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Objectives: Influenza is responsible for considerable health and economic burden every year. Especially older adults are vulnerable for influenza infection and its complications due to immunosenescence and often-underlying medical conditions. Recently, the innovative quadrivalent high-dose influenza vaccine (QIV-HD) has become available in Europe. Through its enhanced immunogenicity, QIV-HD offers improved protection for older adults against respiratory as well as cardiovascular complications. We estimated the potential impact—specifically in terms of hospital admissions and related costs—of a hypothetical past switch from QIV-Standard dose (SD) to QIV-HD in The Netherlands. Methods: Estimates of hospitalizations for the older adults vaccinated with QIV-SD were derived from the seasons 2010/2011-2017/2018. Subsequently, the number of respiratory infections and cardiovascular complications of influenza were estimated for the year 2019/2020 for both QIV-SD and QIV-HD. To calculate the overall corresponding savings, costs for hospital complications, derived from literature, were used. Results: When QIV-HD would have been used instead of QIV-SD during the season 2019/2020, an additional 220 hospitalizations would have been averted among older adults of 60 years and older in the Netherlands. This corresponds to savings of €1 219 779 (uncertainty interval: 1 089 813-1 348 549), of which 69% is attributable to cardiovascular-related hospitalizations. Conclusions: We demonstrate that a relevant improvement in influenza vaccination among older adults in The Netherlands can be achieved by switching from the current QIV-SD to QIV-HD. Not only comes a switch from QIV-SD to QIV-HD with a significant reduction in pressure on hospital capacity but also with notable cost savings.

BACKGROUND: Acute respiratory infections make up a sizable percentage of emergency department (ED) visits and many result in antibiotics being prescribed. Procalcitonin has been found to reduce antibiotic use in both outpatient and critical care settings, yet remains underused in the ED. OBJECTIVE: To evaluate whether point of care molecular influenza and Respiratory Syncytial Virus (RSV) testing, procalcitonin, and a pharmacist driven educational intervention in aggregate optimizes antibiotic and antiviral prescribing in the ED setting. METHODS: A randomized trial of the Cobas Liat Flu/RSV Assay, procalcitonin, and the use of pharmacist-led education in patients 0–50 years of age being seen in the ED for Influenza Like Illness (ILI) or acute respiratory illness. The study enrolled 200 ED patients between March 2018 and April 2022 at the University of California Davis Medical Results: There was little difference in antibiotic or antiviral prescribing between the intervention and control groups in this study (39% - 32% = 7.0%, 95% CI: −6.2, 20.2, P=0.30). However, a post-hoc analysis of the use of PCT showed PCT results were used as indicated in the ED (P=0.001). CONCLUSION: Procalcitonin can be used in both adult and pediatric populations to help guide the decision of whether to treat with antibiotics in the ED setting. Pharmacist guided education may not be a driving factor.

Le solde naturel, différence entre les nombres de naissances et de décès, a été divisé par quatre en France entre 2012 et 2022. Sa baisse provient d’une diminution des naissances et d’une hausse des décès d’ampleurs comparables depuis 10 ans, autour de 100 000 chacune. L’espérance de vie n’a plus progressé au cours des trois dernières années en raison de l’épidémie de Covid-19 à laquelle se sont ajoutées en 2022 les surmortalités liées à plusieurs canicules en été et à une épidémie de grippe saisonnière en fin d’année. La Covid-19 semble avoir peu affecté le nombre des naissances, elle a en revanche modifié temporairement leur saisonnalité en 2021.

International audience; Molecular biology amplification enables sensitive detection of most respiratory viruses through nasopharyngeal swabbing. We developed an innovative approach to detect viral genomes on used facial tissues. In 2 communities of children, used tissues were collected once weekly for 1 year. Pooled analysis of tissues enabled detection of successive virus circulation in 4 age groups over time and forecasted by several weeks the circulation of influenza in the general population. At the individual level, in a proof-of-concept study of 30 volunteers with influenza-like signs/symptoms, we identified common respiratory viruses. The signals for SARS-CoV-2 obtained in parallel from 15 facial tissues and swab samples were similar and often higher for the tissues (11/15). Individual analysis of tissues offers a noninvasive, sensitive, and affordable alternative to self-sampling without a medical care requirement. Pooled analyses may be used to detect virus spread in specific communities, predict seasonal epidemics, and alert the population to viral infections. © 2023 Centers for Disease Control and Prevention (CDC). All rights reserved.

The high economic impact and zoonotic potential of avian influenza call for detailed investigations of dispersal dynamics of epidemics. We integrated phylogeographic and epidemiologic analyses to investigate the dynamics of a low pathogenicity avian influenza (H3N1) epidemic that occurred in Belgium during 2019. Virus genomes from 104 clinical samples originating from 85% of affected farms were sequenced. A spatially explicit phylogeographic analysis confirmed a dominating northeast to southwest dispersal direction and a long-distance dispersal event linked to direct live animal transportation between farms. Spatiotemporal clustering, transport, and social contacts strongly correlated with the phylogeographic pattern of the epidemic. We detected only a limited association between wind direction and direction of viral lineage dispersal. Our results highlight the multifactorial nature of avian influenza epidemics and illustrate the use of genomic analyses of virus dispersal to complement epidemiologic and environmental data, improve knowledge of avian influenza epidemiologic dynamics, and enhance control strategies. ispartof: EMERGING INFECTIOUS DISEASES vol:29 issue:2 pages:351-359 ispartof: location:United States status: published

BackgroundSome studies have reported that influenza vaccination is associated with lower risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and/or coronavirus disease 2019 (COVID-19) morbidity and mortality. This study aims to estimate effectiveness of influenza vaccination, using Abbott’s quadrivalent Influvac Tetra vaccine, against SARS-CoV-2 infection and against severe COVID-19. MethodsThis matched, test-negative, case-control study was implemented on a population of 30,774 healthcare workers (HCWs) in Qatar during the 2020 annual influenza vaccination campaign, September 17, 2020-December 31, 2020, before introduction of COVID-19 vaccination. ResultsOf 30,774 HCWs, 576 with PCR-positive tests and 10,033 with exclusively PCR-negative tests were eligible for inclusion in the study. Matching by sex, age, nationality, reason for PCR testing, and PCR test date yielded 518 cases matched to 2058 controls. Median duration between influenza vaccination and the PCR test was 43 days (IQR, 29–62). Estimated effectiveness of influenza vaccination against SARS-CoV-2 infection> 14 days after receiving the vaccine was 29.7% (95% CI: 5.5–47.7%). Estimated effectiveness of influenza vaccination against severe, critical, or fatal COVID-19 was 88.9% (95% CI: 4.1–98.7%). Sensitivity analyses confirmed the main analysis results. ConclusionsRecent influenza vaccination is associated with a significant reduction in the risk of SARS-CoV-2 infection and COVID-19 severity.

The vast majority of seasonal influenza vaccines administered each year are derived from virus propagated in eggs using technology that has changed little since the 1930s. The immunogenicity, durability, and breadth of response would likely benefit from a recombinant nanoparticle-based approach. Although the E2 protein nanoparticle (NP) platform has been previously shown to promote effective cell-mediated responses to peptide epitopes, it has not yet been reported to deliver whole protein antigens. In this study, we synthesized a novel maleimido tris-nitrilotriacetic acid (NTA) linker to couple protein hemagglutinin (HA) from H1N1 influenza virus to the E2 NP, and we evaluated the HA-specific antibody responses using protein microarrays. We found that recombinant H1 protein alone is immunogenic in mice but requires two boosts for IgG to be detected and is strongly IgG1 (Th2) polarized. When conjugated to E2 NPs, IgG2c is produced leading to a more balanced Th1/Th2 response. Inclusion of the Toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) significantly enhances the immunogenicity of H1-E2 NPs while retaining the Th1/Th2 balance. Interestingly, broader homo- and heterosubtypic cross-reactivity is also observed for conjugated H1-E2 with MPLA, compared to unconjugated H1 with or without MPLA. These results highlight the potential of an NP-based delivery of HA for tuning the immunogenicity, breadth, and Th1/Th2 balance generated by recombinant HA-based vaccination. Furthermore, the modularity of this protein-protein conjugation strategy may have utility for future vaccine development against other human pathogens.

Among the most important influenza virus targets is the RNA-dependent RNA polymerase acidic N-terminal (PAN) endonuclease, which is a critical component of the viral replication machinery. To inhibit the activity of this metalloenzyme, small-molecule inhibitors employ metal-binding pharmacophores (MBPs) that coordinate to the dinuclear Mn2+ active site. In this study, several metal-binding isosteres (MBIs) were examined where the carboxylic acid moiety of a hydroxypyridinone MBP is replaced with other groups to modulate the physicochemical properties of the compound. MBIs were evaluated for their ability to inhibit PAN using a FRET-based enzymatic assay, and their mode of binding in PAN was determined using X-ray crystallography.

Influenza virus has resurfaced recently from inactivity during the early stages of the COVID-19 pandemic, raising serious concerns about the nature and magnitude of future epidemics. The main antigenic targets of influenza virus are two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA). Whereas the structural and dynamical properties of both glycoproteins have been studied previously, the understanding of their plasticity in the whole-virion context is fragmented. Here, we investigate the dynamics of influenza glycoproteins in a crowded protein environment through mesoscale all-atom molecular dynamics simulations of two evolutionary-linked glycosylated influenza A whole-virion models. Our simulations reveal and kinetically characterize three main molecular motions of influenza glycoproteins: NA head tilting, HA ectodomain tilting, and HA head breathing. The flexibility of HA and NA highlights antigenically relevant conformational states, as well as facilitates the characterization of a novel monoclonal antibody, derived from human convalescent plasma, that binds to the underside of the NA head. Our work provides previously unappreciated views on the dynamics of HA and NA, advancing the understanding of their interplay and suggesting possible strategies for the design of future vaccines and antivirals against influenza.One-Sentence SummaryIn situ dynamics of influenza glycoproteins expose antigenically relevant states and a new site of vulnerability in neuraminidase.

Sialidases or neuraminidases are sialic-acid-cleaving enzymes that are expressed by a broad spectrum of organisms, including pathogens. In nature, sialic acids are monosaccharides with diverse structural variations, but the lack of novel probes has made it difficult to determine how sialic acid modifications impact the recognition by sialidases. Here, we used a chemoenzymatic synthon strategy to generate a set of α2-3- and α2-6-linked sialoside probes that contain 7-N-acetyl or 7,9-di-N-acetyl sialic acid as structure mimics for those containing the less stable naturally occurring 7-O-acetyl- or 7,9-di-O-acetyl modifications. These probes were used to compare the substrate specificity of several sialidases from different origins. Our results show that 7-N-acetyl sialic acid was readily cleaved by neuraminidases from H1N1 and H3N2 influenza A viruses, but not by sialidases of human or bacterial origin, thereby indicating that the influenza enzymes possess a distinctive and more promiscuous substrate binding pocket.

To explore the 2020-2021 influenza season by describing the case of Italy.FluNet was searched for Italian data on virological samples. French, German, and Spanish data were collected for comparison. InfluNet was used for Italian epidemiological data on influenza-like illness (ILI). Data were extracted for the period from the 42nd week of 2020 to the 16th week of 2021 and for the previous 5-year period. The Containment and Health Index were used to describe the containment measures.Among 6818 samples, 0% were positive in Italy in the 2020-2021 season (28.8% in the previous 5-year period; the percentage change in the total number of tested specimens was -51.3%). In France, Germany, and Spain, the percentage change was -23%, -7%, and -61%, respectively. The Italian ILI incidence remained below the baseline levels (mean 0.0144/100,000 inhabitants; range 0.0085-0.0204). In the previous 5-year period, the mean incidence was 0.041/100,000 inhabitants. With the increase in containment measures, a deflection of ILI incidence was described (P = .015).Despite the reduced number of collected specimens compared to previous seasons and a slight rise in influenza vaccination rates, containment measures represent the most likely factor that helped to reduce cases in the 2020-2021 influenza season in Italy.

BackgroundTest-negative design (TND) studies have produced validated estimates of vaccine effectiveness (VE) for influenza vaccine studies. However, syndrome-negative controls have been proposed for differentiating bias and true estimates in VE evaluations for COVID-19. To understand the use of alternative control groups, we compared characteristics and VE estimates of syndrome-negative and test-negative VE controls.MethodsAdults hospitalized at 21 medical centers in 18 states March 11-August 31, 2021 were eligible for analysis. Case patients had symptomatic acute respiratory infection (ARI) and tested positive for SARS-CoV-2. Control groups were test-negative patients with ARI but negative SARS-CoV-2 testing, and syndrome-negative controls were without ARI and negative SARS-CoV-2 testing. Chi square and Wilcoxon rank sum tests were used to detect differences in baseline characteristics. VE against COVID-19 hospitalization was calculated using logistic regression comparing adjusted odds of prior mRNA vaccination between cases hospitalized with COVID-19 and each control group.Results5811 adults (2726 cases, 1696 test-negative controls, and 1389 syndrome-negative controls) were included. Control groups differed across characteristics including age, race/ethnicity, employment, previous hospitalizations, medical conditions, and immunosuppression. However, control-group-specific VE estimates were very similar. Among immunocompetent patients aged 18-64years, VE was 93% (95% CI: 90-94) using syndrome-negative controls and 91% (95% CI: 88-93) using test-negative controls.ConclusionsDespite demographic and clinical differences between control groups, the use of either control group produced similar VE estimates across age groups and immunosuppression status. These findings support the use of test-negative controls and increase confidence in COVID-19 VE estimates produced by test-negative design studies.

ObjectiveNorthern Syria faces a large burden of influenza-like illness (ILI) and severe acute respiratory illness (SARI). This study aimed to investigate the trends of Early Warning and Response Network (EWARN) reported ILI and SARI in northern Syria between 2016 and 2021 and the potential impact of SARS-CoV-2.MethodsWe extracted weekly EWARN data on ILI/ SARI and aggregated cases and consultations into 4-week intervals to calculate case positivity. We conducted a seasonal-trend decomposition to assess case trends in the presence of seasonal fluctuations.ResultsIt was observed that 4-week aggregates of ILI cases (n=5,942,012), SARI cases (n=114,939), ILI case positivity, and SARI case positivity exhibited seasonal fluctuations with peaks in the winter months. ILI and SARI cases in individuals aged ≥5 years surpassed those in individuals aged

MF59-adjuvanted standard-dose and nonadjuvanted high-dose seasonal influenza vaccines have been developed to protect the elderly at high risk of severe complications. This study aimed to summarize the available evidence on the comparative efficacy/effectiveness of these two vaccines.A systematic literature review of experimental and observational studies were conducted according to the preferred reporting items for systematic reviews and meta-analyses guidelines. When possible, the extracted effect sizes were pooled in random-effects meta-analyses.Ten studies were identified. Of these, no head-to-head randomized controlled trials were identified. All available studies had retrospective cohort design and large sample sizes, were conducted in the United States between the 2016-2017 and 2019-2020 seasons, and were at moderate risk of bias. Relative effectiveness estimates were limited to nonlaboratory-confirmed clinical end points, such as medical encounters including hospitalizations. Although most pooled relative effectiveness estimates were close to null, few statistically significant pooled effect sizes were small in magnitude, moved in opposite directions, and depended on the study sponsor and specificity of influenza-related outcomes.At present, MF59-adjuvanted standard-dose and nonadjuvanted high-dose vaccines appear to have similar effectiveness in preventing seasonal influenza in the elderly, and no conclusive recommendations on the preference of one vaccine over another could be drawn.

Background: Both influenza and SARS-CoV-2 viruses show a strong seasonal spreading in temperate regions. Several studies indicated that changes in indoor humidity could be one of the key factors explaining this. Objective: The purpose of this study is to quantify the association between relevant epidemiological metrics and humidity in both influenza and SARS-CoV-2 epidemic periods. Methods: The atmospheric dew point temperature serves as a proxy for indoor relative humidity. This study considered the weekly mortality rate in the Netherlands between 1995 and 2019 to determine the correlation between the dew point and the spread of influenza. During influenza epidemic periods in the Netherlands, governmental restrictions were absent; therefore, there is no need to control this confounder. During the SARS-CoV-2 pandemic, governmental restrictions strongly varied over time. To control this effect, periods with a relatively constant governmental intervention level were selected to analyze the reproduction rate. We also examine SARS-CoV-2 deaths in the nursing home setting, where health policy and social factors were less variable. Viral transmissibility was measured by computing the ratio between the estimated daily number of infectious persons in the Netherlands and the lagged mortality figures in the nursing homes. Results: For both influenza and SARS-CoV-2, a significant correlation was found between the dew point temperature and the aforementioned epidemiological metrics. The findings are consistent with the anticipated mechanisms related to droplet evaporation, stability of virus in the indoor environment, and impairment of the natural defenses of the respiratory tract in dry air. Significance: This information is helpful to understand the seasonal pattern of respiratory viruses and motivate further study to what extent it is possible to alter the seasonal pattern by actively intervening in the adverse role of low humidity during fall and winter in temperate regions. Impact: A solid understanding and quantification of the role of humidity on the transmission of respiratory viruses is imperative for epidemiological modeling and the installation of non-pharmaceutical interventions. The results of this study indicate that improving the indoor humidity by humidifiers could be a promising technology for reducing the spread of both influenza and SARS-CoV-2 during winter and fall in the temperate zone. The identification of this potential should be seen as a strong motivation to invest in further prospective testing of this non-pharmaceutical intervention.

This short communication provides an overview of the integrated treatment framework for influenza and COVID-19 in the post-pandemic era. We discuss the available medications for influenza treatment and compare their efficacy. Additionally, we address the issue of antiviral resistance and the safety considerations associated with these medications. The research methods and findings supporting this treatment approach are discussed, highlighting its potential limitations and challenges. This work aims to contribute to the development of effective treatment strategies for influenza and COVID-19, considering the evolving landscape of infectious diseases in the aftermath of the pandemic.

Introduction: The unpredictable evolution of avian influenza viruses (AIVs) presents an ongoing threat to agricultural production and public and wildlife health. Severe outbreaks of highly pathogenic H5N1 viruses in US poultry and wild birds since 2022 highlight the urgent need to understand the changing ecology of AIV. Surveillance of gulls in marine coastal environments has intensified in recent years to learn how their long-range pelagic movements potentially facilitate inter-hemispheric AIV movements. In contrast, little is known about inland gulls and their role in AIV spillover, maintenance, and long-range dissemination.Methods: To address this gap, we conducted active AIV surveillance in ring-billed gulls (Larus delawarensis) and Franklin's gulls (Leucophaeus pipixcan) in Minnesota's natural freshwater lakes during the summer breeding season and in landfills during fall migration (1,686 samples).Results: Whole-genome AIV sequences obtained from 40 individuals revealed three-lineage reassortants with a mix of genome segments from the avian Americas lineage, avian Eurasian lineage, and a global “Gull” lineage that diverged more than 50 years ago from the rest of the AIV global gene pool. No poultry viruses contained gull-adapted H13, NP, or NS genes, pointing to limited spillover. Geolocators traced gull migration routes across multiple North American flyways, explaining how inland gulls imported diverse AIV lineages from distant locations. Migration patterns were highly varied and deviated far from assumed “textbook” routes.Discussion: Viruses circulating in Minnesota gulls during the summer breeding season in freshwater environments reappeared in autumn landfills, evidence of AIV persistence in gulls between seasons and transmission between habitats. Going forward, wider adoption of technological advances in animal tracking devices and genetic sequencing is needed to expand AIV surveillance in understudied hosts and habitats.

The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus (IAV) strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N129D; H1 numbering) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. Functionally, this putative permissive mutation increased HA avidity for its receptor. These results suggest a mechanism of epistasis in IAV, wherein modulating the efficiency of attachment eases evolutionary constraints imposed by the requirement for membrane fusion. Taken together, the data indicate that viral escape from stem-bnAbs is costly but highlights the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain.

Influenza virus poses an ongoing human health threat with pandemic potential. Due to mutations in circulating strains, formulating effective vaccines remains a challenge. The use of computationally optimized broadly reactive antigen (COBRA) hemagglutinin (HA) proteins is a promising vaccine strategy to protect against a wide range of current and future influenza viruses. Though effective in preclinical studies, the mechanistic basis driving the broad reactivity of COBRA proteins remains to be elucidated. Here, we report the crystal structure of the COBRA HA termed P1 and identify antigenic and glycosylation properties that contribute to its immunogenicity. We further report the cryo-EM structure of the P1-elicited broadly neutralizing antibody 1F8 bound to COBRA P1, revealing 1F8 to recognize an atypical receptor binding site epitope via an unexpected mode of binding.

STAT2 is a transcription factor activated by type I and III IFNs. We report 23 patients with loss-of-function variants causing autosomal recessive (AR) complete STAT2 deficiency. Both cells transfected with mutant STAT2 alleles and the patients' cells displayed impaired expression of IFN-stimulated genes and impaired control of in vitro viral infections. Clinical manifestations from early childhood onward included severe adverse reaction to live attenuated viral vaccines (LAV) and severe viral infections, particularly critical influenza pneumonia, critical COVID-19 pneumonia, and herpes simplex virus type 1 (HSV-1) encephalitis. The patients displayed various types of hyperinflammation, often triggered by viral infection or after LAV administration, which probably attested to unresolved viral infection in the absence of STAT2-dependent types I and III IFN immunity. Transcriptomic analysis revealed that circulating monocytes, neutrophils, and CD8+ memory T cells contributed to this inflammation. Several patients died from viral infection or heart failure during a febrile illness with no identified etiology. Notably, the highest mortality occurred during early childhood. These findings show that AR complete STAT2 deficiency underlay severe viral diseases and substantially impacts survival. ispartof: J Clin Invest vol:133 issue:12 pages:e168321- ispartof: location:United States status: Published online

E-cigarette use has rapidly increased as an alternative means of nicotine delivery by heated aerosolization. Recent studies demonstrate nicotine-containing e-cigarette aerosols can have immunosuppressive and pro-inflammatory effects, but it remains unclear how e-cigarettes and the constituents of e-liquids may impact acute lung injury and the development of acute respiratory distress syndrome caused by viral pneumonia. Therefore, in these studies, mice were exposed one hour per day over nine consecutive days to aerosol generated by the clinically-relevant tank-style Aspire Nautilus aerosolizing e-liquid containing a mixture of vegetable glycerin and propylene glycol (VG/PG) with or without nicotine. Exposure to the nicotine-containing aerosol resulted in clinically-relevant levels of plasma cotinine, a nicotine-derived metabolite, and an increase in the pro-inflammatory cytokines IL-17A, CXCL1, and MCP-1 in the distal airspaces. Following the e-cigarette exposure, mice were intranasally inoculated with influenza A virus (H1N1 PR8 strain). Exposure to aerosols generated from VG/PG with and without nicotine caused greater influenza-induced production in the distal airspaces of the pro-inflammatory cytokines IFN-γ, TNFα, IL-1β, IL-6, IL-17A, and MCP-1 at 7 days post inoculation (dpi). Compared to the aerosolized carrier VG/PG, in mice exposed to aerosolized nicotine there was a significantly lower amount of Mucin 5 subtype AC (MUC5AC) in the distal airspaces and significantly higher lung permeability to protein and viral load in lungs at 7 dpi with influenza. Additionally, nicotine caused relative downregulation of genes associated with ciliary function and fluid clearance and an increased expression of pro-inflammatory pathways at 7 dpi. These results show that (1) the e-liquid carrier VG/PG increases the pro-inflammatory immune responses to viral pneumonia and that (2) nicotine in an e-cigarette aerosol alters the transcriptomic response to pathogens, blunts host defense mechanisms, increases lung barrier permeability, and reduces viral clearance during influenza infection. In conclusion, acute exposure to aerosolized nicotine can impair clearance of viral infection and exacerbate lung injury, findings that have implications for the regulation of e-cigarette products.

The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.

IntroductionUptake of COVID-19 vaccination remains suboptimal in the United States and other settings. Though early reports indicated that a strong majority of people were interested in receiving the COVID-19 vaccine, the association between vaccine intention and uptake is not yet fully understood. Ourobjective was todescribe predictors of vaccine uptake, and estimate the sensitivity, specificity, and predictive values of self-reported COVID-19 vaccine status compared to a comprehensive statewide COVID-19 vaccine registry.MethodsA cohort of California residents that received a molecular test for SARS-CoV-2 infection during 24 February-5 December 2021 were enrolled in a telephone-administered survey. Survey participants were matched with records in a statewide immunization registry. Cox proportional hazards model were used to compare time to vaccination among those unvaccinated at survey enrollment by self-reported COVID-19 vaccination intention.ResultsAmong 864 participants who were unvaccinated at the time of interview, 272 (31%) had documentation of receipt of COVID-19 vaccination at a later date; including 194/423 (45.9%) who had initially reported being willing to receive vaccination, 41/185 (22.2%) who reported being unsure about vaccination, and 37/278 (13.3%) who reported unwillingness to receive vaccination.Adjusted hazard ratios (aHRs) for registry-confirmed COVID-19 vaccination were 0.49 (95% confidence interval: 0.32-0.76) and 0.21 (0.12-0.36) for participants expressing uncertainty and unwillingness to receive vaccination, respectively, as compared with participants who reported being willing to receive vaccination. Time to vaccination was shorter among participants from higher-income households (aHR=3.30 [2.02-5.39]) and who reported co-morbidities or immunocompromising conditions (aHR=1.54 [1.01-2.36]).Sensitivity of self-reported COVID-19 vaccination status was 82% (80-85%) overall, and 98% (97-99%) among those referencing vaccination records; specificity was 87% (86-89%).ConclusionWillingness to receive COVID-19 vaccination was an imperfect predictor of real-world vaccine uptake. Improved messaging about COVID-19 vaccination regardless of previous SARS-CoV-2 infection status may help improve uptake.

Background: The infectious diseases of viral etiology with airborne transmission generally dominate in the structure of infectious incidence. Objective: To determine incidence of viral infections with airborne transmission in the north-eastern region of Ukraine, to research the impact of social and natural factors on the intensity of epidemic process. Methods: In order to determine the current epidemiological peculiarities of infections with airborne transmission in the north-eastern region of Ukraine, a retrospective and operative analysis of the incidence, reports of vaccination of decreed child population in 2009‒2019, demographic and natural indicators. Results: Trends in the incidence of influenza were characterized by chaotic nature and disorder, acute respiratory viral infections ‒ high intensity and monotony. Significant correlations were established between the incidence of influenza and number and density of the population, the incidence of acute respiratory viral infections and the coefficient of migration population movement. Direct strong correlations were found between social factors and trends in the incidence of rubella and mumps. Coronavirus infection COVID–19 has become the problem for health care facilities in Sumy oblast. Conclusion: Quantitative and qualitative characteristics of the epidemic process of infections of viral etiology with airborne transmission have changed, which requires new approaches to organization of the system of epidemiological surveillance. Bangladesh Journal of Medical Science Vol. 21 No. 03 July’22 Page: 610-619

Resumen Antecedentes: Recientemente se ha sugerido que la vacunacion contra influenza puede ser un factor asociado con la disminucion de la mortalidad por COVID-19. Metodos: Mediante un estudio de casos y controles pareado por edad, basado en casos hospitalarios. Incluimos sujetos de 18 anos en adelante con diagnostico de COVID-19 moderado a grave. La infeccion se corroboro por RT-PCR para SARS-COV-2. Los sujetos fallecidos fueron considerados casos, los controles fueron los pacientes que egresaron por mejoria del cuadro agudo. Se utilizo analisis bivariado, para determinar los factores asociados con la muerte por COVID-19, con calculo de razon de momios e intervalos de confianza del 95%. Resultados: Un total de 560 pacientes fueron incluidos en el estudio, 214 (38.2%) fueron considerados casos y 346 (61.7%) controles. Se observo diferencia significativa con la presencia de diabetes mellitus tipo 2 [54% vs. 39.3% entre casos y controles, respectivamente (p=0.04)] y haber recibido la vacuna contra la influenza (p= 0.02). La diabetes mellitus tipo 2 se asocio con mayor mortalidad por COVID-19 [OR 1.8 (IC 95% 1.2-2.5) p=0.01], mientras que el haberse inmunizado contra influenza en 2019 se asocio con menor mortalidad en este grupo de pacientes [OR 0.6 (IC 95% 0.4-0.9) p=0.02]. Conclusiones: La vacunacion contra influenza en el ano previo parece asociarse con una menor mortalidad por COVID-19; mientras que se confirma a la diabetes mellitus tipo 2 como una condicion asociada con mayor mortalidad.

IntroductionThe aim of this meta-analysis was to assess the effect of ongoing statin treatment on susceptibility to influenza virus infection and on influenza-associated mortality.Material and methodsStudies investigating the impact of statin treatment on influenza prevalence and mortality were searched in PubMed-Medline, Scopus, ISI Web of Knowledge, Embase, Proquest, OVID, EBSCO and CINAHLdatabases (up to June 30, 2020). Fixed- and random-effects model and generic inverse variance method were used for quantitative data synthesis.ResultsIn the meta-analysis of 15 arms of 3 eligible studies including flu-vaccinated and unvaccinated patients, treatment with statins was associated with a reduction of influenza virus prevalence [Odds Ratio (OR) 0.85, 95% Confidence Interval (CI) 0.73-0.99; p 0.040]. No significant effect of statins on the susceptibility to influenza infection was observed in the distinct communities of either vaccinated or unvaccinated subjects. Among 9 arms of 6 eligible studies, the use of statins among patients with influenza was associated with a reduced mortality [OR (95% CI), 0.68 (0.56, 0.82); pConclusionsA reduced influenza prevalence and anincreased survivalfrom influenza infection was observed in patients on ongoing statin treatment. Further research is needed to define the possible role of statins as adjunctive therapy in patients with influenza infection.

At the beginning of the COVID 19 pandemic, the outcome of patients treated with ECMO was discouraging. Subsequently, it became clear that a certain group of patients may benefit from ECMO treatment. The primary objective of this study was to compare the outcome of ECMO treatment in COVID-19 and influenza patients referred to a tertiary care center. A total of 119 adult patients required ECMO treatment following ARDS secondary to H1N1 (49) and SARS-CoV-2 (70) in the referral ECMO Center based in Zagreb between October 2009 and October 2021. Our study revealed a significantly higher mortality in COVID-19 patients compared to H1N1 influenza when the onset of ARDS was severe enough to require ECMO support. Based on these results and current knowledge, we argue that ECMO treatment for ARDS in COVID-19 patients is more challenging compared to H1N1 influenza patients. Therefore, referral to the most experienced ECMO centers should be considered. Additionally, patient selection and timing for ECMO treatment play a key role in relation to outcome. Mortality rate in COVID-19 patients requiring ECMO treatment may be used as a reference frame for ECMO centers to ensure best possible care and outcome.

Background Respiratory syncytial virus (RSV) and influenza virus infections result in a considerable mortality and morbidity among the aging population globally. Influenza vaccination for older adults before the seasonal influenza epidemic has been evaluated to be cost-effective in many countries. Interventions against RSV in older adults are in the pipeline, and evaluating their cost-effectiveness is crucial for decision making. To inform such evaluations, our aim was to estimate average costs and health-related quality of life (HRQoL) in older adults with RSV and influenza infection. Methods The European RESCEU observational cohort study followed 1040 relatively healthy community-dwelling older adults aged 60 years and older during 2 consecutive winter seasons. Health care resource use and HRQoL were collected and analyzed during RSV episodes, and also during influenza episodes. Country-specific unit cost data were mainly obtained from national databases. Direct costs were estimated from a patient, health care provider, and health care payers’ perspective, whereas indirect costs were estimated from a societal perspective. Due to small sample size, no formal statistical comparisons were made. Results Thirty-six RSV and 60 influenza episodes were reported, including 1 hospitalization. Means (median; first-third quartile) of €26.4 (€5.5; 0–47.3) direct and €4.4 (€0; 0–0) indirect costs were reported per nonhospitalized RSV episode, and €42.5 (€36; 3.3–66.7) direct and €32.1 (€0; 0–0) indirect costs per nonhospitalized influenza episode. For RSV episodes, the utility value decreased from 0.896 (0.928; 0.854–0.953) to 0.801 (0.854; 0.712–0.937) from preseason to 1 week after symptom onset; for influenza, the change was from 0.872 (0.895; 0.828–0.953) to 0.664 (0.686; 0.574–0.797). Conclusions The average costs and HRQoL estimates of older adults treated outside the hospital can be used to inform the design of future studies and the decision making regarding interventions to prevent RSV infection in older adults. Larger studies are needed to provide better country-specific and complementary cost estimates and to allow for formal statistical comparison of costs between RSV and influenza. Clinical Trials Registration NCT03621930.

Background Interactions of Streptococcus pneumoniae with viruses feature in the pathogenesis of numerous respiratory illnesses. Methods We undertook a case-control study among adults at Kaiser Permanente Southern California between 2015 and 2019. Case patients had diagnoses of lower respiratory tract infection (LRTI; including pneumonia or nonpneumonia LRTI diagnoses), with viral infections detected by multiplex polymerase chain reaction testing. Controls without LRTI diagnoses were matched to case patients by demographic and clinical attributes. We measured vaccine effectiveness (VE) for 13-valent (PCV13) against virus-associated LRTI by determining the adjusted odds ratio for PCV13 receipt, comparing case patients and controls. Results Primary analyses included 13 856 case patients with virus-associated LRTI and 227 887 matched controls. Receipt of PCV13 was associated with a VE of 24.9% (95% confidence interval, 18.4%–30.9%) against virus-associated pneumonia and 21.5% (10.9%–30.9%) against other (nonpneumonia) virus-associated LRTIs. We estimated VEs of 26.8% (95% confidence interval, 19.9%–33.1%) and 18.6% (9.3%–27.0%) against all virus-associated LRTI episodes diagnosed in inpatient and outpatient settings, respectively. We identified statistically significant protection against LRTI episodes associated with influenza A and B viruses, endemic human coronaviruses, parainfluenza viruses, human metapneumovirus, and enteroviruses but not respiratory syncytial virus or adenoviruses. Conclusions Among adults, PCV13 conferred moderate protection against virus-associated LRTI. The impacts of pneumococcal conjugate vaccines may be mediated, in part, by effects on polymicrobial interactions between pneumococci and respiratory viruses.

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.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).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.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.

The global pandemic caused by SARS-CoV-2 (COVID-19) has led to significant morbidity and mortality, and unprecedented economic and health system disruption. Non-pharmacologic interventions (NPIs) such as masking and physical distancing have formed the underpinnings of COVID-19 infection control strategies. Concomitantly, numerous jurisdictions have seen a decrease in hospitalizations for non-COVID-19 respiratory illnesses (NCRIs) such as asthma, community-acquired pneumonia, influenza, and chronic obstructive pulmonary disease relative to pre-pandemic levels. These associations give rise to a number of testable hypotheses regarding the efficacy of NPIs in reducing the substantial burden of NCRIs. Here, we review emerging perspectives on the role of NPIs in NCRI prevention with the ultimate goal of informing future research and public policy development as we move into what may be the endemic phase of the COVID-19 pandemic.

A recent disease prevalence study of the largest documented Down syndrome (DS) cohort in the United States strongly suggested significant disparity in general infectious disease conditions among individuals with DS versus those without DS. In this follow-up retrospective analysis, we explored these differences in greater detail by calculating prevalence of 52 infectious diseases, across 28 years of data among 6078 individuals with DS and 30,326 age- and sex-matched controls, abstracted from electronic medical records within a large Midwestern health system. We found that the DS cohort had higher prevalence of pneumonias (including aspiration, viral, bacterial, pneumococcal, and unspecified/atypical); otitis externa; and the skin infections impetigo, abscess, and cellulitis. To the contrary, the DS cohort had lower prevalence of many respiratory infections other than pneumonia (including influenza, strep pharyngitis, upper respiratory infection, sinusitis, tonsillitis, laryngitis, bronchitis, scarlet fever, and otitis media); sexually transmitted infections (including bacterial vaginosis, chlamydia, genital herpes, HIV/AIDS, human papillomavirus, pelvic inflammatory disease, and trichomoniasis); mononucleosis; shingles; unspecified hepatitis; intestinal infections; and enteritis. These findings highlight that individuals with DS could be more or less prone to different infectious diseases than their non-DS matched counterparts. Additional research to understand why these differences exist and how they might affect the clinical approach to patients with DS is warranted.

Introduction. In clinical practice, the differential diagnosis of COVID-19 can be challenging during the flu season, entailing serious consequences such as delays in appropriate control measures against the SARS-CoV-2 pandemic. Another problem is posed by co-infection of SARS-CoV-2 and influenza virus (IV), which significantly contributes to the severity of the COVID-19 disease. This study was aimed to explore the cross-impact of co-administration of Russian influenza and COVID-19 vaccines on development of specific immunity in laboratory animals.Materials and methods. The study was conducted on BALB/c mice. The animals were inoculated intramuscularly with the vaccine for COVID-19 prevention (CoviVac) and the vaccine for influenza prevention (Flu-M). The sera from the immunized animals were examined separately. Three IV strains were used in the hemagglutination inhibition assay. Antibodies (Abs) against SARS-CoV-2 were detected by an enzyme-linked immunosorbent assay (ELISA). The neutralization test was performed to detect virus neutralizing antibodies against SARS-CoV-2 and IV.Results. Relatively high titers of specific Abs were found in the groups of animals inoculated with one vaccine and with two vaccines concurrently. In the groups of animals inoculated with CoviVac and with two vaccines concurrently, both in the ELISA test and in the neutralization test, the average titers of specific Abs against SARSCoV- 2 did not demonstrate any statistical difference. The group of animals inoculated concurrently with two vaccines demonstrated statistically higher titers of Abs against IV after the second immunization compared to the group of animals inoculated with Flu-M.Discussion. The study has shown that post-vaccination immunity both to IV and to SARS-CoV-2 develops after co-vaccination with two vaccines. The observed enhanced post-vaccination immune response to IV in the coimmunized laboratory animals needs further research.Conclusion. The performed studies suggest the possibility of co-administration of two vaccines to prevent influenza and COVID-19.

Influenza NS1 is a promising anti-influenza target, considering its conserved and druggable structure, and key function in influenza replication and pathogenesis. Notwithstanding, target identification and validation, strengthened by experimental data, are lacking. Here, we further explored our previously designed structure-based antiviral rationale directed to highly conserved druggable NS1 regions across a broad spectrum of influenza A viruses. We aimed to identify NS1-mutated viruses exhibiting a reduced growth phenotype and/or an altered cell apoptosis profile. We found that NS1 mutations Y171A, K175A (consensus druggable pocket 1), W102A (consensus druggable pocket 3), Q121A and G184P (multiple consensus druggable pockets) - located at hot spots amenable for pharmacological modulation - significantly impaired A(H1N1)pdm09 virus replication, in vitro. This is the first time that NS1-K175A, -W102A, and -Q121A mutations are characterized. Our map-and-mutate strategy provides the basis to establish the NS1 as a promising target using a rationale with a higher resilience to resistance development. Highlights: Structure-based anti-influenza strategies that facilitate the rapid identification and validation of robust targets are lacking; We have previously identified and characterized 3 NS1 conserved druggable pockets - amenable to pharmacological modulation; NS1 mutations Y171A, K175A (CDP1), W102A (CDP3), Q121A and G184P (Multi-CDPs) impaired A(H1N1)pdm09 virus replication, in vitro; The new NS1 hot spots: NS1–K175, -W102, and -Q121 were characterized for the first time, using the A(H1N1)pdm09 virus; This map-and-mutate antiviral rationale can be promptly applied to other proteins of (re)emergent viruses. This work was funded by the FCT – Fundação para a Ciência e a Tecnologia, I.P. (project number POCI-01 0145-FEDER-032572 | PTDC/QUI-OUT/32572/2017 and PTDC/SAU-INF/30729/2017); and sup ported by the PhD grant PD/BD/128402/2017 from FCT PhD Pro gramme in Medicines and Pharmaceutical Innovation (i3DU) to JTL Ph. D. candidate. info:eu-repo/semantics/publishedVersion

H7 avian influenza viruses (AIVs) normally circulated among birds before. From 1996 to 2012, human infections with H7 AIVs (H7N2, H7N3, and H7N7) were reported in Canada, Italy, Mexico, the Netherlands, the United Kingdom and the USA. Until March 2013, human infections with H7N9 AIVs were reported in China. Since then, H7N9 AIVs have continued to circulate in both humans and birds. Therefore, the detection of antibodies against the H7 subtype of AIVs has become an important topic. In this study, a competitive enzyme-linked immunosorbent assay (cELISA) method for the detection of antibody against H7 AIVs was established. The optimal concentration of antigen coating was 5 μg mL−1, serum dilution was 1/10, and enzyme-labeled antibody was 1/3 000. To determine the cut-off value of cELISA, percent inhibition (PI) was determined by using receiver operating characteristic (ROC) curve analysis in 178 AIVs negative samples and 368 AIVs positive serum samples (n=546). When PI was set at 40%, the specificity and sensitivity of cELISA were 99.4 and 98.9%, respectively. This method could detect the antibodies against H7Nx (N1–N4, N7–N9) AIVs, and showed no reaction with AIVs of H1–H6 and H8–H15 subtypes or common avian viruses such as Newcastle disease virus (NDV), Infectious bronchitis virus (IBV) and Infectious bursal disease virus (IBDV), exhibiting good specificity. This method showed a coincidence rate of 98.56% with hemagglutinin inhibition (HI) test. And the repeatability experiment revealed that the coefficients of variation (CV) of intra- and inter-batch repetition were all less than 12%. The data indicated that the cELISA antibody-detection method established in this study provided a simple and accurate technical support for the detection of a large number of antibody samples of H7-AIV.

Aim: Influenza, also known as flu, is a viral disease with high mortality and morbidity. Although every age group is at risk, people aged six months to 18 years are at high risk of developing serious flu-related complications. This descriptive study had two objectives: 1) determining primary school student’s level of knowledge about the flu, and 2) examining the factors affecting their decision to get flu shots.Material and Method: The sample consisted of 670 sixth-, seventh-, and eighth-grade students from three public and three private schools. Data were presented as percentiles, ratios, chisquares, and means (± standard deviation). The data were analyzed at a significance level of 0.05.Results: Less than a quarter of the participants defined the flu as a viral disease (23.7%). More than half the participants stated that the flu was contagious (65.5%). More than a quarter of the participants noted that the flu was transmitted through aerosols containing the virus, direct contact, or contact with contaminated surfaces (35.5%). More than half the participants said it was necessary to get flu shots (71.3%). Eight in ten of those participants had flu shots (82.8%). More than half of mothers with high school or higher degrees had their children vaccinated against the flu (56.7%). Most fathers with high school or higher degrees had their children vaccinated against the flu (78.4%) (p=0.030). Almost all parents with health insurance had their children vaccinated against the flu (p

Purpose Chloroquine and hydroxychloroquine are effective against respiratory viruses in vitro. However, they lack antiviral efficacy upon oral administration. Translation of in vitro to in vivo exposure is necessary for understanding the disconnect between the two to develop effective therapeutic strategies. Methods We employed an in vitro ion-trapping kinetic model to predict the changes in the cytosolic and lysosomal concentrations of chloroquine and hydroxychloroquine in cell lines and primary human airway cultures. A physiologically based pharmacokinetic model with detailed respiratory physiology was used to predict regional airway exposure and optimize dosing regimens. Results At their reported in vitro effective concentrations in cell lines, chloroquine and hydroxychloroquine cause a significant increase in their cytosolic and lysosomal concentrations by altering the lysosomal pH. Higher concentrations of the compounds are required to achieve similar levels of cytosolic and lysosomal changes in primary human airway cells in vitro. The predicted cellular and lysosomal concentrations in the respiratory tract for in vivo oral doses are lower than the in vitro effective levels. Pulmonary administration of aerosolized chloroquine or hydroxychloroquine is predicted to achieve high bound in vitro-effective concentrations in the respiratory tract, with low systemic exposure. Achieving effective cytosolic concentrations for activating immunomodulatory effects and adequate lysosomal levels for inhibiting viral replication could be key drivers for treating viral respiratory infections. Conclusion Our analysis provides a framework for extrapolating in vitro effective concentrations of chloroquine and hydroxychloroquine to in vivo dosing regimens for treating viral respiratory infections. Graphical abstract

Influenza vaccination is recommended for children. In particular, those aged 6 months to 12 years were recommended two vaccinations in Japan, whereas the recommended year range for the twice vaccination is 6 months to 8 years by the World Health Organization (WHO). This study assessed the effectiveness of influenza vaccination and whether the twice vaccinations enhanced preventive effects against influenza infection among children living in two satellite cities of a metropolitan area in Tokyo, Japan. During the influenza season of 2014-2018, parents of all preschool, elementary school, and junior high school children participated in an annual survey. Adjusted odds ratios (AOR) with 95% confidence intervals (CIs) were calculated via multivariate logistic regression analysis to evaluate influenza vaccination effectiveness and trends in the number of vaccinations. Among the 108,362 children who received the research questionnaire, 76,753 (70.8%) responded. After excluding responses without basic information, 64,586 children were included in the analysis. Vaccination was more effective in preschool and lower grade elementary school children given the increase in the number of vaccinations (test for trend: P < 0.001). The AOR of influenza for pre, grade 1 elementary, and grade 2 schoolchildren who received two vaccinations was 0.63 (95% CI, 0.59-0.69), 0.75 (0.67-0.83), and 0.81 (0.71-0.92), respectively, when compared to those without vaccination. However, no trend in vaccinations and their effectiveness was observed in the third and higher-grade school children. Our findings support the recommendation by the WHO, and could help guide influenza vaccination policies for children in Japan. ispartof: Tohoku J Exp Med vol:258 issue:1 pages:69-78 ispartof: location:Japan status: published

In the midst of the global COVID-19 pandemic and accompanying outbreaks, the controversy of mandatory vaccination is again brought under scrutiny. Although it has been well researched within the scientific community that vaccination is a simple and safe procedure, it continues to face outlash and distrust within societal communities. This literature review is a study of the current perspectives within pro and anti vaccination groups. From childhood illnesses to vaccine production, school mandates to minor consent, these and many more factors influence the current outlook and attitudes of the American general public towards vaccines. From this examination, we propose an actionable solution for the government, public health officials, and individual people. By fact checking widely held myths about vaccination and enforcing stricter standards in academic spheres for life threatening illnesses, we can improve the overall health and livelihood of our communities. In today’s public health crisis, it is paramount for people to understand the methodology behind mass immunity and also provide alternatives to those who may have valid reasons against vaccination.

Background Between October 2022 and January 2023, influenza A(H1N1)pdm09, A(H3N2) and B/Victoria viruses circulated in Europe with different influenza (sub)types dominating in different areas. Aim To provide interim 2022/23 influenza vaccine effectiveness (VE) estimates from six European studies, covering 16 countries in primary care, emergency care and hospital inpatient settings. Methods All studies used the test- negative design, but with differences in other study characteristics, such as data sources, patient selection, case definitions and included age groups. Overall and influenza (sub)type- specific VE was estimated for each study using logistic regression adjusted for potential confounders. Results There were 20, 477 influenza cases recruited across the six studies, of which 16, 589 (81%) were influenza A. Among all ages and settings, VE against influenza A ranged from 27 to 44%. Against A(H1N1)pdm09 (all ages and settings), VE point estimates ranged from 28% to 46%, higher among children (< 18 years) at 49–77%. Against A(H3N2), overall VE ranged from 2% to 44%, also higher among children (62–70%). Against influenza B/Victoria, overall and age-specific VE were ≥ 50% (87–95% among children < 18 years). Conclusions Interim results from six European studies during the 2022/23 influenza season indicate a ≥ 27% and ≥ 50% reduction in disease occurrence among all- age influenza vaccine recipients for influenza A and B, respectively, with higher reductions among children. Genetic virus characterisation results and end-of-season VE estimates will contribute to greater understanding of differences in influenza (sub)type-specific results across studies.

The single-stranded RNA genome of influenza A virus is divided into 8 segments, each of which encodes at least one polypeptide product. This work presents investigations into two aspects of the biology of the smallest (8th) segment: 1) a possible new gene product and 2) interactions of the viral non-structural protein translated from this segment – NS1 – with a host cell protein during infection. 1) The genome of influenza A virus is packaged into virions as negative sense viral RNA. To date, all known viral proteins are encoded in the positive sense. A large open reading frame exists on segment 8 of the influenza A genome in the opposite sense to, yet overlapping with, the established proteins expressed from that segment; this hypothetically encodes a protein named Negative Strand Protein or NSP. This thesis presents work that characterised the NSP polypeptide that would be translated from this open reading frame and the effect it may exert on viral replication. Using a reverse genetics system for the A/Puerto Rico/8/34 influenza A strain, mutant viruses were generated containing negative strand open reading frames of different lengths, as well as one with early stop codons that result in a severe truncation. All viruses replicated to similar titres in cell culture and produced similarly-sized plaques as the wild-type. The synthesis and distribution of the major viral structural proteins as well as the positive-strand segment 8 polypeptides were also not affected by alterations to the open reading frame. Negative strand polypeptide produced by in vitro translation was successfully immunoprecipitated by a specific antibody. However, no specific product could be detected from virus-infected cells. In conclusion, if this negative strand protein is indeed expressed by influenza A virus, it is not significant for virus replication in vitro, nor is it expressed to high levels. 2) The nucleolus is a dynamic hub of post-transcriptional RNA processing in eukaryotic cells. The influenza NS1 protein is a multi-functional inhibitor of many cellular anti-viral pathways, such as the interferon response. Prior to this work, a proteomics study found that influenza A virus infection induces the re-localisation of cellular protein ADAR1 to the nucleolus. ADAR1 is an RNA-editing enzyme that converts adenosine residues to inosines, which are then interpreted by cellular machinery as guanosine. There is a potential that ADAR1 activity may affect the influenza virus genome; either negatively through hypermutation, or positively via a specific coding sequence alterations. Evidence for non-specific editing of influenza RNA species has been reported, but the significance of this has not been demonstrated. For other virus families such as vesicular stomatitis, measles, human immunodeficiency and hepatitis delta viruses, ADAR1 has an apparently pro-viral role. The influenza A NS1 protein was determined to be both necessary and sufficient to induce the re-localisation of ADAR1 to cell nucleoli in several common cell lines. Analysis of viruses expressing mutant forms of the NS1 protein showed that lesions in interaction sites for binding to RNA or a cellular ubiquitin ligase – TRIM25 – prevented induction of this re-localisation. This correlated with the inability of these NS1 mutant proteins to suppress phosphorylation of cellular interferon response factor 3. It was also found, using pull-down assays, that ADAR1 interacted with influenza NS1 in an RNA-independent manner, but not with the NS1 mutant deficient in RNA binding. Additionally, a separate interaction was demonstrated between ADAR1 and components of the viral polymerase complex. In cells that had ADAR1 depleted by RNA interference, viral replication was reduced by 3-fold, thus not supporting the hypothesis that ADAR1 is a restriction factor for influenza A virus and instead suggesting a modest pro-viral function. In conclusion, the influenza A virus NS1 protein induces the nucleolar re-localisation of ADAR1, which does not act as an anti-viral factor for the virus., Wellcome Trust

International audience; The segmented RNA genome of influenza A viruses (IAVs) enables viral evolution through genetic reassortment after multiple IAVs coinfect the same cell, leading to viruses harboring combinations of eight genomic segments from distinct parental viruses. Existing data indicate that reassortant genotypes are not equiprobable; however, the low throughput of available virology techniques does not allow quantitative analysis. Here, we have developed a high-throughput single-cell droplet microfluidic system allowing encapsulation of IAV-infected cells, each cell being infected by a single progeny virion resulting from a coinfection process. Customized barcoded primers for targeted viral RNA sequencing enabled the analysis of 18,422 viral genotypes resulting from coinfection with two circulating human H1N1pdm09 and H3N2 IAVs. Results were highly reproducible, confirmed that genetic reassortment is far from random, and allowed accurate quantification of reassortants including rare events. In total, 159 out of the 254 possible reassortant genotypes were observed but with widely varied prevalence (from 0.038 to 8.45%). In cells where eight segments were detected, all 112 possible pairwise combinations of segments were observed. The inclusion of data from single cells where less than eight segments were detected allowed analysis of pairwise cosegregation between segments with very high confidence. Direct coupling analysis accurately predicted the fraction of pairwise segments and full genotypes. Overall, our results indicate that a large proportion of reassortant genotypes can emerge upon coinfection and be detected over a wide range of frequencies, highlighting the power of our tool for systematic and exhaustive monitoring of the reassortment potential of IAVs.

Viruses have brought humanity many challenges: respiratory infection, cancer, neurological impairment and immunosuppression to name a few. Virology research over the last 60+ years has responded to reduce this disease burden with vaccines and antivirals. Despite this long history, the COVID-19 pandemic has brought unprecedented attention to the field of virology. Some of this attention is focused on concern about the safe conduct of research with human pathogens. A small but vocal group of individuals has seized upon these concerns - conflating legitimate questions about safely conducting virus-related research with uncertainties over the origins of SARS-CoV-2. The result has fueled public confusion and, in many instances, ill-informed condemnation of virology. With this article, we seek to promote a return to rational discourse. We explain the use of gain-of-function approaches in science, discuss the possible origins of SARS-CoV-2 and outline current regulatory structures that provide oversight for virological research in the United States. By offering our expertise, we - a broad group of working virologists - seek to aid policy makers in navigating these controversial issues. Balanced, evidence-based discourse is essential to addressing public concern while maintaining and expanding much-needed research in virology.

BackgroundDespite lower circulation of influenza virus throughout 2020-2022 during the COVID-19 pandemic, seasonal influenza vaccination has remained a primary tool to reduce influenza-associated illness and death. The relationship between the decision to receive a COVID-19 vaccine and/or an influenza vaccine is not well understood.MethodsWe assessed predictors of receipt of 2021-2022 influenza vaccine in a secondary analysis of data from a case-control study enrolling individuals who received SARS-CoV-2 testing. We used mixed effects logistic regression to estimate factors associated with receipt of seasonal influenza vaccine. We also constructed multinomial adjusted marginal probability models of being vaccinated for COVID-19 only, seasonal influenza only, or both as compared with receipt of neither vaccination.ResultsAmong 1261 eligible participants recruited between 22 October 2021-22 June 2022, 43% (545) were vaccinated with both seasonal influenza vaccine and >1 dose of a COVID-19 vaccine, 34% (426) received >1 dose of a COVID-19 vaccine only, 4% (49) received seasonal influenza vaccine only, and 19% (241) received neither vaccine. Receipt of >1 COVID-19 vaccine dose was associated with seasonal influenza vaccination (adjusted odds ratio [aOR]: 3.72; 95% confidence interval [CI]: 2.15-6.43); this association was stronger among participants receiving >1 COVID-19 booster dose (aOR = 16.50 [10.10-26.97]). Compared with participants testing negative for SARS- CoV-2 infection, participants testing positive had lower odds of receipt of 2021-2022 seasonal influenza vaccine (aOR = 0.64 [0.50-0.82]).ConclusionsRecipients of a COVID-19 vaccine were more likely to receive seasonal influenza vaccine during the 2021-2022 season. Factors associated with individuals' likelihood of receiving COVID-19 and seasonal influenza vaccines will be important to account for in future studies of vaccine effectiveness against both conditions. Participants who tested positive for SARS-CoV-2 in our sample were less likely to have received seasonal influenza vaccine, suggesting an opportunity to offer influenza vaccination before or after a COVID-19 diagnosis.

Influenza viruses are one of the main agents causing acute respiratory infections (ARI) in humans resulting in a large amount of illness and death globally.1,2 The influenza viruses classification is based on the nomenclature proposed by the World Health Organization (WHO)3 that is widely accepted and used by the medical and scientific communities throughout the world. Since the pandemic in 2009, two subtypes of human influenza A viruses, A(H1N1)pdm09 and A(H3N2), and two lineages of influenza B, B/Victoria and B/Yamagata, have been responsible for the vast majority of cases each year. Within each subtype and lineage, different clades and genetic groups were described to reflect the continuous viral evolution, driven by antigenic drift. The WHO Global Influenza Surveillance and Response System (GISRS) studies human influenza viruses from >110 countries, to monitor circulating strains, understand epidemiology and evolution, and contribute to verify the vaccine effectiveness and update its formulation each year.4,5 A growing number of laboratories and research centers is contributing to this initiative by sequencing the whole viral genome or the hemagglutinin (HA) gene from local strains...

Uncertainties about the efficacy of influenza vaccination for populations with heart failure (HF) in preventing cardiovascular outcomes, as well as lack of effective vaccination strategies, may contribute to low vaccine coverage rate (VCR) in China and globally. We assessed the feasibility of a strategy to promote influenza vaccines in patients hospitalized with acute HF in China and to inform the design of a hybrid effectiveness-implementation cluster randomized trial to evaluate this strategy on mortality and hospital re-admission. We conducted a cluster randomized pilot trial involving 11 hospitals in Henan Province in China, with mixed-methods evaluation between December 2020 and April 2021. A process evaluation involved interviews with 51 key informants (patients, health professionals, policy makers). The intervention included education about influenza vaccination and availability of free vaccines administered prior to hospital discharge for HF patients, while usual care included attending community-based points of vaccination (PoV) for screening and vaccination. Implementation outcomes focused on reach, fidelity, adoption, and acceptability. Recruitment rates were assessed for trial feasibility. Effectiveness outcomes were influenza VCR, HF-specific rehospitalizations and mortality at 90 days. A total of 518 HF patients were recruited from 7 intervention and 4 usual care hospitals (mean of 45 participants per hospital per month). VCR was 89.9% (311/346, 86.1-92.8%) in the intervention group and 0.6% (1/172, 0.0-3.7%) in the control group. The process evaluation demonstrated reach to patients with lower socioeconomic and education status. There was good fidelity of the intervention components, with education and PoV set up processes being adapted to local hospital workflow and workforce capacity. Intervention was acceptable and adopted by patients and health professionals. However, outside of a trial setting, concerns were raised around vaccination reimbursement costs, workforce accountability and capacity. The intervention strategy appears feasible and acceptable for improving VCR in HF patients at county-level hospitals in China. Trial registration: This pilot trial is registered with the acronym PANDA II Pilot (Population Assessment of Influenza and Disease Activity) at ChiCTR.org.cn (ChiCTR2000039081).

Funder: Horserace Betting Levy Board; Id: http://dx.doi.org/10.13039/501100001280, Funder: Animal Health Trust; Id: http://dx.doi.org/10.13039/100007612, BACKGROUND: During 2019, an epidemic of equine influenza (EI) occurred in Europe. OBJECTIVES: To describe the epidemiology of the 2019 EI epidemic within Great Britain (GB). STUDY DESIGN: Retrospective descriptive study of laboratory confirmed EI cases. METHODS: Epidemiological data were obtained from veterinary surgeons referring samples for EI virus testing. Where available, data on confirmed cases and their wider resident population on EI-infected premises were collated and described. On a national level, spatial and temporal representations, consisting of choropleth maps and epidemic curves, described the spread of EI. EI-infected premises-level factors associated with the first of two epidemic phases were investigated using ordinary logistic regression analysis. RESULTS: There were 412 confirmed cases and 234 EI-infected premises, with the first of two epidemic phases occurring between January and April, followed by a second phase through to August. The median age of confirmed cases was 5 years and Sports horses (24%) and Cobs (16%) made up the highest proportions by general horse type and breed. Among confirmed cases 72% were unvaccinated and 18% were vaccinated against EI. New horses arriving within 2 weeks of a confirmed case were reported by 42% of EI-infected premises. Investigation of EI-infected premises biosecurity measures indicated that 23% quarantined new arrivals, 37% had isolation facilities and 57% of resident horses were vaccinated. EI-infected premises were more likely in the first than second epidemic phase to be classified as professional, have a vaccinated confirmed case and EI confirmed in a newly arrived animal. MAIN LIMITATIONS: Data were collected at a single time point for each EI-infected premises with no follow ups performed. CONCLUSIONS: During 2019, EI-infected premises generally had low levels of population vaccine coverage and implemented limited preventive biosecurity measures, particularly linked to horse movements. Without substantial improvements in infectious disease prevention and control, the GB equine population remains at risk of future EI epidemics.

Filamentous influenza A (IAV) virions can resist inactivation at the level of cell entry. Filaments therefore predominate over spherical particles in clinical infections and may enable viruses to persist and evolve in the face of immune pressure. Despite this, the mechanism of virion shape regulation is not well understood. Shape distribution is currently viewed as a defined feature of a viral genome. However, unpublished data in our lab show that shape can be tuned phenotypically in response to external pressures, without a genetic change. Our goal is to investigate non-genetic determinants of shape in order to begin piecing together the overall mechanism of shape regulation. I performed single-cycle infections with influenza A virus in the presence of inhibitors targeting defined steps in the virus life cycle. I measured the resulting dynamic shape effects using our novel flow virometry approach. Unlike traditional electron microscopy, this technique enables us to measure the shape of many individual fluorescently-labeled virus particles in a high-throughput manner. My results reveal that shape changes actively in response to treatment within a single cycle of infection, in which genetic change is unlikely. Overall, reduced viral yields correlate with increased amounts of filaments. Additionally, I show that inhibiting viral production after endocytosis leads to greater amounts of filaments for greater input particles. This is consistent with host cell membrane surface tension playing a role in phenotypic tuning of shape. I further demonstrate that membrane surface tension can also explain how certain published genetic changes affect shape. Based on our results, we propose shifting the field’s current perspective on virion shape regulation to include both genetics and external environment. Our insight can also be used to inform antiviral strategies, in order to avoid inhibitors which drive formation of filamentous particles.

The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.