Quadrivalent Inactivated Influenza Vaccine Research Articles

The role of cell-mediated immunity against influenza and its implications for vaccine evaluation

Influenza vaccines remain the most effective tools to prevent flu and its complications. Trivalent or quadrivalent inactivated influenza vaccines primarily elicit antibodies towards haemagglutinin and neuraminidase. These vaccines fail to induce high protective efficacy, in particular in older adults and immunocompromised individuals and require annual updates to keep up with evolving influenza strains (antigenic drift). Vaccine efficacy declines when there is a mismatch between its content and circulating strains. Current correlates of protection are merely based on serological parameters determined by haemagglutination inhibition or single radial haemolysis assays. However, there is ample evidence showing that these serological correlates of protection can both over- or underestimate the protective efficacy of influenza vaccines. Next-generation universal influenza vaccines that induce cross-reactive cellular immune responses (CD4+ and/or CD8+ T-cell responses) against conserved epitopes may overcome some of the shortcomings of the current inactivated vaccines by eliciting broader protection that lasts for several influenza seasons and potentially enhances pandemic preparedness. Assessment of cellular immune responses in clinical trials that evaluate the immunogenicity of these new generation vaccines is thus of utmost importance. Moreover, studies are needed to examine whether these cross-reactive cellular immune responses can be considered as new or complementary correlates of protection in the evaluation of traditional and next-generation influenza vaccines. An overview of the assays that can be applied to measure cell-mediated immune responses to influenza with their strengths and weaknesses is provided here.

Enhanced passive safety surveillance of a quadrivalent inactivated split virion influenza vaccine in Finland during the influenza season 2020/21

BackgroundThe European Medicines Agency (EMA) requires enhanced safety surveillance to be conducted for annual seasonal influenza vaccines with the aim of rapidly detecting any potential new safety concerns before the peak immunisation period of the vaccine in any given year. The aim of this study was to detect any clinically significant change in the frequency or severity of expected reactogenicity of the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunisation in Finland for the 2020/21 season. The primary objective was to investigate the frequency of suspected adverse drug reactions (ADRs) occurring within 7 days following vaccination.MethodsEnhanced passive safety surveillance of individuals vaccinated with IIV4 was conducted from October 9, 2020 to November 30, 2020 across seven sites in Finland. The vaccinee reporting rate and ADR reporting rate were calculated and compared with known or expected safety data in order to identify any clinically significant changes.ResultsData were collected from 1008 individuals with 29 vaccinees reporting 82 suspected ADRs. Of these, 28 people reported 79 suspected ADRs within 7 days following vaccination, corresponding to a vaccinee reporting rate of 2.78% (95% CI: 1.85, 3.99) (ADR reporting rate, 7.84% [95% CI: 6.25, 9.67%]). The most frequently reported ADRs were injection site reactions (vaccination site pain, vaccination site erythema and vaccination site swelling) (n = 46, 2.28%), myalgia (n = 9, 0.89%) and headache (n = 8, 0.79%). No serious suspected adverse events were reported at any point post-vaccination and ADR reporting rates were in general lower compared to those reported for IIV4 in the 2019/20 surveillance study.ConclusionNo clinically significant changes in what is known or expected for IIV4 were reported for the 2020/21 season which supports the safety profile of this vaccine and will help maintain public confidence in influenza vaccination.

Immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac) co-administered with an inactivated quadrivalent influenza vaccine: A randomized, open-label, controlled study in healthy adults aged 18 to 59 years in China

BackgroundStudies are needed for evidence of inactivated COVID-19 vaccine co-administered with influenza vaccine. MethodsA randomized, open-label, controlled study was conducted in Zhejiang Province, China. Eligible healthy adults aged 18–59 years underwent randomization at a ratio of 1:1:2 to receive inactivated quadrivalent influenza vaccine (IIV4) either concomitantly with the first (C1 subgroup) or the second (C2 subgroup) dose of CoronaVac, or 14 days after the first dose of CoronaVac (S group). The primary purpose of the study was to prove the non-inferiority in seroconversion rate of antibody against SARS-CoV-2. ResultsOverall, 480 participants were enrolled, with 120, 120, and 240 randomly assigned to the C1, C2, and S groups, respectively. As lower bound of the two-sided 95% confidence interval (CI) of the difference for the seroconversion rate of antibodies against SARS-CoV-2 was over −10%, the immune response for CoronaVac in the C group (93.1% [89.0, 96.0]) was non-inferior to that in the S group (95.2% [91.5, 97.6]) in the per-protocol set. A lower GMT of antibody against SARS-CoV-2 was observed in the C group as compared to the S group (27.5 vs. 38.1, P = 0.0001). Decrease of immune response to CoronaVac was mainly observed in participants received IIV4 concomitantly with their second dose of CoronaVac (C2 subgroup), with a seroconversion rate of 89.7% (95CI: 82.6%-94.5%) and a GMT of 23.3. The occurrences of vaccine related adverse reactions were no more than 20% and comparable among different groups. Most of the adverse reactions were mild and moderate. ConclusionCo-administration of inactivated COVID-19 vaccine and seasonal influenza vaccine, especially the administration regimen that the seasonal influenza vaccine co-administered with the first dose of the inactivated COVID-19 vaccine, would be feasible.

Immunogenicity and safety of an egg culture-based quadrivalent inactivated non-adjuvanted subunit influenza vaccine in subjects ≥3 years: A randomized, multicenter, double-blind, active-controlled phase III, non-inferiority trial

Subunit influenza vaccine only formulated with surface antigen proteins has better safety profiles relative to split-virion influenza vaccine. Compared to the traditional quadrivalent split-virion influenza vaccine, a novel quadrivalent subunit influenza vaccine is urgently needed in China. We completed a phase 3, randomized, double-blind, active-controlled, non-inferiority clinical study at two sites in Henan Province, China. Eligible volunteers were split into four age cohorts (3–8 years, 9–17 years, 18–64 years, and ≥ 65 years, based on their dates of birth) and randomly assigned (1:1) to the subunit and the split-virion ecNAIIV4 groups. All volunteers were intramuscularly administered a single vaccine dose at baseline, and children aged 3–8 years received a boosting dose at day 28. And the immune response was evaluated by measuring hemagglutinin-inhibition antibody titers against the four vaccine strains in blood samples. Safety profiles had nonsignificant differences between the study groups in ≥ 3 years cohort. Most adverse reactions post-vaccination, both local and systemic, were mild to moderate and resolved within 3 days. And no serious adverse events occurred. The immunogenicity of the trial vaccine was non-inferior to the comparator. Further, a two-dose vaccine series can provide better seroprotection than that of a one-dose series in children aged 3–8 years, with clinically acceptable safety profiles.Clinical Trials Registration. ChiCTR2100049934.

Relative Effectiveness of Cell-based Versus Egg-based Quadrivalent Influenza Vaccines in Children and Adolescents in the United States During the 2019-2020 Influenza Season.

Background:Egg-based influenza vaccine production can lead to the accumulation of mutations that affect antigenicity. The mammalian cell-based inactivated quadrivalent influenza vaccine (IIV4c) may improve effectiveness compared with egg-based vaccines. This study estimated the relative vaccine effectiveness (rVE) of IIV4c versus egg-based inactivated quadrivalent influenza vaccine (IIV4e) in preventing influenza-related medical encounters (IRME) among children and adolescents during the 2019–2020 US influenza season.Methods:This retrospective cohort study used a dataset linking primary and specialty care electronic medical records with medical and pharmacy claims data from US residents 4 through 17 years of age vaccinated with IIV4c or IIV4e during the 2019–2020 influenza season. Odds ratios (ORs) were derived from a doubly robust inverse probability of treatment-weighted approach adjusting for age, sex, race, ethnicity, region, index week, health status and two proxy variables for healthcare accessibility and use. Adjusted rVE was estimated by (1-ORadjusted)*100, and an exploratory analysis evaluated IRMEs separately for outpatient and inpatient settings.Results:The final study cohort included 60,480 (IIV4c) and 1,240,990 (IIV4e) vaccine recipients. Fewer IRMEs were reported in subjects vaccinated with IIV4c than IIV4e. The rVE for IIV4c versus IIV4e was 12.2% [95% confidence interval (CI): 7.5–16.6] for any IRME and 14.3% (9.3–19.0) for outpatient IRMEs. Inpatient IRMEs were much less frequent, and effectiveness estimates were around the null.Conclusions:Fewer IRMEs occurred in pediatric subjects vaccinated with IIV4c versus IIV4e. These results support the greater effectiveness of IIV4c over IIV4e in this population during the 2019–2020 US influenza season.

Review of Analyses Estimating Relative Vaccine Effectiveness of Cell-Based Quadrivalent Influenza Vaccine in Three Consecutive US Influenza Seasons.

The adaptation of influenza seed viruses in egg culture can result in a variable antigenic vaccine match each season. The cell-based quadrivalent inactivated influenza vaccine (IIV4c) contains viruses grown in mammalian cell lines rather than eggs. IIV4c is not subject to egg-adaptive changes and therefore may offer improved protection relative to egg-based vaccines, depending on the degree of match with circulating influenza viruses. We summarize the relative vaccine effectiveness (rVE) of IIV4c versus egg-based quadrivalent influenza vaccines (IIV4e) to prevent influenza-related medical encounters (IRMEs) from three retrospective observational cohort studies conducted during the 2017–2018, 2018–2019, and 2019–2020 US influenza seasons using the same underlying electronic medical record dataset for all three seasons—with the addition of linked medical claims for the latter two seasons. We identified IRMEs using diagnostic codes specific to influenza disease (ICD J09*-J11*) from the records of over 10 million people. We estimated rVE using propensity score methods adjusting for age, sex, race, ethnicity, geographic location, week of vaccination, and health status. Subgroup analyses included specific age groups. IIV4c consistently had higher relative effectiveness than IIV4e across all seasons assessed, which were characterized by different dominant circulating strains and variable antigenic drift or egg adaptation.

Public health and budget impacts of switching from a trivalent to a quadrivalent inactivated influenza vaccine in Paraguay

ABSTRACT This study aimed to investigate the public health and economic benefit of using a quadrivalent influenza vaccine (QIV) instead of a trivalent influenza vaccine (TIV) in past seasons in Paraguay. The budget impact of switching from TIV to QIV in the Immunization Program was also evaluated. The adapted model includes two modules. The first compared retrospectively Health and Economic outcomes resulting from the use of QIV instead of TIV. The second forecast the spending and savings that would be associated with the switch from TIV to QIV. Our findings estimate that the switch from TIV to QIV during the seasons 2012 to 2017 could have prevented around 2,600 influenza cases, 67 hospitalizations and 10 deaths. An alternative scenario using standardized estimates of the burden of influenza showed that 234 influenza-related hospitalizations and 29 deaths could have been prevented. The estimated annual budget impact of a full switch from TIV to QIV was around USD1,6 million both from the payer and societal perspectives. Those results are mainly driven by vaccine prices and coverage rate. In sum, this manuscript describes how the use of QIV instead of TIV could have prevented influenza cases and subsequent complications that led to hospitalizations and deaths. This could have generated savings for the health system and society, offsetting part of the additional investment needed to switch from TIV to QIV.

B-cell response to seasonal influenza vaccine in mice is amenable to pharmacological modulation through β-adrenoceptor

AimsGiven that deprivation of noradrenaline acting on lymphocytes through β-adrenoceptor influences antibody response, the effects of propranolol treatment beginning two days before immunization with quadrivalent inactivated influenza vaccine (QIV) on IgG response and underlying cellular molecular mechanism in mice were investigated. Main methodsTwenty-one days post-immunization the total QIV antigen-specific IgG titer and IgG subclass titers in sera were determined using ELISA. Additionally, the total counts of germinal centre (GC) B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells in draining lymph nodes (dLNs) and spleens, in vitro proliferation of interacting B cells and Th cells and IL-21 synthesis in Th cells in response to QIV antigens and/or mitogen were attested using flow cytometry analysis. In QIV antigen-stimulated dLN cell and splenocyte cultures were also measured concentrations of INF-γ and IL-4, cytokines upregulating IgG2a and IgG1 synthesis, respectively. Key findingsPropranolol decreased the total QIV antigen-specific IgG titer. This correlated with lower GC B cell count and the shift in Tfr/Tfh cell and Tfr/GC B cell ratio towards Tfr in propranolol-treated mice compared with controls. Consistently, QIV antigen-stimulated proliferation of B cells and Th cells from propranolol-treated mice in vitro was impaired. This correlated with the lower frequency of QIV antigen-specific IL-21-producing cells among Th cells. Additionally, in propranolol-treated mice, in accordance with the changes in INF-γ/IL-4 ratio in dLN cell/splenocyte cultures, serum IgG2a/IgG1 ratio was shifted towards IgG1 reflecting decreased IgG2a response. SignificanceThe study indicates that chronic propranolol treatment may impair response to QIV.

A novel digital device-based adjuvant-like effect for influenza vaccine: A feasibility and pilot study

Abstract Viral infections such as influenza and COVID-19 have a huge impact on humans. Previous studies showed that some exercise could enhance the anti-viral antibody titers after vaccination. We developed a novel digital device designed to enhance host immune system against viral infection by acting like adjuvants. The digital device, SAT-008, is a mobile application based on an algorithm to regulate physical activity. To assess the feasibility of SAT-008, a randomized, open-label, and controlled study was conducted for 13 weeks (Oct 20 to Jan 21). A total of 42 healthy adults (mostly healthcare workers) aged 24 to 46 years were recruited and finally 32 subjects served for analysis. A single-dose of quadrivalent inactivated influenza vaccine was administered for each subject. The control group maintained daily life without using SAT-008, while the experimental group (Exp) used SAT-008 during the study. As a result, compared to the controls, the Exp showed a significant increase in hemagglutination-inhibition (HI) titers of antigen subtype B Yamagata lineage after 4 weeks of vaccination and antigen subtype B Victoria lineage after 12 weeks of vaccination (P < 0.05), whereas the controls did not. As for type A influenza, there was no significant difference in HI titers between groups. In addition, the Exp was divided into high performers (HP) and low performers (LP) based on the adherence rate. The HP showed significantly higher HI titers of B Yamagata lineage in 12 weeks after vaccination than controls and LP (P < 0.05) and of B Victoria lineage than controls (P < 0.01). Our findings indicate a novel approach using digital device may play an important role to enhance host immune system to act as a vaccine adjuvant against viral diseases such as influenza. Supported by grants from S-Alpha Therapeutics, Inc.

Cost-utility analysis of increasing uptake of universal seasonal quadrivalent influenza vaccine (QIV) in children aged 6 months and older in Germany

ABSTRACT Seasonal influenza causes many cases and related deaths in Europe annually, despite ongoing vaccination programs for older adults and people at high-risk of complications. Children have the highest risk of infection and play a key role in disease transmission. Our cost-utility analysis, based on a dynamic transmission model, estimated the impact of increasing the current vaccination coverage with inactivated quadrivalent influenza vaccine in Germany to all (healthy and high-risk) children under 5 years of age (40% uptake), or under 18 years (40% uptake), or only high-risk children under 18 years (90% uptake). Eight influenza complications were modeled, hospitalization and death rates were based on age and risk status. All three vaccination strategies provided more health benefits than the existing vaccination situation, reducing influenza cases, complications, hospitalizations and deaths across the entire population. The strategy targeting all children under 5 years was highly cost-effective (€6/quality-adjusted life-year gained, payer perspective). The other strategies were cost saving from the payer and societal perspectives. The vaccination strategy targeting all children under 18 years was estimated to provide the most health benefits (preventing on average 1.66 million cases, 179,000 complications, 14,000 hospitalizations and 3,600 deaths due to influenza annually) and the most cost savings (annually €20.5 million and €731.3 million from payer and societal perspectives, respectively). Our analysis provides policy decision-makers with evidence supporting strategies to expand childhood influenza vaccination, to directly protect children, and indirectly all other unvaccinated age groups, in order to reduce the humanistic and economic burden on healthcare systems and society.

Reactogenicity, safety, and immunogenicity of chimeric haemagglutinin influenza split-virion vaccines, adjuvanted with AS01 or AS03 or non-adjuvanted: a phase 1–2 randomised controlled trial

One strategy to develop a universal influenza virus vaccine is to redirect the immune system to the highly conserved haemagglutinin stalk domain by sequentially administering vaccines expressing chimeric (c) haemagglutinins with a conserved stalk domain and divergent head domain, to which humans are naive. We aimed to assess the reactogenicity, safety, and immunogenicity of adjuvanted and unadjuvanted investigational supra-seasonal universal influenza virus vaccines (SUIVs) in healthy young adults. In this observer-masked, randomised, controlled, phase 1-2 trial, we recruited adults aged 18-39 years with no clinically significant conditions from six centres in Belgium and the USA. Participants were randomly assigned to ten equally sized groups via an online system with the MATerial Excellence programme. Vaccines contained heterosubtypic group 1 H8, H5, or H11 haemagglutinin heads, an H1 haemagglutinin stalk, and an N1 neuraminidase (cH8/1N1, cH5/1N1, and cH11/1N1; haemagglutinin dose 15 μg/0·5 mL), administered on days 1 and 57, with a month 14 booster. SUIVs were evaluated in the sequences: cH8/1N1-placebo-cH5/1N1, cH5/1N1-placebo-cH8/1N1, or cH8/1N1-cH5/1N1-cH11/1N1, adjuvanted with either AS03 or AS01, or not adjuvanted. The last group received inactivated quadrivalent influenza vaccine (IIV4)-placebo-IIV4. Primary outcomes were safety (analysed in the exposed population) and immunogenicity in terms of the anti-H1 stalk humoral response at 28 days after vaccination (analysed in the per-protocol population, defined as participants who received the study vaccines according to the protocol). This trial is registered with ClinicalTrials.gov, NCT03275389. Between Sept 25, 2017, and March 26, 2020, 507 eligible participants were enrolled. 468 (92%) participants received at least one dose of study vaccine (exposed population), of whom 244 (52%) were included in the per-protocol population at final analysis at month 26. The safety profiles of all chimeric vaccines were clinically acceptable, with no safety concerns identified. Injection-site pain was the most common adverse event, occurring in 84-96% of participants receiving an adjuvanted SUIV or non-adjuvanted IIV4 and in 40-50% of participants receiving a non-adjuvanted SUIV. Spontaneously reported adverse events up to 28 days after vaccination occurred in 36-60% of participants, with no trends observed for any group. 17 participants had a serious adverse event, none of which were considered to be causally related to the vaccine. Anti-H1 stalk antibody titres were highest in AS03-adjuvanted groups, followed by AS01-adjuvanted and non-adjuvanted groups, and were higher after cH8/1N1 than after cH5/1N1 and after a two-dose primary schedule than after a one-dose schedule. Geometric mean concentrations by ELISA ranged from 21 938·1 ELISA units/mL (95% CI 18 037·8-26 681·8) in the IIV4-placebo-IIV4 group to 116 596·8 ELISA units/mL (93 869·6-144 826·6) in the AS03-adjuvanted cH8/1N1-cH5/1N1-cH11/1N1 group 28 days after the first dose and from 15 105·9 ELISA units/mL (12 007·7-19 003·6) in the non-adjuvanted cH5/1N1-placebo-cH8/1N1 group to 74 639·7 ELISA units/mL (59 986·3-92 872·6) in the AS03-adjuvanted cH8/1N1-cH5/1N1-cH11/1N1 group 28 days after the second dose. The stalk domain seems to be a rational target for development of a universal influenza virus vaccine via administration of chimeric haemagglutinins with head domains to which humans are naive. GlaxoSmithKline Biologicals.

Relative Effectiveness of MF59 Adjuvanted Trivalent Influenza Vaccine vs Nonadjuvanted Vaccines During the 2019-2020 Influenza Season.

BackgroundAge-related immunosenescence may impair the immune response to vaccination in older adults. Adjuvanted influenza vaccines are designed to overcome immune senescence in older adults. This study estimated the relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) vs egg-derived quadrivalent inactivated influenza vaccine (IIV4e) and high-dose trivalent inactivated influenza vaccine (HD-IIV3) in preventing influenza-related medical encounters in the 2019–2020 US season.MethodsThis retrospective cohort study used electronic medical records linked to pharmacy and medical claims data. The study population included adults age ≥65 years with a record of aIIV3, IIV4e, or HD-IIV3 vaccination. A doubly robust inverse probability of treatment weighting model was used to derive adjusted odds ratios (ORs). rVE was calculated by (1 – ORadjusted)*100 and was determined overall and separately for age subgroups. An exploratory analysis evaluated the outcome separately in inpatient and outpatient settings.ResultsSubjects received aIIV3 (n = 936 508), IIV3e (n = 651 034), and HD-IIV3 (n = 1 813 819), and influenza-related medical encounters were recorded in 0.5%, 0.9%, and 0.7% of each cohort, respectively. Overall, the rVE of aIIV3 was 27.5% (95% CI, 24.4% to 30.5%) vs IIV4e and 13.9% (95% CI, 10.7% to 17.0%) vs HD-IIV3. aIIV3 had a more favorable rVE in inpatient and outpatient settings. Findings remained consistent across age subgroups and during alternative seasonal dates.ConclusionsAdults age ≥65 years vaccinated with aIIV3 had fewer influenza-related medical encounters compared with IIV4e or HD-IIV3 during the 2019–2020 US influenza season.

Safety of Live Attenuated Influenza Vaccine in Children With Asthma.

Asthma is considered a precaution for use of quadrivalent live attenuated influenza vaccine (LAIV4) in persons aged ≥5 years because of concerns for wheezing events. We evaluated the safety of LAIV4 in children with asthma, comparing the proportion of children with asthma exacerbations after LAIV4 or quadrivalent inactivated influenza vaccine (IIV4). We enrolled 151 children with asthma, aged 5 to 17 years, during 2 influenza seasons. Participants were randomly assigned 1:1 to receive IIV4 or LAIV4 and monitored for asthma symptoms, exacerbations, changes in peak expiratory flow rate (PEFR), and changes in the asthma control test for 42 days after vaccination. We included 142 participants in the per-protocol analysis. Within 42 days postvaccination, 18 of 142 (13%) experienced an asthma exacerbation: 8 of 74 (11%) in the LAIV4 group versus 10 of 68 (15%) in the IIV4 group (LAIV4-IIV4 = -0.0390 [90% confidence interval -0.1453 to 0.0674]), meeting the bounds for noninferiority. When adjusted for asthma severity, LAIV4 remained noninferior to IIV4. There were no significant differences in the frequency of asthma symptoms, change in PEFR, or childhood asthma control test/asthma control test scores in the 14 days postvaccination between LAIV4 and IIV4 recipients. Vaccine reactogenicity was similar between groups, although sore throat (P = .051) and myalgia (P <.001) were more common in the IIV4 group. LAIV4 was not associated with increased frequency of asthma exacerbations, an increase in asthma-related symptoms, or a decrease in PEFR compared with IIV4 among children aged 5 to 17 years with asthma.

Switching from trivalent to quadrivalent inactivated influenza vaccines in Uruguay: a cost-effectiveness analysis

ABSTRACT We evaluated the cost-utility of replacing trivalent influenza vaccine (TIV) with quadrivalent influenza vaccine (QIV) in the current target populations in Uruguay. An existing decision-analytic static cost-effectiveness model was adapted for Uruguay. The population was stratified into age groups. Costs and outcomes were estimated for an average influenza season, based on observed rates from 2013 to 2019 inclusive. Introducing QIV instead of TIV in Uruguay would avoid around 740 additional influenza cases, 500 GP consultations, 15 hospitalizations, and three deaths, and save around 300 workdays, for the same vaccination coverage during an average influenza season. Most of the influenza-related consultations and hospitalizations would be avoided among children ≤4 and adults ≥65 years of age. Using QIV rather than TIV would cost an additional ~US$729,000, but this would be partially offset by savings in consultations and hospitalization costs. The incremental cost per quality-adjusted life-year (QALY) gained with QIV would be in the order of US$18,000 for both the payor and societal perspectives, for all age groups, and around US$12,000 for adults ≥65 years of age. The main drivers influencing the incremental cost-effectiveness ratio were the vaccine efficacy against the B strains and the percentage of match each season with the B strain included in TIV. Probabilistic sensitivity analysis showed that switching to QIV would provide a favorable cost-utility ratio for 50% of simulations at a willingness-to-pay per QALY of US$20,000. A switch to QIV is expected to be cost-effective for the current target populations in Uruguay, particularly for older adults.

Efficacy and safety of a quadrivalent influenza vaccine in children aged 6–35 months: A global, multiseasonal, controlled, randomized Phase III study

BackgroundChildren are an important target group for influenza vaccination, but few studies have prospectively evaluated influenza vaccine efficacy (VE) in children under 3 years of age. This was a randomized Phase III trial to assess the efficacy, immunogenicity, and safety of an inactivated quadrivalent influenza vaccine (QIV) in young children (EudraCT: 2016–004904–74). MethodsInfluenza-naïve children aged 6–35 months were randomized during three influenza seasons to receive vaccination with QIV or a non-influenza control vaccine. One group of participants was revaccinated with QIV in the subsequent influenza season. The primary efficacy endpoint was the absolute VE of QIV against influenza caused by any circulating strain. Key secondary efficacy endpoints included the absolute VE of QIV against influenza due to antigenically matching strains and immunogenicity. Safety and reactogenicity were also evaluated. ResultsIn total, 1005 children received QIV and 995 received control vaccine. Influenza A/B infection due to any circulating influenza strain occurred less frequently in children who received QIV versus children receiving a control vaccine. The absolute VE of QIV against any circulating influenza strain was 54% (95% confidence interval [CI]: 37%, 66%). The absolute VE of QIV against antigenically matching influenza strains was 68% (95% CI: 45%, 81%). Mean hemagglutination inhibition titers for all influenza strains in the QIV group increased post-vaccination, whereas increases were minimal in the control vaccine group; results from virus neutralization and neuraminidase-inhibition assays were generally consistent with the hemagglutination inhibition assay findings. Approximately 12 months after primary vaccination with QIV, antibody titers remained higher than pre-vaccination titers for most strains. In participants who were revaccinated, QIV elicited strong antibody responses. The overall safety profile and reactogenicity of QIV was comparable with control vaccine. ConclusionPrimary vaccination with QIV was well tolerated and effective in protecting children aged 6–35 months against influenza.

Efficacy of a Cell-Based Influenza Vaccine in Children

Source: Nolan T, Fortanier AC, Leav B, et al. Efficacy of a cell-culture-derived quadrivalent influenza vaccine in children. N Engl J Med. 2021;385(16):1485-1495; doi:10.1056/NEJMoa2024848Investigators from multiple institutions conducted a randomized controlled trial to assess the efficacy of a cell-culture-derived quadrivalent inactivated influenza vaccine (IIV4c). Children ages 2 to <18 years from 8 countries: Australia, the Philippines, Thailand, Estonia, Finland, Lithuania, Poland, and Spain, were enrolled from May 25, 2017 to November 5, 2018 and followed during a total of 3 influenza seasons. At enrollment, participants were randomized to receive IIV4c, or a noninfluenza vaccine (meningococcal ACWY [Groups A, C, W-135, and Y] vaccine) as a control. IIV4c was derived from virus grown on Madin-Darby canine kidney cell lines and included 15 µg of hemagglutinin for 2 influenza A subtypes (H1N1 and H3N2) and 2 influenza B lineages (Yamagata and Victoria) per 0.5 mL dose. Parents of participants were contacted weekly and asked about symptoms consistent with influenza-like illness in their child (temperature ≥37.8°C and at least 1 of the following: cough, sore throat, nasal congestion, or rhinorrhea). A nasal swab was obtained on those with influenza-like illness and tested for influenza by PCR and culture. The primary outcome was first occurrence of influenza, confirmed by PCR and/or culture, occurring >14 days after the last vaccination until the end of the influenza season. Secondary outcomes included occurrence of specific influenza subtypes. Cox proportional-hazards models were used to compare occurrence of influenza in those randomized to IIV4c or the control vaccine; age, country, influenza season, and influenza vaccination history were included in the models. Vaccine efficacy was estimated as 1 minus the hazard ratio.A total of 4,514 participants with a mean age of 8.8 ± 4.1 years were enrolled; 50.7% were <9 years old. Among these children, 65.9% were previously vaccinated against influenza. Outcome data were analyzed on 4,509 participants. Overall, a total of 2,186 influenza-like illnesses were reported in 1,576 participants. Nasal swabs for PCR and culture were obtained during 97.4% of these illnesses, and first occurrence of influenza was confirmed in 539 participants, including 231 cases of influenza B (42.9%), 162 cases of influenza A/H3N2 (30.1%), and 126 of influenza A/H1N1 (23.4%). Among those randomized to IIV4c, influenza occurred in 175 of 2,257 participants (7.8%) vs 364 of 2,252 (16.2%) of those randomized to meningococcal ACWY. Overall efficacy of IIV4c was estimated at 54.6% (95% CI, 45.7, 62.1), 58.7% (95% CI, 47.5, 67.5) in children previously vaccinated, and 48.4% (95% CI, 32.1, 60.8) in those previously unvaccinated. Efficacy against A/H1N1, A/H3N2, and type B were 80.7% (95% CI, 69.2, 87.9), 42.1% (95% CI, 20.3, 57.9) and 47.6% (95% CI, 31.4, 60.0), respectively.The authors conclude that IIV4c was effective in preventing influenza.Dr Brady has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.Most pediatric influenza vaccines in the US are manufactured using virus strains grown in eggs (egg-based).1 During growth in eggs, an influenza virus may undergo mutations in the globular head of the hemagglutinin protein, the major epitope.2 Antibodies to the hemagglutinin elicited by egg-based vaccine strains may fail to recognize the hemagglutinin of wild-type influenza strains, even when the vaccine strains and circulating strains are well-matched.3 This has led to low influenza vaccine effectiveness, especially of the H3N2 vaccine strain, in recent seasons.2 Another disadvantage of egg-based influenza vaccines is the long response time to manufacture vaccines when a new influenza virus emerges.4The IIV4c vaccine has been available for adults and children ≥4 years old since 2016.5 In March 2021, approval was extended to children ≥2 years old based on efficacy data from the current study. In October 2021, approval was further extended to infants ≥6 months based on data from a phase 3 randomized controlled study of children aged 6-47 months.6,5Much of the world is still in the throes of a coronavirus pandemic.7 Influenza also has the potential to cause pandemics, which are difficult to predict.1 Newer vaccine platforms (eg, mRNA vaccines as used in SARS-CoV-2 vaccine development) may offer additional protection against influenza.7Cell-culture-derived influenza vaccines have been approved for children ≥6 months. They are safe and effective in preventing influenza in healthy children. (See AAP Grand Rounds. 2022;47[1]:3).8

Effectiveness of maternal vaccination with quadrivalent inactivated influenza vaccine in pregnant women and their infants in 2019-2020

ABSTRACT Objectives Influenza is associated with an increased risk for serious illness, hospitalization, and death in pregnant women and young infants. Our aim was to estimate the effectiveness of a quadrivalent inactivated influenza vaccine (QIV) in pregnant women and their infants during 2019–2020. Methods A QIV vaccine was offered to pregnant women followed in a maternity hospital. Women were contacted weekly during the influenza season and asked about symptoms. Polymerase chain reaction testing in pharyngeal samples was offered to pregnant women and infants with influenza-like illness. A Bayesian beta-binomial model was used. Results We studied 636 pregnant women (406 vaccinated and 230 unvaccinated) and 474 infants (281 of mothers vaccinated in pregnancy and 193 of unvaccinated mothers). Using a Bayesian beta-binomial model, it was estimated that influenza vaccination of pregnant women reduced their logit to develop laboratory-confirmed influenza by −4.2 (95% CI −3,7 − 4,7) and the logit of their infants to develop laboratory-confirmed influenza by −4.2 (95% CI −3.6, −4.9). The QIV effectiveness against laboratory-confirmed influenza was 43.5% in pregnant women and 31.4% in infants. Conclusion Maternal influenza vaccination with QIV in pregnancy reduced the odds of pregnant women and their infants to develop influenza. Clinical trial registration www.clinicaltrials.gov identifier is NCT04723771.

Lineage-matched versus mismatched influenza B vaccine effectiveness following seasons of marginal influenza B circulation

BackgroundSeveral countries have recently transitioned from the trivalent inactivated influenza vaccine (TIV) to the quadrivalent inactivated influenza vaccine (QIV) in order to outweigh influenza B vaccine-mismatch. However, few studies thus far evaluated its benefits versus the TIV in a systematic manner. Our objective was to compare the QIV VE with lineage-mismatched TIV VE. MethodsWe estimated the 2015–2016, 2017–2018, 2019–2020 end-of season influenza B VE against laboratory-confirmed influenza-like illness (ILI) among community patients, using the test-negative design. VE was estimated for pre-determined age groups and for moving age intervals of 15 years. ResultsSince 2011–2012 season, alternate seasons in Israel were dominated by influenza B circulation. Compared with the lineage-mismatched TIV used during the 2015–2016 and 2017–2018 seasons, the 2019–2020 QIV showed the highest all-ages VE, with VE estimates of 56.9 (95% CI 30.1 to 73.4), 16.5 (95% CI –22.5 to 43.1) and −25.8 (95% CI −85.3 to 14.6) for the 2019–2020, 2017–2018 and 2015–2016 seasons, respectively. The 2019–2020 VE point estimated were the highest for the 0.5–4, 5–17 and 18–44 years age groups and for more 15-year age intervals as compared to the other seasons. ConclusionsOur results support the rapid transition from the TIV to the QIV.

Safety of recombinant quadrivalent influenza vaccine compared to inactivated influenza vaccine in Chinese adults: An observational study

BackgroundRecombinant influenza vaccine (RIV) has been in use in US adults since 2013. This study evaluated the safety of quadrivalent recombinant influenza vaccine (RIV4, Flublok® Quadrivalent, Sanofi Pasteur) compared with standard-dose quadrivalent inactivated influenza vaccine (SD-IIV4) in self-identified Chinese adults at Kaiser Permanente Northern California (KPNC). MethodsThis study evaluated adults aged 18–64 years within KPNC during the 2018–2019 influenza season who self-identified as Chinese (NCT03694392). We compared the rates of prespecified diagnoses of interest in the emergency department and inpatient settings as done in prior influenza studies, for three risk intervals: 0–2 days, 0–13 days, and 0–41 days following influenza vaccination, as well as number of deaths within 0–180 days after vaccination. We estimated the odds ratios (ORs) and 95% confidence intervals using logistic regression adjusted for sex, age group, presence of comorbidities, and same-day concomitant vaccination. ResultsComparing 15,574 adults who received RIV4 with 27,110 who received SD-IIV4, there was no statistically significant difference in the prespecified diagnoses of interest and deaths between the 2 groups. There were 35 deaths total, none of which were considered to be related to influenza vaccination. ConclusionsThis study did not identify any safety concerns regarding RIV4 use among 18–64-year-olds who self-identified as Chinese. This study supports the safety of RIV4 vaccine in this population.

Brand-Specific Enhanced Safety Surveillance Study of GSK's Quadrivalent Seasonal Influenza Vaccine, Conducted During the COVID-19 Pandemic, in Belgium, Germany and Spain, for the 2020/21 Season.

IntroductionSeasonal influenza poses a major public health burden worldwide. Influenza vaccines, updated yearly to match circulating strains based on World Health Organization (WHO) recommendations, are the cornerstone of prevention and require regular monitoring. The COVID-19 pandemic is expected to cause logistical, site access and medical staff constraints and could affect the safety profile of influenza vaccines.MethodsFollowing European Medicines Agency guidance, an enhanced safety surveillance (ESS) study assessed the frequency and severity of predefined and other adverse events (AEs) occurring within 7 days of receiving GSK’s inactivated quadrivalent seasonal influenza vaccine (IIV4), in Belgium, Germany and Spain in 2020/21, using adverse drug reaction (ADR) cards.ResultsDuring the 2020/21 influenza season, 1054 participants vaccinated with GSK’s IIV4 were enrolled (all adults in Belgium and Germany, 30% adults/70% children in Spain); 96 eligible children received a second dose. Overall, 1042 participants completed the study. After doses 1 and 2, 98.9% and 100% of participants, respectively, returned their completed ADR card. After doses 1 and 2, 37.8% (398/1054) and 13.5% (13/96) of participants, respectively, reported at least one AE. The most frequently reported categories of AEs were “general disorders and administration site conditions” (e.g. injection site pain) and “nervous system disorders” (e.g. headache). There were no deaths or serious AEs deemed related to GSK’s IIV4.ConclusionThis ESS study assessed AEs in near real time. The COVID-19 pandemic did not alter the safety profile of GSK’s IIV4. No safety signals were detected during the study, which confirms the excellent safety profile of GSK’s IIV4.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00571-y.