Victoria Lineage Research Articles

Induction and isolation of protective influenza neuraminidase specific antibodies in humans following seasonal vaccination.

Abstract Influenza’s propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed, particularly those with broad activity against diverse strains. Although hemagglutinin (HA) specificity dominates the humoral response to seasonal inactivated influenza vaccines and infection, Abs targeting neuraminidase (NA) are also generated. NA-specific Abs are suggested to act primarily through inhibiting its enzymatic activity and preventing release of virus from infected cells. Relative to HA, there is substantially less diversity among NA from different influenza types and subtypes, suggesting it is a valuable target for inducing broad protective immunity. To determine if humans generate NA-specific Abs with protective activity we examined plasmablasts from subjects that were immunized with the seasonal influenza inactivated vaccine, and isolated several NA-specific human monoclonal Abs (hmAbs), including those with potent in vitro viral neutralizing activity. One of the NA B–specific hmAbs, KPF2 recognized NA from both the Yamagata and Victoria lineages, and when administered prophylactically to mice resulted in sterilizing immunity. These results suggest seasonal influenza vaccine induces protective NA-specific mAbs in humans. Analysis of other NA-specific hmAbs is ongoing.

A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects, assessing both anti-haemagglutinin and virus neutralisation antibody responses

BackgroundTrivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B-strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged ≥18 to ≤60 years) and elderly (aged ≥61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN). MethodsSubjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B-strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post-vaccination. ResultsQIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups. ConclusionsQIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B-strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable.

Native Human Monoclonal Antibodies with Potent Cross-Lineage Neutralization of Influenza B Viruses.

ABSTRACTAlthough antibodies that effectively neutralize a broad set of influenza viruses exist in the human antibody repertoire, they are rare. We used a single-cell screening technology to identify rare monoclonal antibodies (MAbs) that recognized a broad set of influenza B viruses (IBV). The screen yielded 23 MAbs with diverse germ line origins that recognized hemagglutinins (HAs) derived from influenza strains of both the Yamagata and Victoria lineages of IBV. Of the 23 MAbs, 3 exhibited low expression in a transient-transfection system, 4 were neutralizers that bound to the HA head region, 11 were stalk-binding nonneutralizers, and 5 were stalk-binding neutralizers, with 4 of these 5 having unique antibody sequences. Of these four unique stalk-binding neutralizing MAbs, all were broadly reactive and neutralizing against a panel of multiple strains spanning both IBV lineages as well as highly effective in treating lethal IBV infections in mice at both 24 and 72 h postinfection. The MAbs in this group were thermostable and bound different epitopes in the highly conserved HA stalk region. These characteristics suggest that these MAbs are suitable for consideration as candidates for clinical studies to address their effectiveness in the treatment of IBV-infected patients.

Relationship between the frequency of influenza vaccination and cell-mediated immunity

Despite established guidelines for population-level assessments of immunity after vaccination, standard methods for individual-level analyses have not been established, limiting the ability to optimize vaccination strategies within a particular season. In this study, we evaluated changes in cell-mediated immunity (CMI) with respect to the number of influenza vaccine doses. In particular, the influenza vaccine was administered to 21 adults during the 2015–2016 season. IFN-γ production induced by the influenza vaccine antigens [A (H1N1), A (H3N2), B (Yamagata lineage), and B (Victoria lineage)] increased after the first dose of vaccination in 11, 10, 10, and 11 subjects, respectively. In 5 of 10 (H1N1), 4 of 10 (H3N2), 3 of 9 (Yamagata lineage), and 3 of 8 (Victoria lineage) subjects who did not exhibit an increase in IFN-γ production after the first dose, CMI was enhanced after the second dose. The production of IFN-γ increased after the first or second dose of the vaccine in 16, 14, 13, and 14 of the 21 subjects, respectively. The results of this study showed that two doses of the influenza vaccine effectively enhance CMI in subjects with primary vaccine failure.

Neuraminidase inhibitor susceptibility and evolutionary analysis of human influenza B isolates from three Asian countries during 2012–2015

Influenza B viruses of both the Yamagata and the Victoria lineages are implicated in a large proportion of the morbidity and mortality associated with influenza outbreaks. In this study, we characterized the full genomes of 53 influenza B viruses isolated during 2012–2015 in three Asian countries: Japan, Myanmar, and Vietnam. Analysis of the hemagglutinin (HA) genes revealed co-circulation of both the Yamagata and Victoria lineages within the same season in these countries. Our analysis revealed, that a large proportion of viruses circulating during 2013–2014 in Japan and Vietnam were mismatched to the vaccine supporting the rationale for using quadrivalent vaccines. Molecular analysis of the neuraminidase (NA) genes did not reveal any of the previously reported substitutions associated with reduced susceptibility to neuraminidase inhibitors (NAIs). However, one isolate from Nagasaki displayed reduced inhibition by NAIs, associated with an NA-M426I substitution (N2-numbering). Phylogenetic analysis of the eight genome segments identified a 6 + 2 reassortant strain belonging to the Victoria lineage that circulated in Japan during the 2013–2014 season. This strain appears to have evolved from a descendent of a B/Brisbane/60/2008-like strain in an intra-lineage reassortment event involving the nucleoprotein (NP) and nonstructural (NS) genes. Therefore, influenza B strains circulating worldwide continue to evolve via complex reassortment events, which contribute to their survival and the emergence of new strains. These findings highlight the need for ongoing genome-wide studies of circulating viruses and assessing the implications of these evolutionary events on the vaccines.

Identification and characterization of viral defective RNA genomes in influenza B virus.

Influenza B virus (FLUBV) is an important pathogen that infects humans and causes seasonal influenza epidemics. To date, little is known about defective genomes of FLUBV and their roles in viral replication. In this study, by using a next-generation sequencing approach, we analyzed total mRNAs extracted from A549 cells infected with B/Brisbane/60/2008 virus (Victoria lineage), and identified four defective FLUBV genomes with two (PB1∆A and PB1∆B) from the polymerase basic subunit 1 (PB1) segment and the other two (M∆A and M∆B) from the matrix (M) protein-encoding segment. These defective genomes contained significant deletions in the central regions with each having the potential for encoding a novel polypeptide. Significantly, each of the discovered defective RNAs can potently inhibit the replication of B/Yamanashi/166/98 (Yamagata lineage). Furthermore, PB1∆A was able to interfere modestly with influenza A virus (FLUAV) replication. In summary, our study provides important initial insights into FLUBV defective-interfering genomes, which can be further explored to achieve better understanding of the replication, pathogenesis and evolution of FLUBV.

Immunogenicity and safety of the first indigenously developed Indian tetravalent influenza vaccine (split virion) in healthy adults ≥ 18 years of age: A randomized, multicenter, phase II / III clinical trial

ABSTRACTThis phase II / III clinical trial was conducted to evaluate the immunogenicity and safety of the Tetravalent Influenza vaccine (Split virion) I.P. (TetIV) developed indigenously in the country for the first time by M/s Cadila Healthcare Limited, India containing two influenza A and two influenza B strains, one of each, Yamagata (B/Phuket) and Victoria (B/Brisbane) lineage and also compare it to that of an licensed seasonal Trivalent Influenza vaccine (TriIV) of Sanofi Pasteur India Private Limited, containing the two influenza A and only the Yamagata lineage (B/Phuket) strain. Three hundred and fifty subjects of either sex, aged more than 18 years of age, were randomized in a 1:1 ratio to receive either the TetIV or TriIV. Immunogenicity assessments (antibody against A/H1N1, A/H3N2, B/Phuket and B/Brisbane) were done by Haemagglutination Inhibition assay at baseline and 21 d after vaccination. Solicited (local and systemic) and unsolicited adverse events were recorded for up to 42 d following vaccination. The TetIV was found to fulfill the criteria set by the European and the US regulatory authorities and WHO guidance on the requirements of clinical data for licensure of seasonal inactivated influenza vaccines. The seroconversion rates with TetIV were 93.5% for A/H1N1, 90.0% for A/H3N2, 70.0% for B/Phuket and 82.9% for B/Brisbane strain. There was no significant difference in the seroconversion and seroprotection rates at day 21 for A/H1N1, A/H3N2 and B/Phuket in the two groups while the TetIV was superior to the TrivIV for the seroconversion and the seroprotection rate for the B/Brisbane strain (Victoria lineage). Both the vaccines were well tolerated by all the study participants; addition of the fourth strain in the TetIV did not compromise the safety as compared to TriIV. The most common systemic adverse event reported in both the groups was headache followed by fever.

Three Types of Broadly Reacting Antibodies against Influenza B Viruses Induced by Vaccination with Seasonal Influenza Viruses.

We analyzed the antibody (Ab) repertoire against influenza B viruses induced by vaccination with seasonal influenza viruses in one individual who had never been vaccinated until 2009. The vaccine used in this study comprised B/Massachusetts/2/2012 (Yamagata lineage), A/Texas/50/2012 (H3N2), and A/California/7/2009 (H1N1). One month after the subject received two vaccinations, blood (200 ml) was obtained and peripheral mononuclear cells were prepared, and a large Ab library was constructed using phage display technology. The library was screened with HA-enriched fraction of B/Massachusetts/2/2012 and B/Brisbane/60/2008 (Victoria lineage) virus, and a total of 26 Abs that potentially bound to hemagglutinin (HA) molecules were isolated. Their binding activities to six influenza B viruses, three of Yamagata lineage and three of Victoria lineage, and two influenza A viruses, H1N1 and H3N2, were examined. The Abs showed cross-reactivity at three different levels. The first type bound to all Yamagata lineage viruses. The second type bound to both Yamagata and Victoria lineage viruses. The third type bound to both influenza A and B viruses. These results indicate that common epitopes exist on HA molecules of influenza virus at various levels, and humans have capability to produce Abs that bind to such common epitopes.

Forty five percent of the Israeli population were infected with the influenza B Victoria virus during the winter season 2015-16.

While infection with influenza A viruses has been extensively investigated, infections with influenza B viruses which are commonly categorized into the highly homologous Victoria and Yamagata lineages, are less studied, despite their considerable virulence. Here we used RT-PCR assays, hemagglutination inhibition assays and antibody titers to determine the levels of influenza B infection. We report of high influenza B Victoria virus prevalence in the 2015–16 winter season in Israel, affecting approximately half of the Israeli population. We further show that the Victoria B virus infected individuals of all ages and that it was present in the country throughout the entire winter season. The vaccine however included the inappropriate Yamagata virus. We propose that a quadrivalent vaccine, that includes both Yamagata and Victoria lineages, should be considered for future influenza vaccination.

Excess pneumonia and influenza mortality attributable to seasonal influenza in subtropical Shanghai, China

BackgroundDisease burden attributable to influenza is substantial in subtropical regions. Our study aims to estimate excess pneumonia and influenza (P&I) mortality associated with influenza by subtypes/lineages in Shanghai, China, 2010–2015.MethodsQuasi-Poisson regression models were fitted to weekly numbers of deaths from causes coded as P&I for Shanghai general and registered population. Three proxies for influenza activity were respectively used as an explanatory variable. Long-term trend, seasonal trend and absolute humidity were adjusted for as confounding factors. The outcome measurements of excess P&I mortality associated with influenza subtypes/lineages were derived by subtracting the baseline mortality from fitted mortality.ResultsExcess P&I mortality associated with influenza were 0.22, 0.30, and 0.23 per 100,000 population for three different proxies in Shanghai general population, lower than those in registered population (0.34, 0.48, and 0.36 per 100,000 population). Influenza B (Victoria) lineage did not contribute to excess P&I mortality (P = 0.206) while influenza B (Yamagata) lineage did (P = 0.044). Influenza-associated P&I mortality was high in the elderly population.ConclusionsSeasonal influenza A virus had a higher P&I mortality than influenza B virus, while B (Yamagata) lineage is the dominant lineage attributable to P&I mortality.

Safety, immunogenicity, and lot-to-lot consistency of a split-virion quadrivalent influenza vaccine in younger and older adults: A phase III randomized, double-blind clinical trial

ABSTRACTHere, we report a randomized multicenter phase III trial assessing the lot-to-lot consistency of the 2014–2015 Northern Hemisphere quadrivalent split-virion inactivated influenza vaccine (IIV4; Sanofi Pasteur) and comparing its immunogenicity and safety with that of trivalent inactivated influenza vaccine (IIV3) in younger and older adults (EudraCT no. 2014-000785-21). Younger (18–60 y, n = 1114) and older (>60 y, n = 1111) adults were randomized 2:2:2:1:1 to receive a single dose of one of three lots of IIV4, the licensed IIV3 containing the B Yamagata lineage strain, or an investigational IIV3 containing the B Victoria lineage strain. Post-vaccination (day 21) hemagglutination inhibition antibody titers were equivalent for the three IIV4 lots. For the pooled IIV4s vs. IIV3, hemagglutination inhibition antibody titers were also non-inferior for the A strains, non-inferior for the B strain when present in the comparator IIV3, and superior for the B strain lineage when absent from the comparator IIV3. For all vaccine strains, seroprotection rates were ≥98% in younger adults and ≥90% in older adults. IIV4 also increased seroneutralizing antibody titers against all three vaccine strains of influenza. All vaccines were well tolerated, with no safety concerns identified. Solicited injection-site reactions were similar for IIV4 and IIV3 and mostly grade 1 and transient. This study showed that in younger and older adults, IIV4 had a similar safety profile as the licensed IIV3 and that including a second B strain lineage in IIV4 provided superior immunogenicity for the added B strain without affecting the immunogenicity of the three IIV3 strains.

A pharmacologically immunosuppressed mouse model for assessing influenza B virus pathogenicity and oseltamivir treatment

Immunocompromised patients are highly susceptible to influenza virus infections. Although neuraminidase inhibitor (NAI) therapy has proved effective in these patients, the treatment regimens require optimization, which can be partly addressed via animal models. Here, we describe a pharmacologically immunosuppressed mouse model for studying the pathogenesis of influenza B viruses and evaluating the efficacy of antiviral treatment. We modeled clinical regimens for dexamethasone and cyclophosphamide to immunosuppress BALB/c mice that were then inoculated with B/Phuket/3073/2013 (Yamagata lineage) or B/Brisbane/60/2008 (BR/08, Victoria lineage) virus. Although both viruses caused morbidity and mortality in immunosuppressed mice, BR/08 was more virulent, consistently inducing greater morbidity and 100% lethality in mice inoculated with at least 103 TCID50/mouse. The replication of both viruses was prolonged in the lungs of immunosuppressed mice, but the extent of pulmonary inflammation in these mice was markedly less than that in immunocompetent animals. Most of the examined cytokines, including IFN-γ, IL-1β, and RANTES, were significantly decreased in the lungs of immunosuppressed mice, as compared to immunocompetent animals, until at least 10 days post-infection. Treatment with the NAI oseltamivir for 8 or 16 days increased the mean survival time and reduced virus spread in the lungs of immunosuppressed mice challenged with a lethal dose of BR/08 but did not completely provide protection or decrease the virus titers. Our data suggests that the synergy of the viral load and aberrant immune responses is a key contributor to the severity of infection, as well as the limited efficacy of oseltamivir, which in immunosuppressed mice curtails virus release without clearing infected cells.

Molecular epidemiology of influenza B virus among hospitalized pediatric patients in Northern Italy during the 2015-16 season.

BackgroundThe influenza B viruses belong to two lineages distinguished by their genetic and antigenic characteristics, which are referred to as the Yamagata and Victoria lineages, designated after their original isolates, B/Yamagata/16/88 and B/Victoria/2/87. The primary aim of this study was to evaluate the molecular characteristics of influenza B viruses circulating in a region of Northern Italy, Lombardia, during the influenza season of 2015–2016.MethodsInfluenza B virus was detected using a respiratory virus panel of assays and an influenza B-specific real-time polymerase chain reaction. The complete influenza B hemagglutinin (HA) gene was amplified and sequenced directly from clinical specimens. Phylogenetic analysis was performed using nucleotide sequences.ResultsA total of 71 hospitalized pediatric patients were influenza B positive. Phylogenetic analysis showed that the great majority of influenza B strains (66/71, 93.0%) belonged to the Victoria-lineage and were antigenically like vaccine strain (B/Brisbane/60/2008) included only in the quadrivalent vaccine. In the detected influenza B strains, a series of amino acid changes were observed in the antigenic regions: I117V, V124A, N129D, V146I, N197D, T199A, and A202T. However, only 2 amino acid changes were observed in the HA regions involved in receptor binding or in antibody recognition.ConclusionsAll the influenza B strains identified in this study belonged to the influenza B Victoria lineage not included in the trivalent vaccine commonly used by the general population during the 2015–2016 influenza season in Italy. This indicates that protection against influenza B infection in the vaccinated population was in general very poor during the 2015–2016 influenza season.

The susceptibility of circulating human influenza viruses to tizoxanide, the active metabolite of nitazoxanide

Nitazoxanide is a thiazolide compound that was originally developed as an anti-parasitic agent, but has recently been repurposed for the treatment of influenza virus infections. Thought to exert its anti-influenza activity via the inhibition of hemagglutinin maturation and intracellular trafficking in infected cells, the effectiveness of nitazoxanide in treating patients with non-complicated influenza is currently being assessed in phase III clinical trials.Here, we describe the susceptibility of 210 seasonal influenza viruses to tizoxanide, the active circulating metabolite of nitazoxanide. An optimised cell culture-based focus reduction assay was used to determine the susceptibility of A(H1N1)pdm09, A(H3N2), and influenza B viruses circulating in the southern hemisphere from the period March 2014 to August 2016. Tizoxanide showed potent in vitro antiviral activity against all influenza viruses tested, including neuraminidase inhibitor-resistant viruses, allowing the establishment of a baseline level of susceptibility for each subtype. Median EC50 values (±IQR) of 0.48 μM (0.33–0.71), 0.62 μM (0.56–0.75), 0.66 μM (0.62–0.69), and 0.60 μM (0.51–0.67) were obtained for A(H1N1)pdm09, A(H3N2), B(Victoria lineage), and B(Yamagata lineage) influenza viruses respectively. There was no significant difference in the median baseline tizoxanide susceptibility for each influenza subtype tested. This is the first report on the susceptibility of circulating viruses to tizoxanide. The focus reduction assay format described is sensitive, robust, and less laborious than traditional cell based antiviral assays, making it highly suitable for the surveillance of tizoxanide susceptibility in circulating seasonal influenza viruses.

Epidemiology of Influenza Viruses in Canada over the 2011–2012 to 2013–2014 Seasons: A Study from the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN)

BackgroundInfluenza virus activity varies seasonally and within season. Epidemiology of serious influenza outcomes is contingent on the prevalent circulating strain/s and susceptible age group/s. Given the strain variability over the 2011–2012 through 2013–2014 seasons in Canada, this study examined the clinical and epidemiological profiles of different influenza strains causing adult hospitalizations.MethodsDuring these three influenza seasons, the Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) enrolled adults hospitalized with acute respiratory illness across Canada. Nasopharyngeal swabs (NPs) from influenza cases were tested for strain characterization using real-time reverse transcriptase polymerase chain reaction (rtRT-PCR). A primary assay differentiated A and B influenza viruses. Subsequently, influenza A viruses were subtyped as H1N1 or H3N2, and influenza B lineages were differentiated as Victoria or Yamagata. Laboratory results were compared with patient demographic data and clinical outcomes.ResultsOver three consecutive influenza seasons, 3394 cases of hospitalized acute respiratory illness were laboratory-confirmed as influenza. At 72.4%, influenza A was predominant across all seasons, while influenza B caused 27.6%. Most of the influenza A cases were due to H3N2 (58.7%), while H1N1 accounted for 41.3%. For influenza B, the Yamagata lineage was predominant at 88.4% whereas the Victoria lineage accounted for 11.6%. Outcome analyses are presented for each influenza A subtype and influenza B lineage, overall and per season. Considering serious outcomes in patients ≥65, higher proportions of patients hospitalized with the H1N1 strain experienced intensive care unit (ICU) admission and need for mechanical ventilation, while higher proportions of patients hospitalized with B/Yamagata and H3N2 died within 30 days of admission.ConclusionComprehensive collection of surveillance data paired with NP specimens by the CIRN SOS Network was conducive to broader understanding of influenza strain activity and associated outcomes at the subtype and lineage level. This data is important to make informed recommendations for the use of multicomponent influenza vaccines.Disclosures M. Elsherif, Canadian Institutes of Health Research: Investigator, Research grant. Public Health Agency of Canada: Investigator, Research grant. GSK: Investigator, Research grant. T. Hatchette, GSK: Grant Investigator, Grant recipient; Pfizer: Grant Investigator, Grant recipient. Abbvie: Speaker for a talk on biologics and risk of TB reactivation, Speaker honorarium.M. K. Andrew, GSK: Grant Investigator, Research grant. Pfizer: Grant Investigator, Research grant. Sanofi-Pasteur: Grant Investigator, Research grant. J. McElhaney, GSK Vaccines: Scientific Advisor, Speaker honorarium. A. Mcgeer, Hoffman La Roche: Investigator, Research grant. GSK: Investigator, Research grant. sanofi pasteur: Investigator, Research grant. J. Powis, Merck: Grant Investigator, Research grant. GSK: Grant Investigator, Research grant. Roche: Grant Investigator, Research grant. Synthetic Biologicals: Investigator, Research grant. M. Semret, GSK: Investigator, Research grant. Pfizer: Investigator, Research grant. S. Trottier, Canadian Institutes of Health Research: Investigator, Research grant. L. Valiquette, GSK: Investigator, Research grant. S. McNeil, GSK: Contract Clinical Trials and Grant Investigator, Research grant. Merck: Contract Clinical Trials and Speaker’s Bureau, Speaker honorarium. Novartis: Contract Clinical Trials, No personal renumeration. sanofi pasteur: Contract Clinical Trials, No personal renumeration

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

ABSTRACTBackground: 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.

Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2017-18 Influenza Season.

SummaryThis report updates the 2016–17 recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding the use of seasonal influenza vaccines (MMWR Recomm Rep 2016;65[No. RR-5]). Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. A licensed, recommended, and age-appropriate vaccine should be used.For the 2017–18 season, quadrivalent and trivalent influenza vaccines will be available. Inactivated influenza vaccines (IIVs) will be available in trivalent (IIV3) and quadrivalent (IIV4) formulations. Recombinant influenza vaccine (RIV) will be available in trivalent (RIV3) and quadrivalent (RIV4) formulations. Live attenuated influenza vaccine (LAIV4) is not recommended for use during the 2017–18 season due to concerns about its effectiveness against (H1N1)pdm09 viruses during the 2013–14 and 2015–16 seasons. Recommendations for different vaccine types and specific populations are discussed. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended product is available.Updates to the recommendations described in this report reflect discussions during public meetings of ACIP held on October 20, 2016; February 22, 2017; and June 21, 2017. New and updated information in this report includes the following:•Vaccine viruses included in the 2017–18 U.S. trivalent influenza vaccines will be an A/Michigan/45/2015 (H1N1)pdm09–like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008–like virus (Victoria lineage). Quadrivalent influenza vaccines will contain these three viruses and an additional influenza B vaccine virus, a B/Phuket/3073/2013–like virus (Yamagata lineage).• Information on recent licensures and labelling changes is discussed, including licensure of Afluria Quadrivalent (IIV4; Seqirus, Parkville, Victoria, Australia); Flublok Quadrivalent (RIV4; Protein Sciences, Meriden, Connecticut); and expansion of the age indication for FluLaval Quadrivalent (IIV4; ID Biomedical Corporation of Quebec, Quebec City, Quebec, Canada), previously licensed for ≥3 years, to ≥6 months.• Pregnant women may receive any licensed, recommended, age-appropriate influenza vaccine.• Afluria (IIV3; Seqirus, Parkville, Victoria, Australia) may be used for persons aged ≥5 years, consistent with Food and Drug Administration–approved labeling.• FluMist Quadrivalent (LAIV4; MedImmune, Gaithersburg, Maryland) should not be used during the 2017–18 season due to concerns about its effectiveness against influenza A(H1N1)pdm09 viruses in the United States during the 2013–14 and 2015–16 influenza seasons.This report focuses on the recommendations for use of vaccines for the prevention and control of influenza during the 2017–18 season in the United States. A Background Document containing further information and a summary of these recommendations are available at https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html. These recommendations apply to licensed influenza vaccines used within Food and Drug Administration–licensed indications, including those licensed after the publication date of this report. Updates and other information are available at CDC’s influenza website (https://www.cdc.gov/flu). Vaccination and health care providers should check CDC’s influenza website periodically for additional information.

Pathogenicity and peramivir efficacy in immunocompromised murine models of influenza B virus infection

Influenza B viruses are important human pathogens that remain inadequately studied, largely because available animal models are poorly defined. Here, we developed an immunocompromised murine models for influenza B virus infection, which we subsequently used to study pathogenicity and to examine antiviral efficacy of the neuraminidase inhibitor peramivir. We studied three influenza B viruses that represent both the Yamagata (B/Massachusetts/2/2012 and B/Phuket/3073/2013) and Victoria (B/Brisbane/60/2008, BR/08) lineages. BR/08 was the most pathogenic in genetically modified immunocompromised mice [BALB scid and non-obese diabetic (NOD) scid strains] causing lethal infection without prior adaptation. The immunocompromised mice demonstrated prolonged virus shedding with modest induction of immune responses compared to BALB/c. Rather than severe virus burden, BR/08 virus-associated disease severity correlated with extensive virus spread and severe pulmonary pathology, stronger and persistent natural killer cell responses, and the extended induction of pro-inflammatory cytokines and chemokines. In contrast to a single-dose treatment (75 mg/kg/day), repeated doses of peramivir rescued BALB scid mice from lethal challenge with BR/08, but did not result in complete virus clearance. In summary, we have established immunocompromised murine models for influenza B virus infection that will facilitate evaluations of the efficacy of currently available and investigational anti-influenza drugs.

DMAb inoculation of synthetic cross reactive antibodies protects against lethal influenza A and B infections

Influenza virus remains a significant public health threat despite innovative vaccines and antiviral drugs. A major limitation to current vaccinations and therapies against influenza virus is pathogenic diversity generated by shift and drift. A simple, cost-effective passive immunization strategy via in vivo production of cross-protective antibody molecules may augment existing vaccines and antiviral drugs in seasonal and pandemic outbreaks. We engineered synthetic plasmid DNA to encode two novel and broadly cross-protective monoclonal antibodies targeting influenza A and B. We utilized enhanced in vivo delivery of these plasmid DNA-encoded monoclonal antibody (DMAb) constructs and show that this strategy induces robust levels of functional antibodies directed against influenza A and B viruses in mouse sera. Mice receiving a single inoculation with anti-influenza A DMAb survive lethal Group 1 H1 and Group 2 H3 influenza A challenges, while inoculation with anti-influenza B DMAb yields protection against lethal Victoria and Yamagata lineage influenza B morbidity and mortality. Furthermore, these two DMAbs can be delivered coordinately resulting in exceptionally broad protection against both influenza A and B. We demonstrate this protection is similar to that achieved by conventional protein antibody delivery. DMAbs warrant further investigation as a novel immune therapy platform with distinct advantages for sustained immunoprophylaxis against influenza.

Generation of monoclonal pan-hemagglutinin antibodies for the quantification of multiple strains of influenza.

Vaccination is the most effective course of action to prevent influenza. About 150 million doses of influenza vaccines were distributed for the 2015–2016 season in the USA alone according to the Centers for Disease Control and Prevention. Vaccine dosage is calculated based on the concentration of hemagglutinin (HA), the main surface glycoprotein expressed by influenza which varies from strain to strain. Therefore yearly-updated strain-specific antibodies and calibrating antigens are required. Preparing these quantification reagents can take up to three months and significantly slows down the release of new vaccine lots. Therefore, to circumvent the need for strain-specific sera, two anti-HA monoclonal antibodies (mAbs) against a highly conserved sequence have been produced by immunizing mice with a novel peptide-conjugate. Immunoblots demonstrate that 40 strains of influenza encompassing HA subtypes H1 to H13, as well as B strains from the Yamagata and Victoria lineage were detected when the two mAbs are combined to from a pan-HA mAb cocktail. Quantification using this pan-HA mAbs cocktail was achieved in a dot blot assay and results correlated with concentrations measured in a hemagglutination assay with a coefficient of correlation of 0.80. A competitive ELISA was also optimised with purified viral-like particles. Regardless of the quantification method used, pan-HA antibodies can be employed to accelerate process development when strain-specific antibodies are not available, and represent a valuable tool in case of pandemics. These antibodies were also expressed in CHO cells to facilitate large-scale production using bioreactor technologies which might be required to meet industrial needs for quantification reagents. Finally, a simulation model was created to predict the binding affinity of the two anti-HA antibodies to the amino acids composing the highly conserved epitope; different probabilities of interaction between a given amino acid and the antibodies might explain the affinity of each antibody against different influenza strains.