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Background: The 2022–23 US influenza season peaked early in fall 2022. Methods: Late‐season influenza vaccine effectiveness (VE) against outpatient, laboratory‐confirmed influenza was calculated among participants of the US Influenza VE Network using a test‐negative design. Results: Of 2561 participants enrolled from December 12, 2022 to April 30, 2023, 91 laboratory‐confirmed influenza cases primarily had A(H1N1)pdm09 (6B.1A.5a.2a.1) or A(H3N2) (3C.2a1b.2a.2b). Overall, VE was 30% (95% confidence interval −9%, 54%); low late‐season activity precluded estimation for most subgroups. Conclusions: 2022–23 late‐season outpatient influenza VE was not statistically significant. Genomic characterization may improve the identification of influenza viruses that circulate postinfluenza peak. [ABSTRACT FROM AUTHOR]

Patterns of within-host influenza A virus (IAV) diversity and evolution have been described in natural human infections, but these patterns remain poorly characterized in non-human hosts. Elucidating these dynamics is important to better understand IAV biology and the evolutionary processes that govern spillover into humans. Here, we sampled an IAV outbreak in pigs during a week-long county fair to characterize viral diversity and evolution in this important reservoir host. Nasal wipes were collected on a daily basis from all pigs present at the fair, yielding up to 421 samples per day. Subtyping of PCR-positive samples revealed the co-circulation of H1N1 and H3N2 subtype swine IAVs. PCR-positive samples with robust Ct values were deep-sequenced, yielding 506 sequenced samples from a total of 253 pigs. Based on higher-depth re-sequenced data from a subset of these initially sequenced samples (260 samples from 168 pigs), we characterized patterns of within-host IAV genetic diversity and evolution. We find that IAV genetic diversity in single-subtype infected pigs is low, with the majority of intrahost Single Nucleotide Variants (iSNVs) present at frequencies of <10%. The ratio of the number of nonsynonymous to the number of synonymous iSNVs is significantly lower than under the neutral expectation, indicating that purifying selection shapes patterns of within-host viral diversity in swine. The dynamic turnover of iSNVs and their pronounced frequency changes further indicate that genetic drift also plays an important role in shaping IAV populations within pigs. Taken together, our results highlight similarities in patterns of IAV genetic diversity and evolution between humans and swine, including the role of stochastic processes in shaping within-host IAV dynamics. Author summary: Transmission of influenza A viruses among swine occurs commonly at agricultural fairs, where animals from geographically disparate locations come together for a week-long public event. Through dense sampling of one such outbreak, following by viral genome sequencing within positive samples, we evaluated viral evolution within infected pigs. We characterized patterns of viral genetic diversity and investigated the dynamics of variants to understand the forces driving evolutionary change. Our data indicate that influenza virus populations infecting farmed swine have limited genetic diversity and are largely shaped by purifying selection and genetic drift. These observations are similar to those described previously for influenza virus populations within human hosts. [ABSTRACT FROM AUTHOR]

Co-infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and other viruses has been reported. We evaluated cell lines commonly used to isolate viruses and diagnose related diseases for their susceptibility to SARS-CoV-2. Although multiple kidney cell lines from monkeys were susceptible to SARS-CoV-2, we found many cell types derived from humans, dogs, minks, cats, mice, and chicken were not. We analyzed MDCK cells, which are most commonly used for surveillance and study of influenza viruses, and found that they were not susceptible to SARS-CoV-2. The low expression level of the angiotensin converting enzyme 2 receptor and lower receptor affinity to SARS-CoV-2 spike, which could be overcome by overexpression of canine angiotensin converting enzyme 2 in trans, strengthened the cellular barrier to productive infection. Moreover, a D614G mutation in the spike protein did not appear to affect SARS-CoV-2 cell tropism. Our findings should help avert inadvertent propagation of SARS-CoV-2 from diagnostic cell lines. [ABSTRACT FROM AUTHOR]

Background: Increased illness due to antigenically drifted A(H3N2) clade 3C.3a influenza viruses prompted concerns about vaccine effectiveness (VE) and vaccine strain selection. We used US virologic surveillance and US Influenza Vaccine Effectiveness (Flu VE) Network data to evaluate consequences of this clade.Methods: Distribution of influenza viruses was described using virologic surveillance data. The Flu VE Network enrolled ambulatory care patients aged ≥6 months with acute respiratory illness at 5 sites. Respiratory specimens were tested for influenza by means of reverse-transcriptase polymerase chain reaction and were sequenced. Using a test-negative design, we estimated VE, comparing the odds of influenza among vaccinated versus unvaccinated participants.Results: During the 2018-2019 influenza season, A(H3N2) clade 3C.3a viruses caused an increasing proportion of influenza cases. Among 2763 Flu VE Network case patients, 1325 (48%) were infected with A(H1N1)pdm09 and 1350 (49%) with A(H3N2); clade 3C.3a accounted for 977 (93%) of 1054 sequenced A(H3N2) viruses. VE was 44% (95% confidence interval, 37%-51%) against A(H1N1)pdm09 and 9% (-4% to 20%) against A(H3N2); VE was 5% (-10% to 19%) against A(H3N2) clade 3C.3a viruses.Conclusions: The predominance of A(H3N2) clade 3C.3a viruses during the latter part of the 2018-2019 season was associated with decreased VE, supporting the A(H3N2) vaccine component update for 2019-2020 northern hemisphere influenza vaccines. [ABSTRACT FROM AUTHOR]

Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2-98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors. [ABSTRACT FROM AUTHOR]

The United States 2017-18 influenza season (October 1, 2017-May 19, 2018) was a high severity season with high levels of outpatient clinic and emergency department visits for influenza-like illness (ILI), high influenza-related hospitalization rates, and elevated and geographically widespread influenza activity across the country for an extended period. Nationally, ILI activity began increasing in November, reaching an extended period of high activity during January-February, and remaining elevated through March. Influenza A(H3N2) viruses predominated through February and were predominant overall for the season; influenza B viruses predominated from March onward. This report summarizes U.S. influenza activity* during October 1, 2017-May 19, 2018.†. [ABSTRACT FROM AUTHOR]

Influenza activity in the United States was low during October 2017, but has been increasing since the beginning of November. Influenza A viruses have been most commonly identified, with influenza A(H3N2) viruses predominating. Several influenza activity indicators were higher than is typically seen for this time of year. The majority of influenza viruses characterized during this period were genetically or antigenically similar to the 2017-18 Northern Hemisphere cell-grown vaccine reference viruses. These data indicate that currently circulating viruses have not undergone significant antigenic drift; however, circulating A(H3N2) viruses are antigenically less similar to egg-grown A(H3N2) viruses used for producing the majority of influenza vaccines in the United States. It is difficult to predict which influenza viruses will predominate in the 2017-18 influenza season; however, in recent past seasons in which A(H3N2) viruses predominated, hospitalizations and deaths were more common, and the effectiveness of the vaccine was lower. Annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. Multiple influenza vaccines are approved and recommended for use during the 2017-18 season, and vaccination should continue to be offered as long as influenza viruses are circulating and unexpired vaccine is available. This report summarizes U.S. influenza activity* during October 1-November 25, 2017 (surveillance weeks 40-47).†. [ABSTRACT FROM AUTHOR]

This report summarizes U.S. influenza activity* during October 2, 2016-February 4, 2017,† and updates the previous summary (1). Influenza activity in the United States began to increase in mid-December, remained elevated through February 4, 2017, and is expected to continue for several more weeks. To date, influenza A (H3N2) viruses have predominated overall, but influenza A (H1N1)pdm09 and influenza B viruses have also been identified. [ABSTRACT FROM AUTHOR]

During the 2015-16 influenza season (October 4, 2015-May 21, 2016) in the United States, influenza activity* was lower and peaked later compared with the previous three seasons (2012-13, 2013-14, and 2014-15). Activity remained low from October 2015 until late December 2015 and peaked in mid-March 2016. During the most recent 18 influenza seasons (including this season), only two other seasons have peaked in March (2011-12 and 2005-06). Overall influenza activity was moderate this season, with a lower percentage of outpatient visits for influenza-like illness (ILI),(†) lower hospitalization rates, and a lower percentage of deaths attributed to pneumonia and influenza (P&I) compared with the preceding three seasons. Influenza A(H1N1)pdm09 viruses predominated overall, but influenza A(H3N2) viruses were more commonly identified from October to early December, and influenza B viruses were more commonly identified from mid-April through mid-May. The majority of viruses characterized this season were antigenically similar to the reference viruses representing the recommended components of the 2015-16 Northern Hemisphere influenza vaccine (1). This report summarizes influenza activity in the United States during the 2015-16 influenza season (October 4, 2015-May 21, 2016)(§) and reports the vaccine virus components recommended for the 2016-17 Northern Hemisphere influenza vaccines. [ABSTRACT FROM AUTHOR]

Human-to-swine transmission of seasonal influenza viruses has led to sustained human-like influenza viruses circulating in the U.S. swine population. While some reverse zoonotic-origin viruses adapt and become enzootic in swine, nascent reverse zoonoses may result in virus detections that are difficult to classify as "swine-origin" or "human-origin" due to the genetic similarity of circulating viruses. This is the case for human-origin influenza A(H1N1) pandemic 2009 (pdm09) viruses detected in pigs following numerous reverse zoonosis events since the 2009 pandemic. We report the identification of two human infections with A(H1N1)pdm09 viruses originating from swine hosts and classify them as "swine-origin" variant influenza viruses based on phylogenetic analysis and sequence comparison methods. Phylogenetic analyses of viral genomes from two cases revealed these viruses were reassortants containing A(H1N1)pdm09 hemagglutinin (HA) and neuraminidase (NA) genes with genetic combinations derived from the triple reassortant internal gene cassette. Follow-up investigations determined that one individual had direct exposure to swine in the week preceding illness onset, while another did not report swine exposure. The swine-origin A(H1N1) variant cases were resolved by full genome sequence comparison of the variant viruses to swine influenza genomes. However, if reassortment does not result in the acquisition of swine-associated genes and swine virus genomic sequences are not available from the exposure source, future cases may not be discernible. We have developed a pipeline that performs maximum likelihood analyses, a k-mer-based set difference algorithm, and random forest algorithms to identify swine-associated sequences in the hemagglutinin gene to differentiate between human-origin and swine-origin A(H1N1)pdm09 viruses. [ABSTRACT FROM AUTHOR]

Influenza pandemics are associated with severe morbidity, mortality, and social and economic disruption. Every summer in the United States, youths attending agricultural fairs are exposed to genetically diverse influenza A viruses (IAVs) circulating in exhibition swine, resulting in over 450 lab-confirmed zoonotic infections since 2010. Exhibition swine represent a small, defined population (-1.5% of the U.S. herd), presenting a realistic opportunity to mitigate a pandemic threat by reducing IAV transmission in the animals themselves. Through intensive surveillance and genetic sequencing of IAVs in exhibition swine in six U.S. states in 2018 (n-212), we characterized how a heterogeneous circuit of swine shows, comprising fairs with different sizes and geographic coverage, facilitates IAV transmission among exhibition swine and into humans. Specifically, we identified the role of an earlyseason national show in the propagation and spatial dissemination of a specific virus (H1-2) that becomes dominant among exhibition swine and is associated with the majority of zoonotic infections in 2018. These findings suggest that a highly targeted mitigation strategy, such as postponing swine shows for 1 to 2 weeks following the early-season national show, could potentially reduce IAV transmission in exhibition swine and spillover into humans, and this merits further study. [ABSTRACT FROM AUTHOR]

Baloxavir showed broad-spectrum in vitro replication inhibition of 4 types of influenza viruses (90% effective concentration range 1.2-98.3 nmol/L); susceptibility pattern was influenza A ˃ B ˃ C ˃ D. This drug also inhibited influenza A viruses of avian and swine origin, including viruses that have pandemic potential and those resistant to neuraminidase inhibitors. [ABSTRACT FROM AUTHOR]

Bangladesh has reported repeated outbreaks of highly pathogenic avian influenza (HPAI) A(H5) viruses in poultry since 2007. Because of the large number of live poultry markets (LPM) relative to the population density of poultry throughout the country, these markets can serve as sentinel sites for HPAI A(H5) detection. Through active LPM surveillance during June 2016–June 2017, HPAI A(H5N6) viruses along with 14 other subtypes of influenza A viruses were detected. The HPAI A(H5N6) viruses belonged to clade 2.3.4.4 and were likely introduced into Bangladesh around March 2016. Human infections with influenza clade 2.3.4.4 viruses in Bangladesh have not been identified, but the viruses had several molecular markers associated with potential human infection. Vigilant surveillance at the animal-human interface is essential to identify emerging avian influenza viruses with the potential to threaten public and animal health. • HPAI A(H5) viruses have been circulating in Bangladesh since 2007, resulting in hundreds of poultry outbreaks and sporadic human infections. • Market based surveillance was established in Bangladesh in 2007 to identify HPAI viruses that pose a potential threat to human and animal health. • This study describes the influenza A subtypes identified from June 2016 to June 2017 and reports detection of clade 2.3.4.4 H5N6 viruses in Bangladesh. • We also assessed the evolution and antigenic properties of these viruses and potential modes and timing of emergence. [ABSTRACT FROM AUTHOR]

Highlights: [•] Sensitive and strain-specific rRT-PCR assays were developed for each gene segment of influenza viruses used to prepare live attenuated influenza vaccine (LAIV) reassortant viruses. [•] rRT-PCR assays proved to be adequate and sufficient to provide the evidence for the homogeneity of the LAIV reassortant viruses. [•] Complete genome sequencing of all viruses confirmed the stability of the LAIV reassortant genome. [ABSTRACT FROM AUTHOR]

Since its identification in April 2009, an A(H1N1) virus containing a unique combination of gene segments from both North American and Eurasian swine lineages has continued to circulate in humans. The Jack of similarity between the 2009 A(H1N1) virus and its nearest relatives indicates that its gene segments have been circulating undetected for an extended period. Its low genetic diversity suggests that the introduction into humans was a single event or multiple events of similar viruses. Molecular markers predictive of adaptation to humans are not currently present in 2009 A(H1N1) viruses, suggesting that previously unrecognized molecular determinants could be responsible for the transmission among humans. Antigenically the viruses are homogeneous and similar to North American swine A(H1N1) viruses but distinct from seasonal human A(H1N1). [ABSTRACT FROM AUTHOR]

Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required. • Pyrosequencing assay was optimized to improve detection of baloxavir resistant influenza A viruses in mixtures. • Detection of PA-38 variants in virus mixtures of both subtypes was improved by using customized nucleotide dispensation. • Pyrosequencing and NGS data were comparable, except for lysine at PA-38 that was detected by NGS but not by pyrosequencing. • Attempts to recover virus carrying lysine at PA-38 were unsuccessful, raising the rare possibility of an NGS artifact. • Pyrosequencing provides an important addition to genotypic methods that can be used for baloxavir susceptibility testing. [ABSTRACT FROM AUTHOR]