Lineages Of Influenza Research Articles

COVID-19 pandemic interventions reshaped the global dispersal of seasonal influenza viruses.

The global dynamics of seasonal influenza viruses inform the design of surveillance, intervention, and vaccination strategies. The COVID-19 pandemic provided a singular opportunity to evaluate how influenza circulation worldwide was perturbed by human behavioral changes. We combine molecular, epidemiological, and international travel data and find that the pandemic's onset led to a shift in the intensity and structure of international influenza lineage movement. During the pandemic, South Asia played an important role as a phylogenetic trunk location of influenza A viruses, whereas West Asia maintained the circulation of influenza B/Victoria. We explore drivers of influenza lineage dynamics across the pandemic period and reasons for the possible extinction of the B/Yamagata lineage. After a period of 3 years, the intensity of among-region influenza lineage movements returned to pre-pandemic levels, with the exception of B/Yamagata, after the recovery of global air traffic, highlighting the robustness of global lineage dispersal patterns to substantial perturbation.

Post-disappearance scenarios: policy implications following the potential disappearance of B/Yamagata lineage influenza viruses.

The COVID-19 pandemic and related preventive measures reduced influenza virus circulation, notably causing the disappearance of the B/Yamagata lineage of influenza viruses. In this Perspective, we discuss the implications that this development may have for global influenza epidemiology, and the adjustments that may need to be implemented concerning surveillance strategies and practices, laboratory safety protocols, and influenza vaccine formulations. The disappearance of the B/Yamagata lineage might indeed alter the dynamics of the influenza disease burden (although in a way that is difficult to predict at the moment), and associated diagnostic practices, and may also necessitate updated biosafety levels and revised influenza surveillance strategies. Furthermore, the World Health Organization (WHO) recommended in September 2023 the exclusion of B/Yamagata antigens from future vaccines, with a shift towards trivalent vaccines or modified quadrivalent vaccines; this new scenario underscores the importance of robust global respiratory virus surveillance, effective communication with healthcare professionals and the population to maintain trust in vaccines, and a collaborative approach among health policymakers and vaccine manufacturers to navigate this epidemiological change.

Contrasting dynamics of two incursions of low-pathogenicity avian influenza virus into Australia.

The current panzootic of high pathogenicity avian influenza virus H5N1 demonstrates how viral incursions can have major ramifications for wildlife and domestic animals. Herein, we describe the recent incursion into Australia of two low pathogenicity avian influenza virus subtypes, H4 and H10, that exhibited contrasting evolutionary dynamics. Viruses detected from national surveillance and disease investigations between 2020 and 2022 revealed 27 genomes, 24 of which have at least one segment more closely related to Eurasian or North American avian influenza lineages than those already circulating in Australia. Phylogenetic analysis revealed that H4 viruses circulating in shorebirds represent a recent incursion from Asia that is distinct from those circulating concurrently in Australian waterfowl. Analysis of the internal segments further demonstrates exclusive, persistent circulation in shorebirds. This contrasts with H10, where a novel lineage has emerged in wild waterfowl, poultry, and captive birds across Australia and has likely replaced previously circulating H10 lineages through competitive exclusion. Elucidating different dynamics for avian influenza incursions supports effective disease risk identification and communication that better informs disease preparedness and response.

INFLUENZA B VIRUS EVOLUTION: DIVERSITY OF BIOLOGICAL PROPERTIES THROUGH THE PRISM OF GENETIC VARIABILITY

Although the history of the influenza virus existence goes back thousands of years, the first human influenza A virus was discovered only in 1933, when proper models and substrates for virus isolation became available; then the influenza B virus was isolated and, some later, the influenza C virus. Influenza A viruses evolve most rapidly. Influenza B viruses mutate 2–3 times slower, with influenza C viruses being most conservative. From the moment of isolation until the end of the 1970s, the antigenic evolution of influenza B viruses proceeded smoothly; the isolates were genetically quite homogeneous. In the 1970s–1980s, influenza B viruses diverged into two genetic lineages, “B/Victoria/2/87-like virus lineage” and the “B/Yamagata/16/88-like virus lineage.” For some time, B/Yamagata lineage viruses were widespread throughout the world, while the circulation area of B/Victoria viruses was limited to East Asia. Then the Victorian lineage began its triumphal march across the globe. From this moment on, both lineages of influenza B virus circulated together, with dominance of one or the other lineage in different geographic regions and different epidemiological seasons. Later, the B/Yamagata lineage dominated in many countries, but by the onset of the COVID–19 pandemic, Victorian viruses were already dominant. At the same time, the last representatives of the B/Yamagata lineage were identified. Today, the B/Yamagata lineage has disappeared from circulation and the WHO has concluded that its inclusion in influenza vaccine strains is no longer necessary. Antigenic variability undoubtedly plays a decisive role in the virus evolution. It is accompanied by changes in biological characteristics that, to one degree or another, determine the virus’s ability to self-preserve. No matter how antigenically new a next influenza virus variant is, it will bear a certain set of biological properties, the combination of which will allow the pathogen to best survive in sensitive host. In this review, we have summarized information on the most striking biological properties of influenza B viruses, such as sensitivity to nonspecific blood serum inhibitors, hemagglutinin receptor specificity, its thermostability, sensitivity to low pH values, and temperature sensitivity of reproduction.

Comparing Phylogeographies to Reveal Incompatible Geographical Histories within Genomes.

Modern phylogeography aims at reconstructing the geographic movement of organisms based on their genomic sequences and spatial information. Phylogeographic approaches are often applied to pathogen sequences and therefore tend to neglect the possibility of recombination, which decouples the evolutionary and geographic histories of different parts of the genome. Genomic regions of recombining or reassorting pathogens often originate and evolve at different times and locations, which characterize their unique spatial histories. Measuring the extent of these differences requires new methods to compare geographic information on phylogenetic trees reconstructed from different parts of the genome. Here we develop for the first time a set of measures of phylogeographic incompatibility, aimed at detecting differences between geographical histories in terms of distances between phylogeographies. We study the effect of varying demography and recombination on phylogeographic incompatibilities using coalescent simulations. We further apply these measures to the evolutionary history of human and livestock pathogens, either reassorting or recombining, such as the Victoria and Yamagata lineages of influenza B and the O/Ind-2001 foot-and-mouth disease virus strain. Our results reveal diverse geographical paths of migration that characterize the origins and evolutionary histories of different viral genes and genomic segments. These incompatibility measures can be applied to any phylogeography, and more generally to any phylogeny where each tip has been assigned either a continuous or discrete "trait" independent of the sequence. We illustrate this flexibility with an analysis of the interplay between the phylogeography and phylolinguistics of Uralic-speaking human populations, hinting at patrilinear language transmission.

Establishment of Reference Reagents for Single-Radial-Immunodiffusion Assay on the 2022/23 Seasonal Influenza Vaccine in Japan and Their Quality Validation.

Potency tests for influenza vaccines are currently performed using a single-radial immunodiffusion (SRID) assay, which requires a reference antigen and anti-hemagglutinin (HA) serum as reference reagents. Reagents must be newly prepared each time a strain used for vaccine production is modified. Therefore, establishing reference reagents of consistent quality is crucial for conducting vaccine potency tests accurately and precisely. Here, we established reference reagents for the SRID assay to conduct lot release tests of quadrivalent influenza vaccines in Japan during the 2022/23 influenza season. The potency of reference antigens during storage was confirmed. Furthermore, we evaluated the cross-reactivity of each antiserum raised against the HA protein of the 2 lineages of influenza B virus toward different lineages of influenza B virus antigens to select a suitable procedure for the SRID assay for accurate measurement. Finally, the intralaboratory reproducibility of the SRID assay using the established reference reagents was validated, and the SRID reagents had sufficient consistent quality, comparable to that of the reagents used for testing vaccines during previous influenza seasons. Our study contributes to the quality control of influenza vaccines.

Influenza D virus in cattle (review)

The influenza D virus was first detected and identified in 2011. The overall amino acid sequence of influenza D virus shares approximately 50% identity with that of influenza C virus, suggesting that both viruses had a common ancestor. Cattle is considered to be the primary natural reservoir for influenza D virus. The involvement of this virus into the bovine respiratory disease complex has been confirmed. The virus causes mild to moderate disease in calves and replicates in both the upper and lower respiratory tracts, promoting bronchopneumonia. The influenza D virus can be transmitted by contact or aerosol over short distances, has a high transmission rate and can potentiate the effects of other respiratory pathogens. There are currently no vaccines or specific treatment for influenza D virus. This virus can replicate and be transmitted by direct contact in ferrets and guinea pigs, which are surrogate models of human influenza infection, as well as in well-differentiated human airway epithelial cells (hAECs). Currently five distinctive lineages of influenza D virus have been identified, co-circulating in worldwide bovine and pig populations that may facilitate genetic re-assortment between different viral strains. The virus has a zoonotic potential, and if its pathogenicity for humans changes, its importance for public health will be great. Very high seropositivity rates among persons working with cattle in the USA and Italy have been reported. There is no data in the available literature on the circulation of the influenza D virus in the Russian Federation. Research is needed to study this new virus, as well as monitoring of the virus spread and circulation in our country to understand its role in bovine respiratory disease complex and its zoonotic potential.

Characteristics of two zoonotic swine influenza A(H1N1) viruses isolated in Germany from diseased patients

Interspecies transmission of influenza A viruses (IAV) from pigs to humans is a concerning event as porcine IAV represent a reservoir of potentially pandemic IAV. We conducted a comprehensive analysis of two porcine A(H1N1)v viruses isolated from human cases by evaluating their genetic, antigenic and virological characteristics. The HA genes of those human isolates belonged to clades 1C.2.1 and 1C.2.2, respectively, of the A(H1N1) Eurasian avian-like swine influenza lineage. Antigenic profiling revealed substantial cross-reactivity between the two zoonotic H1N1 viruses and human A(H1N1)pdm09 virus and some swine viruses, but did not reveal cross-reactivity to H1N2 and earlier human seasonal A(H1N1) viruses. The solid-phase direct receptor binding assay analysis of both A(H1N1)v showed a predominant binding to α2–6–sialylated glycans similar to human-adapted IAV. Investigation of the replicative potential revealed that both A(H1N1)v viruses grow in human bronchial epithelial cells to similar high titers as the human A(H1N1)pdm09 virus. Cytokine induction was studied in human alveolar epithelial cells A549 and showed that both swine viruses isolated from human cases induced higher amounts of type I and type III IFN, as well as IL6 compared to a seasonal A(H1N1) or a A(H1N1)pdm09 virus. In summary, we demonstrate a remarkable adaptation of both zoonotic viruses to propagate in human cells. Our data emphasize the needs for continuous monitoring of people and regions at increased risk of such trans-species transmissions, as well as systematic studies to quantify the frequency of these events and to identify viral molecular determinants enhancing the zoonotic potential of porcine IAV.

Development of Cross-Reactive Live Attenuated Influenza Vaccine Candidates against Both Lineages of Influenza B Virus.

Influenza viruses continue to cause a significant social and economic burden globally. Vaccination is recognized as the most effective measure to control influenza. Live attenuated influenza vaccines (LAIVs) are an effective means of preventing influenza, especially among children. A reverse genetics (RG) system is required to rapidly update the antigenic composition of vaccines, as well as to design LAIVs with a broader spectrum of protection. Such a system has been developed for the Russian LAIVs only for type A strains, but not for influenza B viruses (IBV). All genes of the B/USSR/60/69 master donor virus (B60) were cloned into RG plasmids, and the engineered B60, as well as a panel of IBV LAIV reassortants were rescued from plasmid DNAs encoding all viral genes. The engineered viruses were evaluated in vitro and in a mouse model. The B60 RG system was successfully developed, which made it possible to rescue LAIV reassortants with the desired antigenic composition, including hybrid strains with hemagglutinin and neuraminidase genes belonging to the viruses from different IBV lineages. The LAIV candidate carrying the HA of the B/Victoria-lineage virus and NA from the B/Yamagata-lineage virus demonstrated optimal characteristics in terms of safety, immunogenicity and cross-protection, prompting its further assessment as a broadly protective component of trivalent LAIV. The new RG system for B60 MDV allowed the rapid generation of type B LAIV reassortants with desired genome compositions. The generation of hybrid LAIV reassortants with HA and NA genes belonging to the opposite IBV lineages is a promising approach for the development of IBV vaccines with broad cross-protection.

Influenza incidence, lineages, and vaccine effectiveness estimates in Lima, Peru, 2023

Influenza incidence, lineages, and vaccine effectiveness estimates in Lima, Peru, 2023

Persistent predominance of the Victoria lineage of influenza B virus during COVID-19 epidemic in Nanchang, China.

The sentinel hospital-based influenza-like illness (ILI) surveillance network was established in China since the 2009 H1N1 pandemic. This network plays important roles in monitoring influenza virus variation and identifying novel respiratory pathogens. In this study, we characterized the pathogen spectrum pattern (PSP) of ILI based on three sentinel hospitals and analyzed the significant change of PSP during the COVID-19 epidemic. The notable change of influenza virus spectrum was observed since the beginning of COVID-19 outbreak, and we found persistent domination of Victoria lineage of influenza B virus and "extinction" of A/H1N1, A/H3N2, and B/Yamagata during the dynamic Zero-COVID-19 pandemic in Nanchang, China. However, these strains intermittently co-circulated before the COVID-19.

Age- and sex-specific differences in immune responses to BNT162b2 COVID-19 and live-attenuated influenza vaccines in UK adolescents.

The key to understanding the COVID-19 correlates of protection is assessing vaccine-induced immunity in different demographic groups. Young people are at a lower risk of COVID-19 mortality, females are at a lower risk than males, and females often generate stronger immune responses to vaccination. We studied immune responses to two doses of BNT162b2 Pfizer COVID-19 vaccine in an adolescent cohort (n = 34, ages 12-16), an age group previously shown to elicit significantly greater immune responses to the same vaccine than young adults. Adolescents were studied with the aim of comparing their response to BNT162b2 to that of adults; and to assess the impacts of other factors such as sex, ongoing SARS-CoV-2 infection in schools, and prior exposure to endemic coronaviruses that circulate at high levels in young people. At the same time, we were able to evaluate immune responses to the co-administered live attenuated influenza vaccine. Blood samples from 34 adolescents taken before and after vaccination with COVID-19 and influenza vaccines were assayed for SARS-CoV-2-specific IgG and neutralising antibodies and cellular immunity specific for SARS-CoV-2 and endemic betacoronaviruses. The IgG targeting influenza lineages contained in the influenza vaccine were also assessed. Robust neutralising responses were identified in previously infected adolescents after one dose, and two doses were required in infection-naïve adolescents. As previously demonstrated, total IgG responses to SARS-CoV-2 Spike were significantly higher among vaccinated adolescents than among adults (aged 32-52) who received the BNT162b2 vaccine (comparing infection-naïve, 49,696 vs. 33,339; p = 0.03; comparing SARS-CoV-2 previously infected, 743,691 vs. 269,985; p <0.0001) by the MSD v-plex assay. There was no evidence of a stronger vaccine-induced immunity in females compared than in males. These findings may result from the introduction of novel mRNA vaccination platforms, generating patterns of immunity divergent from established trends and providing new insights into what might be protective following COVID-19 vaccination.

Discovery of Influenza A (H7N2) in a Cat After Admission to an Animal Shelter: A Case Report

This case report describes the discovery of a low pathogenic avian lineage influenza A (H7N2) (A/feline/New York/16-040082-1/2016) infecting a cat in a shelter environment. Low pathogenic avian influenza virus H7N2 had previously circulated in poultry and farmed waterfowl and had reportedly been eradicated from live bird markets in 2006. Its appearance in a cat caused concern for the local cat population and had the potential to negatively impact the agricultural industry and human health. The first cat diagnosed presented to the shelter with no apparent clinical signs. Later, conjunctivitis developed and then upper respiratory congestion, which progressed to severe pneumonia that was unresponsive to treatment and characterized by dyspnea, tachypnea, and collapse. A second cat, who had entered the shelter 17 days earlier and had died at an emergency clinic, was later considered to be the index case. The second cat had similarly arrived with no apparent clinical signs, developed respiratory congestion leading to pneumonia with tachypnea and dyspnea, and tested positive for influenza A. Clinical consultation and diagnostic testing through multiple organizations identified the virus as an avian lineage H7N2 influenza virus.

The Influenza B Virus Victoria and Yamagata Lineages Display Distinct Cell Tropism and Infection-Induced Host Gene Expression in Human Nasal Epithelial Cell Cultures.

Understanding Influenza B virus infections is of critical importance in our efforts to control severe influenza and influenza-related diseases. Until 2020, two genetic lineages of influenza B virus-Yamagata and Victoria-circulated in the population. These lineages are antigenically distinct, but the differences in virus replication or the induction of host cell responses after infection have not been carefully studied. Recent IBV clinical isolates of both lineages were obtained from influenza surveillance efforts of the Johns Hopkins Center of Excellence in Influenza Research and Response and characterized in vitro. B/Victoria and B/Yamagata clinical isolates were recognized less efficiently by serum from influenza-vaccinated individuals in comparison to the vaccine strains. B/Victoria lineages formed smaller plaques on MDCK cells compared to B/Yamagata, but infectious virus production in primary human nasal epithelial cell (hNEC) cultures showed no differences. While ciliated epithelial cells were the dominant cell type infected by both lineages, B/Victoria lineages had a slight preference for MUC5AC-positive cells, and B/Yamagata lineages infected more basal cells. Finally, while both lineages induced a strong interferon response 48 h after infection of hNEC cultures, the B/Victoria lineages showed a much stronger induction of interferon-related signaling pathways compared to B/Yamagata. This demonstrates that the two influenza B virus lineages differ not only in their antigenic structure but also in their ability to induce host innate immune responses.

Reverse-zoonoses of 2009 H1N1 pandemic influenza A viruses and evolution in United States swine results in viruses with zoonotic potential.

The 2009 H1N1 pandemic (pdm09) lineage of influenza A virus (IAV) crosses interspecies barriers with frequent human-to-swine spillovers each year. These spillovers reassort and drift within swine populations, leading to genetically and antigenically novel IAV that represent a zoonotic threat. We quantified interspecies transmission of the pdm09 lineage, persistence in swine, and identified how evolution in swine impacted zoonotic risk. Human and swine pdm09 case counts between 2010 and 2020 were correlated and human pdm09 burden and circulation directly impacted the detection of pdm09 in pigs. However, there was a relative absence of pdm09 circulation in humans during the 2020-21 season that was not reflected in swine. During the 2020-21 season, most swine pdm09 detections originated from human-to-swine spillovers from the 2018-19 and 2019-20 seasons that persisted in swine. We identified contemporary swine pdm09 representatives of each persistent spillover and quantified cross-reactivity between human seasonal H1 vaccine strains and the swine strains using a panel of monovalent ferret antisera in hemagglutination inhibition (HI) assays. The swine pdm09s had variable antigenic reactivity to vaccine antisera, but each swine pdm09 clade exhibited significant reduction in cross-reactivity to one or more of the human seasonal vaccine strains. Further supporting zoonotic risk, we showed phylogenetic evidence for 17 swine-to-human transmission events of pdm09 from 2010 to 2021, 11 of which were not previously classified as variants, with each of the zoonotic cases associated with persistent circulation of pdm09 in pigs. These data demonstrate that reverse-zoonoses and evolution of pdm09 in swine results in viruses that are capable of zoonotic transmission and represent a potential pandemic threat.

Rapid determination of influenza vaccine potency by an SPR-based method using subtype or lineage-specific monoclonal antibodies.

Potency testing and release of annual influenza vaccines require preparation, calibration, and distribution of reference antigens (RAs) and antisera every year, which takes an average of 8 to 12 weeks, and can be a major limiting factor in pandemic situations. Here we describe for the first time a robust Surface Plasmon Resonance (SPR)-based method that employs influenza subtype or lineage hemagglutinin (HA) specific monoclonal antibodies (mAbs) to measure the HA concentration in influenza multivalent vaccines. Implementing such an advanced test method will at the very least eliminate the rate-limiting and laborious efforts of making antisera reagents annually, and thus expedite the influenza vaccine delivery to the public by at least 6 weeks. Results demonstrate that the SPR-based method, developed using Biacore, is robust and not influenced by the type of RAs (inactivated whole virus, split, or subunit vaccine-derived materials), whether they are used as monovalent or multivalent preparations. HA concentrations obtained for monovalent drug substances (DS) or quadrivalent drug products (DP) of inactivated influenza split vaccine showed a tight correlation (the best fit value for the slope is 1.001 with R2 of 0.9815 and P-value <0.0001) with the corresponding values obtained by the current potency assay, Single Radial Immunodiffusion (SRID). Supplementary analysis of the results by the Bland-Altman plot demonstrated good agreement between the SPR and SRID methods, with no consistent bias of the SPR versus SRID method. We further demonstrate that the SPR-based method can be used to estimate HA concentrations in intermediates of the influenza vaccine manufacturing process containing varying matrices and impurity levels. Further, the results demonstrate that the method is sensitive to detecting degradation of HA caused by elevated temperature, low pH, and freezing. It is evident from this report and other published work that the advancement of analytical techniques and the early findings are encouraging for the implementation of alternate potency assays with far-reaching benefits covering both seasonal and pandemic influenza.

Anti-neuraminidase and anti-hemagglutinin immune serum can confer inter-lineage cross protection against recent influenza B.

Influenza B viruses (IBV) are responsible for a considerable part of the burden caused by influenza virus infections. Since their emergence in the 1980s, the Yamagata and Victoria antigenic lineages of influenza B circulate in alternate patterns across the globe. Furthermore, their evolutionary divergence and the appearance of new IBV subclades complicates the prediction of future influenza vaccines compositions. It has been proposed that the addition of the neuraminidase (NA) antigen could potentially induce a broader protection and compensate for hemagglutinin (HA) mismatches in the current vaccines. Here we show that anti-NA and -HA sera against both Victoria and Yamagata lineages have limited inter-lineage cross-reactivity. When transferred to mice prior to infection with a panel of IBVs, anti-NA sera were as potent as anti-HA sera in conferring protection against homologous challenge and, in some cases, conferred superior protection against challenge with heterologous IBV strains.

Antiviral Susceptibilities of Distinct Lineages of Influenza C and D Viruses.

The emergence and spread of antiviral-resistant influenza viruses are of great concern. To minimize the public health risk, it is important to monitor antiviral susceptibilities of influenza viruses. Analyses of the antiviral susceptibilities of influenza A and B viruses have been conducted globally; however, those of influenza C and D viruses are limited. Here, we determined the susceptibilities of influenza C viruses representing all six lineages (C/Taylor, C/Yamagata, C/Sao Paulo, C/Aichi, C/Kanagawa, and C/Mississippi) and influenza D viruses representing four lineages (D/OK, D/660, D/Yama2016, and D/Yama2019) to RNA polymerase inhibitors (baloxavir and favipiravir) by using a focus reduction assay. All viruses tested were susceptible to both drugs. We then performed a genetic analysis to check for amino acid substitutions associated with baloxavir and favipiravir resistance and found that none of the viruses tested possessed these substitutions. Use of the focus reduction assay with the genotypic assay has proven valuable for monitoring the antiviral susceptibilities of influenza C and D viruses as well as influenza A and B viruses. Antiviral susceptibility monitoring of all influenza virus types should continue in order to assess the public health risks posed by these viruses.

Influenza-Associated Excess Mortality by Age, Sex, and Subtype/Lineage: Population-Based Time-Series Study With a Distributed-Lag Nonlinear Model.

Accurate estimation of the influenza death burden is of great significance for influenza prevention and control. However, few studies have considered the short-term harvesting effects of influenza on mortality when estimating influenza-associated excess deaths by cause of death, age, sex, and subtype/lineage. This study aimed to estimate the cause-, age-, and sex-specific excess mortality associated with influenza and its subtypes and lineages in Guangzhou from 2015 to 2018. Distributed-lag nonlinear models were fitted to estimate the excess mortality related to influenza subtypes or lineages for different causes of death, age groups, and sex based on daily time-series data for mortality, influenza, and meteorological factors. A total of 199,777 death certificates were included in the study. The average annual influenza-associated excess mortality rate (EMR) was 25.06 (95% empirical CI [eCI] 19.85-30.16) per 100,000 persons; 7142 of 8791 (81.2%) deaths were due to respiratory or cardiovascular mortality (EMR 20.36, 95% eCI 16.75-23.74). Excess respiratory and cardiovascular deaths in people aged 60 to 79 years and those aged ≥80 years accounted for 32.9% (2346/7142) and 63.7% (4549/7142) of deaths, respectively. The male to female ratio (MFR) of excess death from respiratory diseases was 1.34 (95% CI 1.17-1.54), while the MFR for excess death from cardiovascular disease was 0.72 (95% CI 0.63-0.82). The average annual excess respiratory and cardiovascular mortality rates attributed to influenza A (H3N2), B/Yamagata, B/Victoria, and A (H1N1) were 8.47 (95% eCI 6.60-10.30), 5.81 (95% eCI 3.35-8.25), 3.68 (95% eCI 0.81-6.49), and 2.83 (95% eCI -1.26 to 6.71), respectively. Among these influenza subtypes/lineages, A (H3N2) had the highest excess respiratory and cardiovascular mortality rates for people aged 60 to 79 years (20.22, 95% eCI 14.56-25.63) and ≥80 years (180.15, 95% eCI 130.75-227.38), while younger people were more affected by A (H1N1), with an EMR of 1.29 (95% eCI 0.07-2.32). The mortality displacement of influenza A (H1N1), A (H3N2), and B/Yamagata was 2 to 5 days, but 5 to 13 days for B/Victoria. Influenza was associated with substantial mortality in Guangzhou, occurring predominantly in the elderly, even after considering mortality displacement. The mortality burden of influenza B, particularly B/Yamagata, cannot be ignored. Contrasting sex differences were found in influenza-associated excess mortality from respiratory diseases and from cardiovascular diseases; the underlying mechanisms need to be investigated in future studies. Our findings can help us better understand the magnitude and time-course of the effect of influenza on mortality and inform targeted interventions for mitigating the influenza mortality burden, such as immunizations with quadrivalent vaccines (especially for older people), behavioral campaigns, and treatment strategies.

Influenza virus subtype/lineage-specific seasonal patterns and age-related infection risk, in Eastern China.

Differences in seasonal pattern and age-related infection risk have been reported between Influenza type A and B, but have not been elaborated at subtype/lineage level. All laboratory-confirmed influenza cases reported in the influenza surveillance system of Jiangsu Province, China from January 2011 to August 2019 were analyzed. Influenza seasonality was characterized using the Seasonal Decomposition method. Binary and multinomial logistic regressions were employed to calculate the odds ratios of influenza subtypes/lineages in relation to age. A total of 28,772 confirmed influenza cases were included. Among them, a majority (64.1%) were influenza A infections. One annual peak was observed for A (H1N1) pdm and B-Yamagata in winter months, and for B-Victoria in spring months, while biannual peaks were observed for A (H3N2) in winter and summer months. Using all ages as the reference, children younger than 5 years and adults of 25-59 years were more likely to infect with A (H1N1) pdm. Older children aged 5-14 years had significantly higher odds of infection with influenza B of both lineages, while individuals aged 15-24 years had higher odds for A (H3N2) and B-Victoria. The elderly (60 years or older) were prone to be infected with A (H3N2) and B-Yamagata. For a specific age group, their likelihood of getting infected with an influenza subtype or lineage was related to the co-circulating influenza subtype or lineage. Influenza viruses have divergent seasonal peak times and age-related infection risk at subtype/lineage level.