meta-Analysis.

Cell-based seasonal influenza vaccine viruses may more closely match recommended vaccine strains than egg-based options. We sought to evaluate the effectiveness of seasonal cell-based quadrivalent influenza vaccine (QIVc), as reported in the published literature. A systematic literature review was conducted (PROSPERO CRD42020160851) to identify publications reporting on the effectiveness of QIVc in persons aged ≥6 months relative to no vaccination or to standard-dose, egg-based quadrivalent or trivalent influenza vaccines (QIVe/TIVe). Publications from between 1 January 2016 and 25 February 2022 were considered. The review identified 18 relevant publications spanning three influenza seasons from the 2017-2020 period, with an overall pooled relative vaccine effectiveness (rVE) of 8.4% (95% CI, 6.5-10.2%) for QIVc vs. QIVe/TIVe. Among persons aged 4-64 years, the pooled rVE was 16.2% (95% CI, 7.6-24.8%) for 2017-2018, 6.1% (4.9-7.3%) for 2018-2019, and 10.1% (6.3-14.0%) for 2019-2020. For adults aged ≥65 years, the pooled rVE was 9.9% (95% CI, 6.9-12.9%) in the egg-adapted 2017-2018 season, whereas there was no significant difference in 2018-2019. For persons aged 4-64 years, QIVc was consistently more effective than QIVe/TIVe over the three influenza seasons. For persons aged ≥65 years, protection with QIVc was greater than QIVe or TIVe during the 2017-2018 season and comparable in 2018-2019.

Additional Burden Averted in the United States From Use of MF59-Adjuvanted Seasonal Influenza Vaccine Compared With Standard Seasonal Influenza Vaccine Among Adults ≥65 Years.

Background: The MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) is designed to overcome immunosenescence and enhance vaccine responses in older adults. We expanded on the Centers for Disease Control and Prevention (CDC) modeling method to estimate the number of additional influenza-related outcomes averted with aIIV3 versus generic quadrivalent inactivated influenza vaccine (IIV4) in adults ≥65 years over 3 influenza seasons (2017-2018 to 2019-2020) in the United States. Methods: A static compartmental model was developed based on an existing CDC model with 2 previously recommended calculation methods that increased the accuracy of the model in providing estimates of burden averted. Model inputs included vaccine effectiveness, vaccine coverage, population counts, and disease burden estimates. Additional burden averted (symptomatic cases, outpatient visits, hospitalizations, intensive care unit [ICU] admissions, and deaths) was expressed as total incremental cases averted between the vaccines. Sensitivity analyses tested the resilience of the model results to uncertainties in model inputs. Results: The model estimated that vaccination with aIIV3 versus IIV4 would avert 2.24 times as many symptomatic cases, outpatient visits, hospitalizations, ICU stays, and deaths during 2017-2018; the burden averted in 2018-2019 and 2019-2020 with aIIV3 would be 3.44 and 1.72 times that averted with IIV4, respectively. Disease burden estimates and relative vaccine effectiveness of aIIV3 had the greatest impact on model estimates. Conclusions: Over 3 influenza seasons, the model estimated that aIIV3 was more effective than IIV4 in averting influenza-related outcomes, preventing 1.72 to 3.44 times as many influenza illnesses with proportionate decreases in related healthcare use and complications.

Evaluating risk of bias using ROBINS-I tool in nonrandomized studies of adjuvanted influenza vaccine.

Seasonal variation in influenza vaccine effectiveness (VE) makes real-world evidence (RWE) useful in supplementing the clinical-evidence base from randomized clinical trials. Adjuvanted inactivated influenza vaccine (aIIV) VE has been evaluated in multiple nonrandomized RWE studies. A systematic literature review of RWE studies evaluating the absolute or relative VE of aIIV was conducted. Identified studies were assessed by evaluators for risk of bias (RoB) by means of the ROBINS-I (Reduction of Bias In Non-randomized Studies of Interventions) tool to inform evidence-based medicine deliberations. Differences in evaluator assessments were resolved by consensus. The literature review yielded 14 follow-up studies, seven test-negative case-control (TNCC) studies, five traditional case-control studies, and one cluster-randomized clinical trial. Most follow-up studies and three TNCC studies were judged at low RoB. Issues increasing RoB included inadequate control of confounding, selection of controls, and reliance on recall of vaccination. The concerns identified in any of the designs could be mitigated with straightforward revisions to design or implementation. 17 of 27 nonrandomized studies of adjuvanted influenza-vaccine effectiveness, some from each of four study designs, were judged at low risk of material bias. These studies merit credence in assessing aIIV effectiveness relative to other influenza vaccines.

Correction: Rockman et al. Cell-Based Manufacturing Technology Increases Antigenic Match of Influenza Vaccine and Results in Improved Effectiveness. Vaccines 2023, 11, 52.

The authors would like to make the following corrections to this published paper [...].

Epidemiology and Burden of Influenza in Children 0-14 Years Over Ten Consecutive Seasons in Italy.

BACKGROUND: In Europe, influenza vaccination coverage in the pediatric population is low. This study describes the influenza incidence and associated healthcare utilization in the pediatric population in Italy. METHODS: Deidentified data from electronic medical records for children 0-14 years old seen by >150 family pediatricians in the Pedianet network in Italy were evaluated for 10 influenza seasons spanning 2010-2020. Incidence of influenza (cases per 1000 person-months), related sequelae and associated healthcare resource use were determined using diagnostic, prescription and medical examination data. RESULTS: Over 10 seasons, an average of 8892 influenza cases (range, 4700-12,419; total 88,921) were diagnosed in a cohort of 1,432,384 children 0-14 years of age. Influenza vaccination coverage was 3.6% among children with an influenza diagnosis and 6.8% among children without. Influenza-related healthcare resource utilization included 1.58 family pediatrician visits per influenza episode and 220 ED and 111 hospital admissions, with the highest resource usage among children 1-4 years and lowest among children <6 months old. The most common influenza complications were acute otitis media (2.9% of influenza cases) and pneumonia (0.5%). Antibiotics were prescribed in 38.7% of influenza cases; no antiviral agents were prescribed. One intensive care unit admission and 2 cases requiring ventilatory support were documented. No influenza-related deaths were reported. CONCLUSION: Pediatric influenza vaccination was low despite the burden and healthcare use related to seasonal influenza in the pediatric population during a 10-year period in Italy.

Investigating confounding in network-based test-negative design influenza vaccine effectiveness studies-Experience from the DRIVE project.

BACKGROUND: Establishing a large study network to conduct influenza vaccine effectiveness (IVE) studies while collecting appropriate variables to account for potential bias is important; the most relevant variables should be prioritized. We explored the impact of potential confounders on IVE in the DRIVE multi-country network of sites conducting test-negative design (TND) studies. METHODS: We constructed a directed acyclic graph (DAG) to map the relationship between influenza vaccination, medically attended influenza infection, confounders, and other variables. Additionally, we used the Development of Robust and Innovative Vaccines Effectiveness (DRIVE) data from the 2018/2019 and 2019/2020 seasons to explore the effect of covariate adjustment on IVE estimates. The reference model was adjusted for age, sex, calendar time, and season. The covariates studied were presence of at least one, two, or three chronic diseases; presence of six specific chronic diseases; and prior healthcare use. Analyses were conducted by site and subsequently pooled. RESULTS: The following variables were included in the DAG: age, sex, time within influenza season and year, health status and comorbidities, study site, health-care-seeking behavior, contact patterns and social precautionary behavior, socioeconomic status, and pre-existing immunity. Across all age groups and settings, only adjustment for lung disease in older adults in the primary care setting resulted in a relative change of the IVE point estimate >10%. CONCLUSION: Our study supports a parsimonious approach to confounder adjustment in TND studies, limited to adjusting for age, sex, and calendar time. Practical implications are that necessitating fewer variables lowers the threshold for enrollment of sites in IVE studies and simplifies the pooling of data from different IVE studies or study networks.

Influenza Vaccine Uptake in the United States before and during the COVID-19 Pandemic.

The COVID-19 pandemic, along with disruptions to routine medical care, brought renewed urgency to public health messaging about the importance of influenza vaccination. This retrospective cohort study used a database of linked claims and electronic medical record data to evaluate clinical and demographic characteristics and influenza vaccination history associated with changes in influenza vaccine uptake following the start of the COVID-19 pandemic. Influenza vaccine uptake was examined in six seasons (2015−2016 through 2020−2021). Individuals were grouped by vaccination history in the five seasons before 2020−2021. Characteristics of 2020−2021 vaccinated vs. unvaccinated individuals were compared, stratified by vaccination history. Overall influenza vaccination uptake was highest in 2020−2021 (35.4%), following a trend of increasing uptake since 2016−2017 (31.4%). Uptake in 2020−2021 was observed in all age groups except ≥65 years, and the increase was particularly notable in individuals <18 years. In the previous five seasons, individuals ≤17 and >65 years, White, and Asian individuals were most likely, while 18-to-49-year-olds and those with fewer comorbidities were least likely, to be consistently vaccinated. Influenza vaccination status in 2020−2021 aligned with vaccination history; few differences in patient characteristics (age, comorbidities, state of residence) were observed when stratified by vaccination history.

Review of Analyses Estimating Relative Vaccine Effectiveness of Cell-Based Quadrivalent Influenza Vaccine in Three Consecutive US Influenza Seasons.

The adaptation of influenza seed viruses in egg culture can result in a variable antigenic vaccine match each season. The cell-based quadrivalent inactivated influenza vaccine (IIV4c) contains viruses grown in mammalian cell lines rather than eggs. IIV4c is not subject to egg-adaptive changes and therefore may offer improved protection relative to egg-based vaccines, depending on the degree of match with circulating influenza viruses. We summarize the relative vaccine effectiveness (rVE) of IIV4c versus egg-based quadrivalent influenza vaccines (IIV4e) to prevent influenza-related medical encounters (IRMEs) from three retrospective observational cohort studies conducted during the 2017-2018, 2018-2019, and 2019-2020 US influenza seasons using the same underlying electronic medical record dataset for all three seasons-with the addition of linked medical claims for the latter two seasons. We identified IRMEs using diagnostic codes specific to influenza disease (ICD J09*-J11*) from the records of over 10 million people. We estimated rVE using propensity score methods adjusting for age, sex, race, ethnicity, geographic location, week of vaccination, and health status. Subgroup analyses included specific age groups. IIV4c consistently had higher relative effectiveness than IIV4e across all seasons assessed, which were characterized by different dominant circulating strains and variable antigenic drift or egg adaptation.

Global patterns of seasonal influenza activity, duration of activity and virus (sub)type circulation from 2010 to 2020.

BACKGROUND: Seasonal influenza viruses undergo unpredictable changes, which may lead to antigenic mismatch between circulating and vaccine strains and to a reduced vaccine effectiveness. A continuously updated knowledge of influenza strain circulation and seasonality is essential to optimize the effectiveness of influenza vaccination campaigns. We described the global epidemiology of influenza between the 2009 A(H1N1)p and the 2020 COVID-19 pandemic. METHODS: Influenza virological surveillance data were obtained from the WHO-FluNet database. We determined the median proportion of influenza cases caused by the different influenza virus types, subtypes, and lineages; the typical timing of the epidemic peak; and the median duration of influenza epidemics (applying the annual average percentage method with a 75% threshold). RESULTS: We included over 4.6 million influenza cases from 149 countries. The median proportion of influenza cases caused by type A viruses was 75.5%, highest in the Southern hemisphere (81.6%) and lowest in the intertropical belt (73.0%), and ranged across seasons between 60.9% in 2017 and 88.7% in 2018. Epidemic peaks typically occurred during winter months in Northern and Southern hemisphere countries, while much more variability emerged in tropical countries. Influenza epidemics lasted a median of 25 weeks (range 8-42) in countries lying between 30°N and 26°S, and a median of 9 weeks (range 5-25) in countries outside this latitude range. CONCLUSIONS: This work will establish an important baseline to better understand factors that influence seasonal influenza dynamics and how COVID-19 may have affected seasonal activity and influenza virus types, subtypes, and lineages circulation patterns.

Cell-Based Manufacturing Technology Increases Antigenic Match of Influenza Vaccine and Results in Improved Effectiveness.

To ensure that vaccination offers the best protection against an infectious disease, sequence identity between the vaccine and the circulating strain is paramount. During replication of nucleic acid, random mutations occur due to the level of polymerase fidelity. In traditional influenza vaccine manufacture, vaccine viruses are propagated in fertilized chicken eggs, which can result in egg-adaptive mutations in the antigen-encoding genes. Whilst this improves infection and replication in eggs, mutations may reduce the effectiveness of egg-based influenza vaccines against circulating human viruses. In contrast, egg-adaptive mutations are avoided when vaccine viruses are propagated in Madin-Darby canine kidney (MDCK) cell lines during manufacture of cell-based inactivated influenza vaccines. The first mammalian cell-only strain was included in Flucelvax® Quadrivalent in 2017. A sequence analysis of the viruses selected for inclusion in this vaccine (n = 15 vaccine strains, containing both hemagglutinin and neuraminidase) demonstrated that no mutations occur in the antigenic sites of either hemagglutinin or neuraminidase, indicating that cell adaptation does not occur during production of this cell-based vaccine. The development of this now entirely mammalian-based vaccine system, which incorporates both hemagglutinin and neuraminidase, ensures that the significant protective antigens are equivalent to the strains recommended by the World Health Organization (WHO) in both amino acid sequence and glycosylation pattern. The inclusion of both proteins in a vaccine may provide an advantage over recombinant vaccines containing hemagglutinin alone. Findings from real world effectiveness studies support the use of cell-based influenza vaccines.