Seasonal Influenza Research Articles

Characterizing the seasonal influenza disease burden attributable to climate variability: A nationwide time-series modelling study in Japan, 2000−2019

BackgroundAmbient temperature and humidity are established environmental stressors with regard to influenza infections; however, mapping disease burden is difficult owing to the complexities of the underlying associations and differences in vulnerable population distributions. In this study, we aimed to quantify the burden of influenza attributable to non-optimal ambient temperature and absolute humidity in Japan considering geographical differences in vulnerability. MethodsThe exposure−lag−response relationships between influenza incidence, ambient temperature, and absolute humidity in all 47 Japanese prefectures for 2000−2019 were quantified using a distributed lag non-linear model for each prefecture; the estimates from all the prefectures were then pooled using a multivariate mixed-effects meta-regression model to derive nationwide average associations. Association between prefecture-specific indicators and the risk were also examined. Attributable risks were estimated for non-optimal ambient temperature and absolute humidity according to the exposure−lag−response relationships obtained before. ResultsA total of 25,596,525 influenza cases were reported during the study period. Cold and dry conditions significantly increased influenza incidence risk. Compared with the minimum incidence weekly mean ambient temperature (29.8 °C) and the minimum incidence weekly mean absolute humidity (20.2 g/m3), the cumulative relative risks (RRs) of influenza in cold (2.5 °C) and dry (3.6 g/m3) conditions were 2.79 (95% confidence interval [CI]: 1.78−4.37) and 3.20 (95% CI: 2.37−4.31), respectively. The higher RRs for cold and dry conditions were associated with geographical and climatic indicators corresponding to the central and northern prefectures; demographic, socioeconomic, and health resources indicators showed no clear trends. Finally, 27.25% (95% empirical CI [eCI]: 5.54−36.35) and 32.35% (95% eCI: 22.39−37.87) of all cases were attributable to non-optimal ambient temperature and absolute humidity (6,976,300 [95% eCI: 1,420,068−9,306,128] and 8,280,981 [95% eCI: 8,280,981−9,693,532] cases), respectively. ConclusionsThese findings could help identify the most vulnerable populations in Japan and design adaptation policies to reduce the attributable burden of influenza due to climate variability.

Evolutionary Insights from Association Rule Mining of Co-Occurring Mutations in Influenza Hemagglutinin and Neuraminidase.

Seasonal influenza viruses continuously evolve via antigenic drift. This leads to recurring epidemics, globally significant mortality rates, and the need for annually updated vaccines. Co-occurring mutations in hemagglutinin (HA) and neuraminidase (NA) are suggested to have synergistic interactions where mutations can increase the chances of immune escape and viral fitness. Association rule mining was used to identify temporal relationships of co-occurring HA-NA mutations of influenza virus A/H3N2 and its role in antigenic evolution. A total of 64 clusters were found. These included well-known mutations responsible for antigenic drift, as well as previously undiscovered groups. A majority (41/64) were associated with known antigenic sites, and 38/64 involved mutations across both HA and NA. The emergence and disappearance of N-glycosylation sites in the pattern of N-X-[S/T] were also identified, which are crucial post-translational processes to maintain protein stability and functional balance (e.g., emergence of NA:339ASP and disappearance of HA:187ASP). Our study offers an alternative approach to the existing mutual-information and phylogenetic methods used to identify co-occurring mutations, enabling faster processing of large amounts of data. Our approach can facilitate the prediction of critical mutations given their occurrence in a previous season, facilitating vaccine development for the next flu season and leading to better preparation for future pandemics.

Impact of COVID-19 Nonpharmaceutical Interventions on Bordetella pertussis, Human Respiratory Syncytial Virus, Influenza Virus, and Seasonal Coronavirus Antibody Levels: A Systematic Review.

During the COVID-19 pandemic, nonpharmaceutical interventions (NPIs) were introduced to reduce the spread of SARS-CoV-2. This also resulted in a reduction of notifications of other acute respiratory infections and an altered seasonality when NPIs were lifted. Without circulation of pathogens, waning of antibodies is expected, which is a first indicator of decreased immunity. Here, by performing a systematic literature review, we investigated whether reduced antibody levels due to waning immunity contributed to the altered seasonality after NPIs were lifted. Thirteen articles met the inclusion criteria and reported antibody levels or seroprevalence of human respiratory syncytial virus, seasonal human coronavirus, Bordetella pertussis, and influenza virus. We show that the COVID-19 pandemic most likely led to waning of pathogen-specific antibodies, with the strongest evidence for human respiratory syncytial virus and seasonal human coronavirus and with a larger decrease in children vs adults. Waning antibodies might have resulted in out-of-season activity for these pathogens.

Pediatric Respiratory Hospitalizations in the Pre-COVID-19 Era: The Contribution of Viral Pathogens and Comorbidities to Clinical Outcomes, Valencia, Spain.

Viral respiratory diseases place a heavy burden on the healthcare system, with children making up a significant portion of related hospitalizations. While comorbidities increase the risk of complications and poor outcomes, many hospitalized children lack clear risk factors. As new vaccines for respiratory viral diseases emerge, this study examined pediatric respiratory hospitalizations, focusing on viral etiology, complication rates, and the impact of comorbidities to guide future policy. Data were analyzed from eight pre-COVID influenza seasons (2011/2012-2018/2019) involving patients under 18 years hospitalized with respiratory complaints across 4-10 hospitals in Valencia, Spain. Respiratory specimens were tested for eight viral targets using multiplex real-time reverse-transcription polymerase chain reaction. Demographics, clinical outcomes, discharge diagnoses, and laboratory results were examined. Among the hospitalized children, 26% had at least one comorbidity. These children had higher rates of pneumonia, asthma exacerbation, and pneumothorax, and were twice as likely to require ICU admission, though mechanical ventilation and length of stay were similar to those without comorbidities. Respiratory syncytial virus (RSV) was the most common virus detected (23.1%), followed by rhinovirus/enterovirus (9.5%) and influenza (7.2%). Viral codetection decreased with age, occurring in 4.6% of cases. Comorbidities increase the risk of complications in pediatric respiratory illnesses, however, healthcare utilization is driven largely by otherwise healthy children. Pediatric viral vaccines could reduce this burden and should be further evaluated.

Influenza vaccine effectiveness in immunocompromised patients with cancer: A Danish nationwide register‐based cohort study

AbstractBackgroundInfluenza vaccination is free of charge for Danish citizens with acquired immunodeficiency but recommendations do not specifically target patients with cancer. This study investigated whether influenza vaccination reduces the main outcome of overall mortality and the secondary outcomes of influenza requiring treatment, pneumonia, myocardial infarction, stroke, heart failure, and venous thromboembolism in patients with cancer.MethodsThis was a register‐based nationwide cohort study. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for overall mortality and secondary outcomes were estimated using Cox proportional hazards models. Analyses were conducted separately for four subgroups: patients aged <65 years with solid tumors, patients aged ≥65 years with solid tumors, patients aged <65 years with hematological cancer, and patients aged ≥65 years with hematological cancer.ResultsA total of 53,249 adult patients with solid tumors who received chemotherapy and 22,182 adult patients with hematological cancer were followed for up to five influenza seasons in the study period of 2007–2018. In the main analysis covering December–March, influenza vaccination was associated with reduced overall mortality in all four subgroups. The reduction was most pronounced in patients with hematological cancer aged <65 years (aHR, 0.66; 95% CI, 0.51–0.87) and smallest in patients with solid tumors aged <65 years (aHR, 0.91; 95% CI, 0.84–0.99). In sensitivity analyses covering January–March, the aHR was 0.87 (95% CI, 0.65–1.16) in patients with hematological cancer aged <65 years and 1.01 (95% CI, 0.92–1.10) in patients with solid tumors aged <65 years. Results for the secondary outcomes were inconclusive.ConclusionsThe results of this study cannot reject that influenza vaccination reduces overall mortality in immunocompromised patients with cancer. The results must be interpreted with caution because of potential unmeasured confounding, which can result in the overestimation of influenza vaccine effectiveness.

Relative effectiveness of adjuvanted versus non-adjuvanted influenza vaccines in older adults with risk factors for influenza complications during the 2019–2020 U.S. influenza season

This study estimated the relative vaccine effectiveness (rVE) of the MF59®-adjuvanted trivalent influenza vaccine (aTIV) versus standard-dose nonadjuvanted egg-based quadrivalent influenza vaccines (QIVe) for the prevention of influenza-related medical encounters (IRMEs), outpatient IRMEs, and influenza- and pneumonia-related hospitalizations during the 2019–2020 US influenza season among adults ≥65 years of age who had ≥1 high-risk condition. A secondary objective evaluated the rVE of aTIV versus QIVe in preventing these outcomes among older adults with specific high-risk conditions. This retrospective cohort study included US adults ≥65 years of age vaccinated with aTIV or QIVe between August 1, 2019, and January 31, 2020. Exposures, covariates, risk factors, and outcomes were captured from a linked dataset comprised of electronic health records (EHR) (Veradigm Network EHR) linked to insurance claims (Komodo Healthcare Map). A doubly robust approach was applied wherein multivariable-adjusted odds ratios were derived using inverse probability of treatment-weighted samples to calculate rVEs and 95 % confidence interval independently for individuals ≥1 high-risk condition and those with specific high-risk conditions. The study included 954,707 aTIV and 719,125 QIVe recipients. For all outcomes, aTIV was more effective than QIVe among adults ≥65 years of age who had ≥1 high-risk condition (any IMRE: 23.6 % [20.9 %–26.1 %]), outpatient IRME: 23.3 % [20.4 %–26.1 %], and influenza- or pneumonia-related hospitalizations: 19.0 % [16.3 %–21.6 %]), during the 2019–2020 influenza season. Similarly, aTIV was more effective than QIVe at preventing outcomes among individuals with specific high-risk conditions except for body mass index ≥40. This study demonstrated higher effectiveness of aTIV versus QIVe in preventing any IRMEs, outpatient IRMEs, and influenza- or pneumonia-related hospitalizations among adults ≥65 years of age who had ≥1 high-risk condition.

Safety of the Seasonal Influenza Vaccine in 2 Successive Pregnancies

ImportanceAlthough influenza vaccination has been found to be safe in pregnancy, few studies have assessed repeated influenza vaccination over successive pregnancies, including 2 vaccinations in a year, in terms of adverse perinatal outcomes.ObjectiveTo examine the association of seasonal influenza vaccination across successive pregnancies with adverse perinatal outcomes and whether the association varies by interpregnancy interval (IPI) and vaccine type (quadrivalent or trivalent).Design, Setting, and ParticipantsThis retrospective cohort study included individuals with at least 2 successive singleton live-birth pregnancies between January 1, 2004, and December 31, 2018. Data were collected from the Vaccine Safety Datalink, a collaboration between the Centers for Disease Control and Prevention and integrated health care organizations. Data analysis was performed between January 8, 2021, and July 17, 2024.ExposuresInfluenza vaccination was identified using vaccine administration codes. The vaccinated cohort consisted of people who received influenza vaccines during the influenza season (August 1 through April 30) in 2 successive pregnancies. The comparator cohort consisted of people identified as unvaccinated during both pregnancies.Main Outcomes and MeasuresMain outcomes were risk of preeclampsia or eclampsia, placental abruption, fever, preterm birth, preterm premature rupture of membranes, chorioamnionitis, and small for gestational age among individuals with and without vaccination in both pregnancies. Adjusted relative risks (RRs) from Poisson regression were used to assess the magnitude of associations. The associations with adverse outcomes by IPI and vaccine type were evaluated.ResultsOf 82 055 people with 2 singleton pregnancies between 2004 and 2018, 44 879 (54.7%) had influenza vaccination in successive pregnancies. Mean (SD) age at the start of the second pregnancy was 32.2 (4.6) years for vaccinated individuals and 31.2 (5.0) years for unvaccinated individuals. Compared with individuals not vaccinated in both pregnancies, vaccination in successive pregnancies was not associated with increased risk of preeclampsia or eclampsia (adjusted RR, 1.10; 95% CI, 0.99-1.21), placental abruption (adjusted RR, 1.01; 95% CI, 0.84-1.21), fever (adjusted RR, 0.87; 95% CI, 0.47-1.59), preterm birth (adjusted RR, 0.83; 95% CI, 0.78-0.89), preterm premature rupture of membranes (RR, 1.00; 95% CI, 0.94-1.06), chorioamnionitis (adjusted RR, 1.03; 95% CI, 0.90-1.18), or small for gestational age birth (adjusted RR, 0.99; 95% CI, 0.93-1.05). IPI and vaccine type did not modify the observed associations.Conclusions and RelevanceIn this large cohort study of successive pregnancies, influenza vaccination was not associated with increased risk of adverse perinatal outcomes, irrespective of IPI and vaccine type. Findings support recommendations to vaccinate pregnant people or those who might be pregnant during the influenza season.

Rain on the Parade of Influenza Vaccine Hesitancy

Abstract: Background: Following the protection motivation theory (PMT), a lack of risk perception is one of the reasons for differences in vaccine uptake ( Rogers, 1975 ). When the risk for diseases like seasonal influenza is underestimated, protective measures such as vaccination are used less. Aims: In this paper, we propose that the sequelae approach, which involves providing information about the severe complications of diseases, can influence people’s risk perceptions and their intention to vaccinate. This is in comparison to providing merely information about the disease itself. Method: Three preregistered online experiments (2017–2019) were conducted to examine whether risk perceptions and vaccination intentions increase when (1) information about sequelae is presented as statistical texts or narratives (vs. not presented at all), (2) known or unknown sequelae (myocardial infarction vs. sepsis), and (3) different target populations (e.g., health literacy) are considered. Results: An internal meta-analysis showed that the sequelae approach increases intentions ( SMD = .39[.20;.59]) but not risk perception ( SMD = .09[−.10;.27]). Unknown and known sequelae had an equal impact on vaccination intentions. None of the strategies (narratives vs. statistical texts, sequelae type) produced adverse reactions in people with low health literacy. In addition, no evidence was found for boomerang effects. Limitations: Even though our research was based on PMT, we cannot add evidence on self-efficacy or response efficacy as influential factors. Conclusion: Although increased risk perception is not the primary mechanism behind the sequelae approach, the results support the use of this strategy in educational interventions that target vaccine hesitancy.

Epidemiology and genetic characterization of influenza viruses circulating in Bhutan in 2022.

Influenza (Flu) causes considerable morbidity and mortality globally, and in Bhutan, Flu viruses are a leading cause of acute respiratory infection and cause outbreaks during Flu seasons. In this study, we aim to analyze the epidemiology and the genetic characterization of Flu viruses circulated in Bhutan in 2022. Respiratory specimens were collected from patients who meet the case definition for influenza-like illness (ILI) and severe acute respiratory infection (SARI) from sentinel sites. Specimens were tested for Flu and SARS-CoV-2 viruses by RT-PCR using the Multiplex Assay. Selected positive specimens were utilized for Flu viral genome sequencing by next-generation sequencing. Descriptive analysis was performed on patient demographics to see the proportion of Flu-associated ILI and SARI. All data were analyzed using Epi Info7 and QGIS 3.16 software. A weekly average of 16.2 ILI cases per 1000 outpatient visits and 18 SARI cases per 1000 admitted cases were reported in 2022. The median age among ILI was 12 years (IQR: 5-28) and SARI was 6.2 (IQR: 2.5-15) years. Flu A(H3N2) (70.2%) subtype was the most predominant circulating strain. Flu A(H1N1)pdm09 and Flu B viruses belonged to subclades that were mismatched to the vaccine strains recommended for the 2021-2022 season but matched the vaccine strain for the 2022-2023 season with vaccine efficacy 85.14% and 88.07% respectively. Flu A(H3N2) virus belonged to two subclades which differed from the vaccine strains recommended in both the 2021-2022 and 2022-2023 seasons with vaccine efficacy 68.28%. Flu virus positivity rates were substantially elevated during the Flu season in 2022 compared to 2021. Flu A(H3N2) subtype was the most predominant circulating strain in the country and globally. Genetic characterization of the Flu viruses in Bhutan showed a close relatedness of high vaccine efficacy with the vaccine strain that WHO recommended for the 2022-23 season.

From Fax to Secure File Transfer Protocol: The 25-Year Evolution of Real-Time Syndromic Surveillance in England.

The purpose of syndromic surveillance is to provide early warning of public health incidents, real-time situational awareness during incidents and emergencies, and reassurance of the lack of impact on the population, particularly during mass gatherings. The United Kingdom Health Security Agency (UKHSA) currently coordinates a real-time syndromic surveillance service that encompasses 6 national syndromic surveillance systems reporting on daily health care usage across England. Each working day, UKHSA analyzes syndromic data from over 200,000 daily patient encounters with the National Health Service, monitoring over 140 unique syndromic indicators, risk assessing over 50 daily statistical exceedances, and taking and recommending public health action on these daily. This English syndromic surveillance service had its origins as a small exploratory pilot in a single region of England in 1999 involving a new pilot telehealth service, initially reporting only on "cold or flu" calls. This pilot showed the value of syndromic surveillance in England, providing advanced warning of the start of seasonal influenza activity over existing laboratory-based surveillance systems. Since this initial pilot, a program of real-time syndromic surveillance has evolved from the single-system, -region, -indicator pilot (using manual data transfer methods) to an all-hazard, multisystem, automated national service. The suite of systems now monitors a wide range of syndromes, from acute respiratory illness to diarrhea to cardiac conditions, and is widely used in routine public health surveillance and for monitoring seasonal respiratory disease and incidents such as the COVID-19 pandemic. Here, we describe the 25-year evolution of the English syndromic surveillance system, focusing on the expansion and improvements in data sources and data management, the technological and digital enablers, and novel methods of data analytics and visualization.

Sequential immunization with chimeric hemagglutinin ΔNS1 attenuated influenza vaccines induces broad humoral and cellular immunity

Influenza viruses pose a threat to public health as evidenced by severe morbidity and mortality in humans on a yearly basis. Given the constant changes in the viral glycoproteins owing to antigenic drift, seasonal influenza vaccines need to be updated periodically and effectiveness often drops due to mismatches between vaccine and circulating strains. In addition, seasonal influenza vaccines are not protective against antigenically shifted influenza viruses with pandemic potential. Here, we have developed a highly immunogenic vaccination regimen based on live-attenuated influenza vaccines (LAIVs) comprised of an attenuated virus backbone lacking non-structural protein 1 (ΔNS1), the primary host interferon antagonist of influenza viruses, with chimeric hemagglutinins (cHA) composed of exotic avian head domains with a highly conserved stalk domain, to redirect the humoral response towards the HA stalk. In this study, we showed that cHA-LAIV vaccines induce robust serum and mucosal responses against group 1 stalk and confer antibody-dependent cell cytotoxicity activity. Mice that intranasally received cH8/1-ΔNS1 followed by a cH11/1-ΔNS1 heterologous booster had robust humoral responses for influenza A virus group 1 HAs and were protected from seasonal H1N1 influenza virus and heterologous highly pathogenic avian H5N1 lethal challenges. When compared with mice immunized with the standard of care or cold-adapted cHA-LAIV, cHA-ΔNS1 immunized mice had robust antigen-specific CD8+ T-cell responses which also correlated with markedly reduced lung pathology post-challenge. These observations support the development of a trivalent universal influenza vaccine for the protection against group 1 and group 2 influenza A viruses and influenza B viruses.

A case of Mycoplasma pneumoniae‐induced rash and mucositis with recent influenza vaccination

AbstractA 33‐year‐old female presented with coryzal symptoms, facial swelling, severe haemorrhagic stomatitis, blistering oral mucositis, conjunctival injection and a sparse targetoid rash on the back and face, requiring admission to hospital. She had received the seasonal influenza vaccination 3 days prior to feeling unwell. Differential diagnosis included erythema multiforme major (EMM) secondary to the influenza vaccine or Mycoplasma pneumoniae‐induced rash and mucositis (MIRM). Oropharyngeal swabs were negative on PCR for cutaneous viruses and Mycoplasma pneumoniae (MP). A skin biopsy from a targetoid lesion on the body showed full thickness epidermal necrosis with epidermal–dermal clefting, numerous civatte bodies and a moderate perivascular infiltrate of lymphocytes and plasma cells in the papillary dermis. She was successfully treated with oral prednisolone and azithromycin. Following discharge from hospital, the paired serological testing for MP returned positive, confirming a diagnosis of MIRM. Our case highlights the difficulties in detecting MP as two diagnostic methods yielded different results, and so we advocate performing both MP PCR and serology to maximise the yield and speed of diagnosis. Secondly, our case highlights the clinical challenge in differentiating MIRM from EMM or Stevens–Johnson syndrome, particularly if there is a potential drug trigger (in our case the influenza vaccine), as all these conditions can feature a severe mucositis with often indistinguishable histological findings. Correct diagnosis of MIRM is important for appropriate and timely administration of anti‐MP antibiotic therapy to facilitate recovery and minimise complications.

Immunogenicity and Reactogenicity of High-dose or Standard-dose Influenza Vaccine in a Second Consecutive Influenza Season.

Pediatric hematopoietic cell transplant (HCT) recipients are at high-risk for morbidity from influenza virus infection. We demonstrated in a primary phase II randomized controlled trial that two post-HCT doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart were more immunogenic than two doses of standard-dose quadrivalent influenza vaccine (SD-QIV). Herein, we present immunogenicity and safety of influenza vaccination in a consecutive season post-HCT using the same dosing regimen. A subcohort of study participants re-enrolled and had hemagglutinin inhibition (HAI) titers measured at baseline and four weeks after each vaccine dose in year two. We estimated geometric mean fold rise (GMFR) in HAI titer from baseline for each group and used linear mixed effects models to estimate adjusted geometric mean ratios (aGMR, comparing HD-TIV to SD-QIV) for each antigen at each time point. We described systemic and injection-site reactions. A total of 65 subcohort patients participated (33 SD-QIV, 32 HD-TIV). Post-vaccine GMFR and aGMR estimates were higher for both groups following a single influenza vaccine dose in year two compared to two doses of the same formulation in year one. Both groups had similar frequencies of injection-site and systemic reactions. A single dose of HD-TIV or SD-QIV was more immunogenic in year two than two doses of the same formulation in year one. Reactogenicity was comparable between groups. One dose of influenza vaccine may be sufficient after a two-dose schedule in the prior year post-HCT.

Immunity Debt Regarding the Aspect of Influenza in the Post-COVID-19 Era in Taiwan.

Immunity debt for various viral infections was reported globally in the post-COVID-19 era, but the data about influenza are lacking. This study collected data from Taiwan's CDC Open Data Portal. We analyzed the weekly number of influenza hospitalizations from January 2017 to May 2024. We divided the study period into four phases: the pre-COVID-19 without influenza epidemics, pre-COVID-19 with an influenza epidemic, COVID-19 pandemic lockdown control, and COVID-19 pandemic unlock periods. The Wilcoxon rank-sum test and interrupted time series analysis were used. The median case numbers of the four time periods were 174 (IQR = 98), 431 (IQR = 160), 8, and 155 (IQR = 175), respectively. Under the COVID-19 pandemic lockdown control, the weekly influenza hospitalization case number decreased by 90.2% (p < 0.001). The non-pharmaceutical intervention (NPI) policies during the COVID-19 pandemic helped Taiwan reduce influenza hospitalizations significantly. Till now, a comparison of the prevalence of influenza pre-COVID-19 and post-COVID-19 has yet to be reported. In our study, with the pandemic unlocking, it increased by 20-fold (p < 0.001), but the case number was still significantly lower than that pre-COVID-19. Amongst other factors, this may be associated with continuing self-induced NPIs in Taiwan.

Mapping the Characteristics of Respiratory Infectious Disease Epidemics in China Based on the Baidu Index from November 2022 to January 2023.

Infectious diseases pose a significant global health and economic burden, underscoring the critical need for precise predictive models. The Baidu index provides enhanced real-time surveillance capabilities that augment traditional systems. Baidu search engine data on the keyword "fever" were extracted from 255 cities in China from November 2022 to January 2023. Onset and peak dates for influenza epidemics were identified by testing various criteria that combined thresholds and consecutive days. The most effective scenario for indicating epidemic commencement involved a 90th percentile threshold exceeded for seven consecutive days, minimizing false starts. Peak detection was optimized using a 7-day moving average, balancing stability and precision. The use of internet search data, such as the Baidu index, significantly improves the timeliness and accuracy of disease surveillance models. This innovative approach supports faster public health interventions and demonstrates its potential for enhancing epidemic monitoring and response efforts.

Timely vaccine strain selection and genomic surveillance improves evolutionary forecast accuracy of seasonal influenza A/H3N2.

For the last decade, evolutionary forecasting models have influenced seasonal influenza vaccine design. These models attempt to predict which genetic variants circulating at the time of vaccine strain selection will be dominant 12 months later in the influenza season targeted by vaccination campaign. Forecasting models depend on hemagglutinin (HA) sequences from the WHO's Global Influenza Surveillance and Response System to identify currently circulating groups of related strains (clades) and estimate clade fitness for forecasts. However, the average lag between collection of a clinical sample and the submission of its sequence to the Global Initiative on Sharing All Influenza Data (GISAID) EpiFlu database is ~3 months. Submission lags complicate the already difficult 12-month forecasting problem by reducing understanding of current clade frequencies at the time of forecasting. These constraints of a 12-month forecast horizon and 3-month average submission lags create an upper bound on the accuracy of any long-term forecasting model. The global response to the SARS-CoV-2 pandemic revealed that modern vaccine technology like mRNA vaccines can reduce how far we need to forecast into the future to 6 months or less and that expanded support for sequencing can reduce submission lags to GISAID to 1 month on average. To determine whether these recent advances could also improve long-term forecasts for seasonal influenza, we quantified the effects of reducing forecast horizons and submission lags on the accuracy of forecasts for A/H3N2 populations. We found that reducing forecast horizons from 12 months to 6 or 3 months reduced average absolute forecasting errors to 25% and 50% of the 12-month average, respectively. Reducing submission lags provided little improvement to forecasting accuracy but decreased the uncertainty in current clade frequencies by 50%. These results show the potential to substantially improve the accuracy of existing influenza forecasting models by modernizing influenza vaccine development and increasing global sequencing capacity.

Development of Influenza-Specific CD4 T Cell-Mediated Immunity in Children Following Inactivated Influenza Vaccination.

While both cellular and humoral immunity are important in immunologic protection against influenza, how the influenza-specific CD4 T cell response is established in response to early vaccination remains inadequately understood. In this study, we sought to understand how the CD4 T cell response to IIV is established and develops throughout early childhood. Influenza-specific CD4 T cell responses were quantified following IIV over two influenza seasons in 47 vaccinated children between 6 months and 8 years of age who had no documented history of natural influenza infection during the study. PBMCs were stimulated with peptide pools encompassing the translated regions of the pH1, H3, HAB, and NP proteins and CD4 T cell responses were assessed via multiparameter flow cytometry. There was boosting of H3- and HAB-specific CD4 T cells but not cells specific for the pH1 HA protein post-vaccination. A positive correlation between age and the magnitude of the influenza-specific CD4 T cell response was seen, with an overall greater magnitude of IFNγ-producing cells in subjects ≥3 years of age. Changes in CD4 T cell functionality were also noted in older compared to younger children, with increases in CD4 T cells producing IFNγ and TNF or IL-2 as well as IFNγ alone. IIV elicits a CD4 T cell response to H3 and HAB, with increases in the magnitude of the CD4 T cell response and changes in cellular functionality throughout childhood. This suggests that repeated influenza vaccination contributes to the development of anti-influenza CD4 T cell memory in children.

Molecular characterisation of influenza B virus from the 2017/18 season in primary models of the human lung reveals improved adaptation to the lower respiratory tract

ABSTRACT The 2017/18 influenza season was characterized by unusual high numbers of severe infections and hospitalizations. Instead of influenza A viruses, this season was dominated by infections with influenza B viruses of the Yamagata lineage. While this IBV/Yam dominance was associated with a vaccine mismatch, a contribution of virus intrinsic features to the clinical severity of the infections was speculated. Here, we performed a molecular and phenotypic characterization of three IBV isolates from patients with severe flu symptoms in 2018 and compared it to an IBV/Yam isolate from 2016 using experimental models of increasing complexity, including human lung explants, lung organoids, and alveolar macrophages. Viral genome sequencing revealed the presence of clade but also isolate specific mutations in all viral genes, except NP, M1, and NEP. Comparative replication kinetics in different cell lines provided further evidence for improved replication fitness, tolerance towards higher temperatures, and the development of immune evasion mechanisms by the 2018 IBV isolates. Most importantly, immunohistochemistry of infected human lung explants revealed an impressively altered cell tropism, extending from AT2 to AT1 cells and macrophages. Finally, transcriptomics of infected human lung explants demonstrated significantly reduced amounts of type I and type III IFNs by the 2018 IBV isolate, supporting the existence of additional immune evasion mechanisms. Our results show that the severeness of the 2017/18 Flu season was not only the result of a vaccine mismatch but was also facilitated by improved adaptation of the circulating IBV strains to the environment of the human lower respiratory tract.

Comparison of the risk of pneumothorax in COVID-19 and seasonal influenza

Limited evidence exists regarding the link between coronavirus disease 2019 (COVID-19) and pneumothorax. Therefore, we aimed to evaluate the occurrence rate of pneumothorax in hospitalized patients with COVID-19 and compare the risk of pneumothorax between patients with COVID-19 and influenza. This retrospective cohort study used patient data from the National Health Insurance Service of South Korea. Patients diagnosed with COVID-19 (December 2019 to December 2021) and influenza (January 2019 to December 2021) who required hospitalization and respiratory support were included. We identified 46,460 patients with COVID-19 and 6,117 with influenza. The occurrence rate of pneumothorax was 0.74% in patients with COVID-19. In an inverse probability of treatment weighting matched cohort, the Cox proportional hazards regression model showed that COVID-19 was not associated with an increased risk of pneumothorax compared to influenza (hazard ratio, 1.22; 95% confidence interval, 0.75–1.99). However, the risk of pneumothorax associated with COVID-19 compared to influenza was significantly higher in patients without chronic lung disease than in those with (P for heterogeneity = 0.037). In conclusion, COVID-19, compared with influenza, is not associated with an increased risk of pneumothorax; however, it is associated with an increased risk in patients without chronic lung disease.

Safety and Immunogenicity of a Carbohydrate Fatty Acid Monosulphate Ester Adjuvant Combined with a Low-Dose Quadrivalent Split-Virion Inactivated Influenza Vaccine: A Randomised, Observer-Blind, Active-Controlled, First-in-Human, Phase 1 Study.

Seasonal influenza vaccine effectiveness is low. Carbohydrate fatty acid monosulphate ester (CMS), a new oil-in-water adjuvant, has proven potency in animal models with suggested capacity for dose-sparing. The objective was to evaluate safety and immunogenicity of CMS when added to a low-dose influenza vaccine (QIV) in humans. In a randomised, double-blind, active-controlled, first-in-human study, sixty participants (18-50 years) received either 0.5 mg CMS or 2 mg CMS with 1/5th dose QIV, or a full dose QIV without CMS. Adverse events (AE) were monitored until 7 days post-vaccination. Haemagglutinin inhibition (HI) titres in serum and CD4+ T cells in PBMCs were determined at day 0, 7, 28, and 180. Mean age was 37.6 (±10.1) years and 42/60 (70.0%) were female. Pain at injection site (42/60, 86.7%) and headache (34/60, 56.7%) were reported most and more frequently in the 2 mg CMS group. HI titres and the frequency of influenza specific CD4+ T cells were equal across strains for the three cohorts on all visits, increased until day 28 and decreased at day 180 to values higher than baseline. CMS was safe in humans. Humoral and cell-mediated immunogenicity was similar across vaccines, even with 1/5th antigen dose. CMS can have beneficial implications in low-resource settings or in a pandemic context.