Prevalence of Influenza B/Yamagata Viruses From Season 2012/2013 to 2021/2022 in Italy as an Indication of a Potential Lineage Extinction.

BACKGROUND: Influenza B/Yamagata viruses exhibited weak antigenic selection in recent years, reducing their prevalence over time and requiring no update of the vaccine component since 2015. To date, no B/Yamagata viruses have been isolated or sequenced since March 2020. METHODS: The antibody prevalence against the current B/Yamagata vaccine strain in Italy was investigated: For each influenza season from 2012/2013 to 2021/2022, 100 human serum samples were tested by haemagglutination inhibition (HAI) assay against the vaccine strain B/Phuket/3073/2013. In addition, the sequences of 156 B/Yamagata strains isolated during the influenza surveillance activities were selected for analysis of the haemagglutinin genome segment. RESULTS: About 61.9% of the human samples showed HAI antibodies, and 21.7% had protective antibody levels. The prevalence of antibodies at protective levels in the seasons between the isolation of the strain and its inclusion in the vaccine was between 11% and 25%, with no significant changes observed in subsequent years. A significant increase was observed in the 2020/2021 season, in line with the increase in influenza vaccine uptake during the pandemic. Sequence analysis showed that from 2014/2015 season onward, all B/Yamagata strains circulating in Italy were closely related to the B/Phuket/2013 vaccine strain, showing only limited amino acid variation. CONCLUSIONS: A consistent prevalence of antibodies to the current B/Yamagata vaccine strain in the general population was observed. The prolonged use of a well-matched influenza vaccine and a low antigenic diversity of B/Yamagata viruses may have facilitated a strong reduction in B/Yamagata circulation, potentially contributing to the disappearance of this lineage.

Multivalent Epigraph Hemagglutinin Vaccine Protects against Influenza B Virus in Mice.

Influenza B virus is a respiratory pathogen that contributes to seasonal epidemics, accounts for approximately 25% of global influenza infections, and can induce severe disease in young children. While vaccination is the most commonly used method of preventing influenza infections, current vaccines only induce strain-specific responses and have suboptimal efficacy when mismatched from circulating strains. Further, two influenza B virus lineages have been described, B/Yamagata-like and B/Victoria-like, and the limited cross-reactivity between the two lineages provides an additional barrier in developing a universal influenza B virus vaccine. Here, we report a novel multivalent vaccine using computationally designed Epigraph hemagglutinin proteins targeting both the B/Yamagata-like and B/Victoria-like lineages. When compared to the quadrivalent commercial vaccine, the Epigraph vaccine demonstrated increased breadth of neutralizing antibody and T cell responses. After lethal heterologous influenza B virus challenge, mice immunized with the Epigraph vaccine were completely protected against both weight loss and mortality. The superior cross-reactive immunity conferred by the Epigraph vaccine immunogens supports their continued investigation as a universal influenza B virus vaccine.

Corrigendum: Impact of adjuvant: trivalent vaccine with quadrivalent-like protection against heterologous Yamagata-lineage influenza B virus.

[This corrects the article DOI: 10.3389/fimmu.2022.1002286.].

Impact of adjuvant: Trivalent vaccine with quadrivalent-like protection against heterologous Yamagata-lineage influenza B virus.

As new vaccine technologies and platforms, such as nanoparticles and novel adjuvants, are developed to aid in the establishment of a universal influenza vaccine, studying traditional influenza split/subunit vaccines should not be overlooked. Commercially available vaccines are typically studied in terms of influenza A H1 and H3 viruses but influenza B viruses need to be examined as well. Thus, there is a need to both understand the limitations of split/subunit vaccines and develop strategies to overcome those limitations, particularly their ability to elicit cross-reactive antibodies to the co-circulating Victoria (B-V) and Yamagata (B-Y) lineages of human influenza B viruses. In this study, we compared three commercial influenza hemagglutinin (HA) split/subunit vaccines, one quadrivalent (H1, H3, B-V, B-Y HAs) and two trivalent (H1, H3, B-V HAs), to characterize potential differences in their antibody responses and protection against a B-Y challenge. We found that the trivalent adjuvanted vaccine Fluad, formulated without B-Y HA, was able to produce antibodies to B-Y (cross-lineage) on a similar level to those elicited from a quadrivalent vaccine (Flucelvax) containing both B-V and B-Y HAs. Interestingly, Fluad protected mice from a lethal cross-lineage B-Y viral challenge, while another trivalent vaccine, Fluzone HD, failed to elicit antibodies or full protection following challenge. Fluad immunization also diminished viral burden in the lungs compared to Fluzone and saline groups. The success of a trivalent vaccine to provide protection from a cross-lineage influenza B challenge, similar to a quadrivalent vaccine, suggests that further analysis of different split/subunit vaccine formulations could identify mechanisms for vaccines to target antigenically different viruses. Understanding how to increase the breadth of the immune response following immunization will be needed for universal influenza vaccine development.

Los linajes Victoria y Yamagata de los virus gripales B, desconocidos y poco valorados / The Victoria and Yamagata Lineages of Influenza B Viruses, unknown and undervalued

El virus gripal B pertenece a la familia Orthomyxoviriridae y al género Influenzavirus B. Presenta un genoma de tipoARN negativo formado por unos 14.648 nucleótidos divididosen ocho segmentos distintos que codifican unas 11 proteínas.Antes de 1980 todos los virus de la gripe B pertenecían a unúnico linaje genético; pero en este año emergieron dos linajesantigénica y genéticamente distintos que se denominaron B/Victoria/2/1987 y B/Yamagata/16/1988. Se han podido demostrar procesos de intercambio genético intralinajes y entrelinajes; de ellos los mas frecuentes son aquellos en los que el linajeVictoria adquiere genes del linaje Yamagata. Se ha propuestoque las diferencias en las dinámicas evolutivas de los dos linajesse deban a las diferentes preferencias de unión de la hemaglutinina gripal al receptor celular. El linaje Victoria ha mostradocapacidad para unirse a los receptores celulares con restos deácido siálico en las posiciones a-2,3 y a-2,6; mientras que ellinaje Yamagata lo hace exclusivamente en las posiciones humanas a-2,6 del tracto respiratorio. La escasa circulación enlos últimos meses podría haber contribuido a la eliminación(“extinción”) temporal del linaje Yamagata. Desde 2017 la casitotalidad de las cepas de este linaje pertenecen al clado 3A,cuando con anterioridad se detectaban clados múltiples circulando. Aunque este clado 3A es diverso a nivel genético y haadquirido mutaciones sustitutivas en el gen de la hemaglutinina, éstas no han determinado cambios antigénicos significativos que hayan obligado a sustituir su componente antigénico(B/Pukhet/3073/2013) en la vacuna gripal desde 2015. (AU)

The influenza virus B belongs to the family Orthomyxoviriridae and to the genus Influenzavirus B. It has a negativeRNA-type genome made up of about 14,648 nucleotides divided into eight different segments that encode about 11 proteins.Before 1980 all influenza B viruses belonged to a single geneticlineage; but in this year two antigenically and genetically distinct lineages emerged which were named B/Victoria/2/1987and B/Yamagata/16/1988. Intralineage and interlineage genetic exchange processes have been demonstrated; The most frequent of them are those in which the Victoria lineage acquiresgenes from the Yamagata lineage. It has been proposed thatthe differences in the evolutionary dynamics of the two lineages are due to the different binding preferences of influenzahemagglutinin to the cellular receptor. The Victoria lineage hasshown the ability to bind to cell receptors with sialic acid residues at the α-2,3 and α-2,6 positions; whereas the Yamagatalineage does so exclusively in the human α-2,6 positions of therespiratory tract. Low circulation in recent months may havecontributed to the temporary elimination (“extinction”) of theYamagata lineage. Since 2017, almost all of the strains of thislineage belong to clade 3A, when previously multiple circulating clades were detected. Although this clade 3A is diverse atthe genetic level and has acquired surrogate mutations in thehemagglutinin gene, these have not determined significantantigenic changes that have made it necessary to replace itsantigenic component (B/Pukhet/3073/2013) in the influenzavaccine since 2015. (AU)

[The Victoria and Yamagata Lineages of Influenza B Viruses, unknown and undervalued]. / Los linajes Victoria y Yamagata de los virus gripales B, desconocidos y poco valorados.

The influenza virus B belongs to the family Orthomyxoviriridae and to the genus Influenzavirus B. It has a negative RNA-type genome made up of about 14,648 nucleotides divided into eight different segments that encode about 11 proteins. Before 1980 all influenza B viruses belonged to a single genetic lineage; but in this year two antigenically and genetically distinct lineages emerged which were named B/Victoria/2/1987 and B/Yamagata/16/1988. Intralineage and interlineage genetic exchange processes have been demonstrated; The most frequent of them are those in which the Victoria lineage acquires genes from the Yamagata lineage. It has been proposed that the differences in the evolutionary dynamics of the two lineages are due to the different binding preferences of influenza hemagglutinin to the cellular receptor. The Victoria lineage has shown the ability to bind to cell receptors with sialic acid residues at the α-2,3 and α-2,6 positions; whereas the Yamagata lineage does so exclusively in the human α-2,6 positions of the respiratory tract. Low circulation in recent months may have contributed to the temporary elimination ("extinction") of the Yamagata lineage. Since 2017, almost all of the strains of this lineage belong to clade 3A, when previously multiple circulating clades were detected. Although this clade 3A is diverse at the genetic level and has acquired surrogate mutations in the hemagglutinin gene, these have not determined significant antigenic changes that have made it necessary to replace its antigenic component (B/Pukhet/3073/2013) in the influenza vaccine since 2015.

Characterization of Influenza A and B Viruses Circulating in Southern China During the 2017-2018 Season.

The trivalent seasonal influenza vaccine was the only approved and available vaccine during the 2016-2018 influenza seasons. It did not include the B/Yamagata strain. In this study, we report an acute respiratory disease outbreak associated with influenza B/Yamagata infections in Guangzhou, Southern China (January through March, 2018). Among the 9914 patients, 2241 (22.6%) were positive for the influenza B virus, with only 312 (3.1%) positive for the influenza A virus. The influenza B/Yamagata lineage dominated during this period in Southern China. The highest incidence of influenza A virus infection occurred in the children aged 5-14 years. In contrast, populations across all age groups were susceptible to the influenza B virus. Phylogenetic, mutations, and 3D structure analyses of hemagglutinin (HA) genes were performed to assess the vaccine-virus relatedness. The recommended A/H1N1 vaccine strain (A/Michigan/45/2015) during both 2017-2018 and 2018-2019 was antigen-specific for these circulating isolates (clade 6B.1) in Spring 2018. An outbreak of influenza B/Yamagata (clade 3) infections in 2018 occurred during the absence of the corresponding vaccine during 2016-2018. The recommended influenza B/Yamagata vaccine strain (B/Phuket/3073/2013) for the following season (2018-2019) was antigen-specific. Although there were only a few influenza B/Victoria infections in Spring 2018, five amino acid mutations were identified in the HA antigenic sites of the 19 B/Victoria isolates (clade 1A), when compared with the 2016-2018 B/Victoria vaccine strain. The number was larger than expected and suggested that the influenza B HA gene may be more variable than previously thought. One of the mutations (K180N) was noted to likely alter the epitope and to potentially affect the viral antigenicity. Seven mutations were also identified in the HA antigenic sites of 2018-2020 B/Victoria vaccine strain, of which some or all may reduce immunogenicity and the protective efficacy of the vaccine, perhaps leading to more outbreaks in subsequent seasons. The combined epidemiological, phylogenetic, mutations, and 3D structural analyses of the HA genes of influenza strains reported here contribute to the understanding and evaluation of how HA mutations affect vaccine efficacy, as well as to providing important data for screening and selecting more specific, appropriate, and effective influenza vaccine candidate strains.

Structural insights into the potential changes in receptor binding site found in the 1998-2018 influenza B/Yamagata hemagglutinin: A putative correlation between receptor binding site structural variability and seasonal infection.

Influenza B virus has two distinct lineages (Victoria and Yamagata) and are associated with seasonal influenza epidemics that cause respiratory illness. Influenza B hemagglutinin (HA) is a major surface glycoprotein with the receptor-binding site (RBS) primarily involved in viral pathogenesis. Generally, influenza B exclusively infects the human population which would insinuate that the structural variability of the influenza B HA RBS rarely changes. However, to our knowledge, the potential impact of variations in the influenza B HA RBS structural variability was not fully elucidated. Throughout this study, we generated models from the transitioning (evolving viral lineage) 1998-2018 influenza B/Yamagata HA, verified the quality of each HA model, performed HA RBS structural variability measurements, superimposed varying HA models for comparison, and designed a phylogenetic tree network for further analyses. We found that measurements of the transitioning HA RBS structural variability were generally maintained and, similarly, measurements of the altered (years that differed from the evolving viral lineage, specifically 2003, 2007, 2017) HA RBS structural variability differed from the transitioning HA RBS. Moreover, we observed that the altered HA RBS structural variability favored the formation of a putative Y202-H191 hydrogen bond which we postulate may increase structural stability, thereby, allowing for a winter infection of the virus. Furthermore, we established that changes in HA RBS structural variability does not influence viral evolution, but putatively seasonal infection.

Influenza B viruses from different genetic backgrounds are variably impaired by neuraminidase inhibitor resistance-associated substitutions.

Identifying evolutionary routes to antiviral resistance among influenza viruses informs molecular-based resistance surveillance and clinical decisions. To improve antiviral management and understand whether clinically identified neuraminidase (NA) inhibitor (NAI) resistance-associated markers affect influenza B viruses of the Victoria- or Yamagata-lineages differentially, we generated a panel of NAI-resistant viruses (carrying E105K, G145E, R150K, D197N, I221 L/N/T/V, H273Y, N294S, or G407S substitutions; B numbering) in B/Brisbane/60/2008 (BR/08) and B/Phuket/3073/2013 (PH/13). In both backgrounds, I221 L/N/T/V resulted in reduced or highly reduced inhibition (HRI) by one to three currently available NAIs. D197N reduced inhibition by all NAIs in BR/08 but only by oseltamivir and peramivir in PH/13; R150K caused HRI by all NAIs in PH/13. Although PH/13 generally retained or enhanced NA activity in the presence of the substitutions, enzymatic activity in BR/08 was detrimentally affected. Similarly, substrate affinity and catalysis were relatively stable in PH/13, but not in the BR/08 variants. E105K, R150K, and D197N attenuated replication efficiency of BR/08 in vitro and in mice; only E105K had this effect in PH/13. Notably, the I221 L/N/T/V substitutions did not severely impair replication, particularly in PH/13. Overall, our data show differential effects of NA substitutions in representative Victoria- and Yamagata-lineage viruses, suggesting distinct evolution of these viruses caused variable fitness and NAI susceptibility profiles when similar key NA substitutions arise. Because the viruses harboring the I221 NA substitutions displayed undiminished fitness and are commonly reported, this position is likely to be the most clinically relevant marker for NAI resistance among contemporary influenza B viruses.

Molecular characteristics of the hemagglutinin 1 and neuraminidase genes of influenza B viruses isolated in Yancheng city from 2015 to 2017 / 中华疾病控制杂志

Objective To analyze the genetic characteristics of the hemagglutinin （HA) and neuraminidase （NA) genes of influenza B viruses isolated in Yancheng City from 2015 to 2017. Methods The throat swab specimens of influenza-like illness( ILI) from sentinel surveillance hospital and outbreak sites were collected and sent to Yancheng CDC for virus nucleic acids and virus isolation testing. After validation with serological tests, eighteen strains of influenza B virus isolates were selected to amplify their HA1 and NA genes through RT-PCR assay. Their molecular characteristics of the obtained viral HA1 and NA gene sequences were analyzed using bioinformation software from three aspects, including nucleic acid level, amino acid level and molecular evolution level. Results Basically, the clustering relationships and the branche patterns between HA1 and NA genes from the 18 Yancheng influenza B virus strains were similar. The Yamagata lineage strains in 2015 were distributed in the Yamagata Clade 3 branch, belonging to Phuket/3073 strains. The Victoria lineage strains in 2016-2017 were distributed in the Victoria Clade 1A branch, belonging to Brisbane/60 strains. D196N substitution was detected on HA1 protein in all of Yamagata lineage strains at 190-helix epitope; Amino acid substitutions of victoria lineage strains involved two antigenic epitopes, 117 and 129 sites of 120-loop epitope and 197 and 199 sites of 190-helix epitope. No Intra-lineage or inter-lineage rearrangements occurred in Yancheng strains. Eighteen influenza B strains had no mutations in catalytic residues and drug resistant sites of NA genes. Conclusion The Yamagata strains well matched with vaccine strain B/Phuket/3073/2013. The HA1 and NA genes of victoria lineage strains circulated in Yancheng City during 2016 to 2017 are changing gradually. The accumulation of these mutations will result in antigenic drift of victoria lineage strains and increase the mismatch of the IFV field stains with the available vaccine strains, which may reduce the protective effect of flu vaccine.

Co-circulation of the two influenza B lineages during 13 consecutive influenza surveillance seasons in Italy, 2004-2017.

BACKGROUND: Since 1985, two antigenically distinct lineages of influenza B viruses (Victoria-like and Yamagata-like) have circulated globally. Trivalent seasonal influenza vaccines contain two circulating influenza A strains but a single B strain and thus provide limited immunity against circulating B strains of the lineage not included in the vaccine. In this study, we describe the characteristics of influenza B viruses that caused respiratory illness in the population in Italy over 13 consecutive seasons of virological surveillance, and the match between the predominant influenza B lineage and the vaccine B lineage, in each season. METHODS: From 2004 to 2017, 26,886 laboratory-confirmed influenza cases were registered in Italy, of which 18.7% were type B. Among them, the lineage of 2465 strains (49%) was retrieved or characterized in this study by a real-time RT-PCR assay and/or sequencing of the hemagglutinin (HA) gene. RESULTS: Co-circulation of both B lineages was observed each season, although in different proportions every year. Overall, viruses of B/Victoria and B/Yamagata lineages caused 53.3 and 46.7% of influenza B infections, respectively. A higher proportion of infections with both lineages was detected in children, and there was a declining frequency of B/Victoria detections with age. A mismatch between the vaccine and the predominant influenza B lineage occurred in eight out of thirteen influenza seasons under study. Considering the seasons when B accounted for > 20% of all laboratory-confirmed influenza cases, a mismatch was observed in four out of six seasons. Phylogenetic analysis of the HA1 domain confirmed the co-circulation of both lineages and revealed a mixed circulation of distinct evolutionary viral variants, with different levels of match to the vaccine strains. CONCLUSIONS: This study contributes to the understanding of the circulation of influenza B viruses in Italy. We found a continuous co-circulation of both B lineages in the period 2004-2017, and determined that children were particularly vulnerable to Victoria-lineage influenza B virus infections. An influenza B lineage mismatch with the trivalent vaccine occurred in about two-thirds of cases.

An Inexpensive and Accurate Reverse Transcription-PCR-Melting Temperature Analysis Assay for Real-Time Influenza Virus B Lineage Discrimination.

In this work, we describe a SYBR-Green one-step reverse transcription-PCR protocol coupled with a melting temperature analysis (RT-PCR-Tm ), which allows the discrimination of influenza B lineages Yamagata and Victoria. The assay is performed using a regular real-time thermocycler and is based on differences in melting temperature (Tm ) of a 131-bp amplicon, obtained from a conserved region of hemagglutinin gene. A total of 410 samples collected during the 2004, 2008, and 2010-2017 influenza seasons in Brazil were tested, and the lineages were correctly characterized using their melting profiles. The temperature range is significantly different between both lineages throughout the time (Mann-Whitney test; P < 0.0001, confidence interval = 95%), and the Tm is not affected by viral load (Spearman correlation test; r = 0.287, P = 2.245 × 10-9). The simplicity and cost-effectiveness of this protocol make it an option for influenza B lineage surveillance worldwide.

Immunogenicity and safety of an egg-based inactivated quadrivalent influenza vaccine (GC3110A) versus two inactivated trivalent influenza vaccines with alternate B strains: A phase â ¢ randomized clinical trial in adults.

Two antigenically distinct influenza B lineage viruses (Yamagata/Victoria) have been co-circulating globally since the mid-1980s. The quadrivalent influenza vaccine (QIV) may provide better protection against unpredictable B strains. We conducted a randomized, double-blind, phase III trial to evaluate the immunogenicity and safety of an egg-based inactivated, split-virion QIV (GC3110A). Subjects aged ≥ 19 years were randomized 2:1:1 to be vaccinated with QIV- GC3110A, trivalent influenza vaccine (TIV) containing the Yamagata lineage strain (TIV-Yamagata), or TIV containing the Victoria lineage strain (TIV-Victoria). Hemagglutination inhibition assays were performed 21 days post-vaccination. Solicited/unsolicited adverse events (AEs) were assessed within 21 days after vaccination, while serious AEs were reported up to six months after vaccination. A total of 1,299 were randomized to receive QIV-GC3110A (648 subjects), TIV-Yamagata (325 subjects), or TIV-Victoria (326 subjects). Compared to the TIVs, the QIV-GC3110A met the non-inferiority criteria for all four subtype/lineage strains with respect to the geometric mean titer (GMT) ratio and the difference of seroconversion rate. The safety profiles of QIV-GC3110A were consistent with those of TIV. In conclusion, QIV-GC3110A is safe, immunogenic, and comparable to strain-matched TIV.

Genetic characterization of influenza B virus in Cameroon and high frequency of reassortant strains.

Influenza B is broadly divided into B/Victoria and B/Yamagata lineages based on its genetic and antigenic properties. We describe in this study the first report on genome characterization of type B influenza virus in the Cameroon National Influenza Center (NIC) between 2014 and 2017. Respiratory samples were collected as part of the influenza surveillance activity in the NIC. RNA products were tested for the presence of influenza using the CDC Influenza A/B typing panel. Thirty-five samples positive for influenza B were selected for sequencing three gene segments (HA, NA, and M) and phylogenetic trees were generated by MEGA version 6.0. Nucleotide phylogenetic analysis of the HA gene revealed the presence of three major clades among Cameroonian strains. All Victoria lineages grouped into B/Victoria clade 1A, while, Yamagata lineages grouped into Yamagata clade 2 (2014 strains) and Yamagata clade 3 (2015-2017). We observed a high frequency of reassortant viruses with Yamagata-like HA gene and Victoria-like NA gene (27.4%; 23/84). The results from this study confirm variations in the genome composition of type B influenza virus and emphasize on the relevance of molecular surveillance for spotting peculiar genetic variants of public health and clinical significance.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccines in participants >/=3 years of age: a double-blind, randomized, parallel-controlled phase III clinical trial in China.

BACKGROUND: Viruses from two antigenically distinct influenza B strains have co-circulated since the mid-1980s, yet inactivated trivalent influenza vaccines (TIVs) with either the Victoria or Yamagata lineage could only provide limited protection from influenza B strain. Quadrivalent influenza vaccine (QIV) including both influenza B lineages can improve protection against circulating influenza B viruses. METHODS: Participants >/ = 3 years of age were recruited, stratified by age, and then randomly allocated at a ratio of 2:1:1 to receive one-injection of the experimental QIV, TIV-Victoria (Vic) or TIV-Yamagata (Yam). The primary objective of this study was to demonstrate that the hemagglutination-inhibition (HI) antibodies induced by the QIV candidate are not inferior to the licensed TIVs. RESULTS: First, 3661 participants received the inoculation. The QIV was found to be non-inferior to TIVs in terms of the geometric mean titers (GMTs) and seroconversion rates (SCRs) of the HI antibodies against shared strains 28 days after completion of inoculation, and was superior to the TIVs against the alternate B strain, which is absent from the TIVs. The occurrences of adverse events (AEs) post-vaccination were similar across the treatment groups. CONCLUSION: The experimental QIV showed good immunogenicity and an acceptable safety profile.

Epidemiology of influenza B in Australia: 2001-2014 influenza seasons.

BACKGROUND: Influenza B is characterised by two antigenic lineages: B/Victoria and B/Yamagata. These lineages circulate together with influenza A during influenza seasons, with varying incidence from year to year and by geographic region. OBJECTIVE: To determine the epidemiology of influenza B relative to influenza A in Australia. METHODS: Laboratory-confirmed influenza notifications between 2001 and 2014 in Australia were obtained from the Australian National Notifiable Diseases Surveillance System. RESULTS: A total of 278 485 laboratory-confirmed influenza cases were notified during the study period, comprising influenza A (82.2%), B (17.1%) and 'other and untyped' (0.7%). The proportion of notifications that were influenza B was highest in five- to nine-year-olds (27.5%) and lowest in persons aged 85 years and over (11.5%). Of all B notifications with lineage determined, 77.1% were B/Victoria and 22.9% were B/Yamagata infections. Mismatches between the dominant B lineage in a season and the trivalent vaccine B lineage occurred in over one-third of seasons during the study years. In general, influenza B notifications peaked later than influenza A notifications. CONCLUSION: The proportion of circulating influenza B in Australia during 2001-2014 was slightly lower than the global average and was dominated by B/Victoria. Compared with influenza A, influenza B infection was more common among older children and young adults and less common in the very elderly. Influenza B lineage mismatch with the trivalent vaccine occurred about one-third of the time.

Development of high-yield influenza B virus vaccine viruses.

The burden of human infections with influenza A and B viruses is substantial, and the impact of influenza B virus infections can exceed that of influenza A virus infections in some seasons. Over the past few decades, viruses of two influenza B virus lineages (Victoria and Yamagata) have circulated in humans, and both lineages are now represented in influenza vaccines, as recommended by the World Health Organization. Influenza B virus vaccines for humans have been available for more than half a century, yet no systematic efforts have been undertaken to develop high-yield candidates. Therefore, we screened virus libraries possessing random mutations in the six "internal" influenza B viral RNA segments [i.e., those not encoding the major viral antigens, hemagglutinin (HA) and neuraminidase NA)] for mutants that confer efficient replication. Candidate viruses that supported high yield in cell culture were tested with the HA and NA genes of eight different viruses of the Victoria and Yamagata lineages. We identified combinations of mutations that increased the titers of candidate vaccine viruses in mammalian cells used for human influenza vaccine virus propagation and in embryonated chicken eggs, the most common propagation system for influenza viruses. These influenza B virus vaccine backbones can be used for improved vaccine virus production.

Comparative Epidemiology of Influenza B Yamagata- and Victoria-Lineage Viruses in Households.

Influenza B viruses split into 2 distinct lineages in the early 1980s, commonly named the Victoria and Yamagata lineages. There are few data on the comparative epidemiology of Victoria- and Yamagata-lineage viruses. In 2007-2011, we enrolled 75 and 34 households containing index patients with acute respiratory illness who tested positive for Yamagata- and Victoria-lineage viruses, respectively, from outpatient clinics in Hong Kong, China. These index patients and their household contacts were followed up for 7-10 days. We examined overall risk of polymerase chain reaction-confirmed infection among household contacts and the risk of secondary infection within households using an individual-based hazard model that accounted for tertiary transmission and infections occurring outside the household. We found that for Victoria-lineage viruses, the risk of within-household infection among household contacts aged ≤15 years was significantly higher (risk ratio = 12.9, 95% credibility interval: 4.2, 43.6) than that for older household contacts, while for Yamagata-lineage viruses, the risk of within-household infection for household contacts did not differ by age. Influenza B Yamagata- and Victoria-lineage viruses have similar characteristics in terms of viral shedding and clinical illness. The mechanisms underlying these epidemiologic differences deserve further investigation.

Cost-effectiveness of quadrivalent influenza vaccine in Hong Kong - A decision analysis.

Trivalent influenza vaccine (TIV) selects one of the 2 co-circulating influenza B lineages whereas quadrivalent influenza vaccine (QIV) includes both lineages. We examined potential cost-effectiveness of QIV versus TIV from perspectives of healthcare provider and society of Hong Kong. A decision tree was designed to simulate the outcomes of QIV vs. TIV in 6 age groups: 0-4 years, 5-9 years, 10-14 years, 15-64 years, 65-79 y and ≥80 years. Direct cost alone, direct and indirect costs, and quality-adjusted life-years (QALYs) loss due to TIV-unmatched influenza B infection were simulated for each study arm. Outcome measure was incremental cost per QALY (ICER). In base-case analysis, QIV was more effective than TIV in all-age population with additional direct cost per QALY (ICER-direct cost) and additional total cost per QALY (ICER-total cost) of USD 22,603 and USD 12,558, respectively. Age-stratified analysis showed that QIV was cost-effective in age groups 6 months to 9 y and ≥80 years from provider's perspective, and it was cost-effective in all age group except 15-64 y from societal perspective. Percentage of TIV-unmatched influenza B in circulation and additional vaccine cost of QIV were key influential factors. From perspectives of healthcare provider and society, QIV was the preferred option in 52.77% and 66.94% of 10,000 Monte Carlo simulations, respectively. QIV appears to be cost-effective in Hong Kong population, except for age group 15-64 years, from societal perspective. From healthcare provider's perspective, QIV seems to be cost-effective in very young (6 months-9 years) and older (≥80 years) age groups.