Quadrivalent Inactivated Influenza Vaccine Research Articles

Quadrivalent Influenza Vaccine-Induced Antibody Response and Influencing Determinants in Patients ≥ 55 Years of Age in the 2018/2019 Season.

The effects of immunization with subunit inactivated quadrivalent influenza vaccine (QIV) are not generally well assessed in the elderly Polish population. Therefore, this study evaluated vaccine-induced antibody response and its determinants. Methods: Consecutive patients ≥ 55 years old, attending a Primary Care Clinic in Gryfino, Poland, received QIV (A/Michigan/ 45/2015(H1N1)pdm09, A/Singapore/INFIMH-16-0019/2016 (H3N2), B/Colorado/06/2017, B/Phuket/ 3073/2013) between October-December 2018. Hemagglutination inhibition assays measured antibody response to vaccine strains from pre/postvaccination serum samples. Geometric mean titer ratio (GMTR), protection rate (PR) and seroconversion rate (SR) were also calculated. Results: For 108 patients (54.6% males, mean age: 66.7 years) the highest GMTR (61.5-fold) was observed for A/H3N2/, then B/Colorado/06/2017 (10.3-fold), A/H1N1/pdm09 (8.4-fold) and B/Phuket/ 3073/2013 (3.0-fold). Most patients had post-vaccination protection for A/H3N2/ and B/Phuket/3073/ 2013 (64.8% and 70.4%, respectively); lower PRs were observed for A/H1N1/pdm09 (41.8%) and B/Colorado/06/ 2017 (57.4%). The SRs for A/H3N2/, A/H1N1/pdm09, B Victoria and B Yamagata were 64.8%, 38.0%, 46.8%, and 48.2%, respectively. Patients who received QIV vaccination in the previous season presented lower (p < 0.001 and p = 0.03, respectively) response to B Victoria and B Yamagata. Conclusions: QIV was immunogenic against the additional B lineage strain (B Victoria) without significantly compromising the immunogenicity of the other three vaccine strains, therefore, adding a second B lineage strain in QIV could broaden protection against influenza B infection in this age group. As the QIV immunogenicity differed regarding the four antigens, formulation adjustments to increase the antigen concentration of the serotypes that have lower immunogenicity could increase effectiveness. Prior season vaccination was associated with lower antibody response to a new vaccine, although not consistent through the vaccine strains.

Formulation Design, Optimization and In Vivo Evaluations of an α-Tocopherol-Containing Self-Emulsified Adjuvant System using Inactivated Influenza Vaccine

α-Tocopherol has been used as an immune supplement in humans, as an emulsion adjuvant component in several veterinary vaccines as well as an immunomodulatory component of AS03, an emulsion adjuvant that was used in an H1N1 pandemic vaccine (Pandemrix). AS03 is manufactured using microfluidization and high-pressure homogenization. Such high energy and complex manufacturing processes make it difficult and expensive to produce emulsion adjuvants on a large scale, especially in developing countries. In this study we have explored simpler, comparatively inexpensive methods, to formulate emulsion adjuvants containing α-tocopherol, that have the potential to be made in any well-established scale-up facility. This might facilitate producing and stock-piling adjuvant doses and therefore aide in pandemic preparedness. We used design of experiment as a tool to explore incorporating α-tocopherol into self-emulsified systems containing squalene oil and polysorbate 80. We created novel self-emulsified adjuvant systems (SE-AS) and evaluated their potency in vivo in BALB/c mice with inactivated quadrivalent influenza vaccine (QIV) and tested the cellular and humoral immune responses against the four vaccine strains.

Responses to Quadrivalent Influenza Vaccine Reveal Distinct Circulating CD4+CXCR5+ T Cell Subsets in Men Living with HIV

T cell help for B cells may be perturbed in people living with HIV (PLWH), even when HIV is suppressed, as evidenced by reports of suboptimal responses to influenza vaccination. We investigated cTFH responses to the 2017–18 inactivated quadrivalent influenza vaccine (QIV) in men living with antiretroviral therapy (ART)-suppressed HIV infection who were treated in the early or chronic phase of infection, and control subjects. Here we show that seroprotective antibody responses in serum and oral fluid correlated with cTFH activation and were equivalent in all three groups, irrespective of when ART was started. These responses were attenuated in those reporting immunisation with influenza vaccine in the preceding three years, independent of HIV infection. Measurement of influenza-specific IgG in oral fluid was closely correlated with haemagglutination inhibition titre. T-SNE and two-dimensional analysis revealed a subset of CD4+CXCR3+CXCR5+ cTFH activated at one week after vaccination. This was distinguishable from cTFH not activated by vaccination, and a rare, effector memory CD4+CXCR5hiCD32hi T cell subset. The data support the use of QIV for immunisation of PLWH, reveal distinct circulating CD4+CXCR5+ T cell subsets and demonstrate oral fluid sampling for influenza-specific IgG is an alternative to phlebotomy.

LB12. A Randomized Controlled Trial of Antibody Response to 2018–2019 Cell-based vs. Egg-based Quadrivalent Inactivated Influenza Vaccine in Children

BackgroundWhile vaccine effectiveness varies across seasons and age groups, influenza vaccination is still the most effective means of preventing influenza infection. Current vaccine effectiveness improvement efforts are focused on manufacturing methods whereby the use of eggs as a growth medium is being minimized to prevent egg adaptation mutations that render the vaccine less effective. This study compared children’s immune response to two FDA-approved influenza vaccines, cell-based vs. egg-based, in an unblinded randomized controlled trial.MethodsRacially diverse, healthy children ages 4–20 years were randomly assigned 1:1 in blocks of 4 to receiveeither quadrivalent inactivated cell-based or egg-based influenza vaccine. Blood was drawn at Day 0 before vaccination and at Day 28 post vaccination (range = 19–35 days) and analyzed for hemagglutination inhibition (HAI) titers using standard protocols against egg-grown vaccine antigens. Primary outcome measures were seropositivity, defined as HAI titer ≥1:110 and ≥1:40; seroconversion, defined as the HAI titer ratio of Day 28/Day 0 ≥4 and HAI titer at Day 28 ≥40; and fold-rise, defined as antilog of average log2HAI titer ratio of Day 28/Day 0. Secondary outcomes were compared for those vaccinated and not vaccinated the previous year.ResultsBaseline demographics including age, sex, race, ethnicity, parental educational status, health insurance coverage, and exposure to household smoking did not differ between vaccine groups. There were no differences in any HAI antibody response between the two vaccine groups (table). Participants unvaccinated in the prior season (2017–2018, N = 62) were more likely than those vaccinated (N = 86) to seroconvert to any strain in 2018–2019 (≥1 strain seroconverted: 68% unvaccinated vs. 35% vaccinated in 2017–2018, P < 0.001). Day 28 titer fold-rise difference was 2.0 for A/H1N1, 0.65 for A/H3N2, 1.1 for B/Colorado and 0.9 for B/Phuket.ConclusionThere were no differences for any HAI antibody titer outcome between children receiving the two vaccines. Overall, the cohort had HAI titers at levels sufficient to be considered seropositive at baseline. Those unvaccinated in the preceding season had higher seroconversion rates than those vaccinated in both seasons. DisclosuresPatricia Nowalk, PhD, Merck & Co. (Grant/Research Support); others, no reported disclosures .

Effectiveness of influenza vaccine in children in preventing influenza associated hospitalisation, 2018/19, England

2013/14 saw the start of the introduction of a new live attenuated influenza vaccine (LAIV) programme for children in England. 2018/19 saw co-circulation of both A(H1N1)pdm09 and A(H3N2), when LAIV was offered to all healthy children 2–9 years of age. LAIV effectiveness against influenza hospitalisation is not well described. This paper presents the 2018/19 end-of-season adjusted vaccine effectiveness (aVE) against laboratory confirmed influenza related hospitalisation in children aged 2–17. The test negative case control approach was used to estimate aVE by influenza A subtype and vaccine type. Cases and controls were selected from a sentinel laboratory surveillance system which collates details of individuals tested for influenza with reverse-transcription polymerase chain reaction (RT-PCR) on respiratory samples. Vaccine and clinical history was obtained from general practitioners of study participants. There were 307 hospitalised cases and 679 hospitalised controls. End-of-season influenza aVE was 53.0% (95% CI: 33.3, 66.8) against influenza confirmed hospitalisation; 63.5% (95% CI: 34.4, 79.7) against influenza A(H1N1)pdm09 hospitalisation and 31.1% (95% CI: −53.9, 69.2) against influenza A(H3N2). LAIV aVE was 49.1% (95% CI: 25.9, 65.0) for any influenza and 70.7% (95% CI: 41.8, 85.3) for A(H1N1)pdm09, whereas for those receiving quadrivalent inactivated influenza vaccine (QIV), aVE was 64.4% (95% CI: 29.4, 82.0) and 44.4% (95% CI: −51.9, 79.6) respectively. We provide evidence of overall significant VE for both LAIV and QIV against influenza associated hospitalisation in children 2–17 years of age, most notably against influenza A(H1N1)pdm09, with non-significant protection against A(H3N2).

Enhanced Safety Surveillance of GSK's Quadrivalent Seasonal Influenza Vaccine in Belgium, Germany, and Spain for the 2018/19 Season: Interim Analysis.

IntroductionInfluenza is an important cause of morbidity and mortality in Europe. Prevention by annual vaccination is most effective but with yearly vaccine reformulation to match circulating virus strains, vaccine safety must be continuously monitored. The European Medicines Agency published guidance on safety monitoring of influenza vaccines.MethodsAn enhanced safety surveillance study of GSK’s inactivated quadrivalent influenza vaccine (IIV4) was conducted in Belgium, Germany, and Spain in influenza season 2018/19. The objective was to collect adverse event (AE) reports from subjects within 7 days of vaccination. A customized AE reporting card (AERC) with predefined AEs of interest was used to rapidly detect and evaluate potential new safety concerns. Interim results are presented here.ResultsBetween week 40 and 52, 1060 vaccinated subjects were enrolled (31.0% Belgium, 26.2% Germany, and 42.7% Spain) covering all ages for which IIV4 is indicated (32.0% aged 6 months–17 years, 33.8% 18–65 years, and 34.2% over 65 years). Pediatric subjects less than 9 years old (n = 139) received two doses. Following dose 1 and dose 2, 98.2% and 100%, respectively, returned the completed AERC recording any AEs. Following dose 1 and dose 2, 454 and 34 subjects, respectively, reported at least one AE (most frequently expected general and injection site symptoms and respiratory symptoms).ConclusionAll reported AEs were expected as per summary product characteristics (smPC). No safety signals that impact public health or alter the benefit–risk profile of GSK’s IIV4 were identified. Subjects from all vaccinated age groups were enrolled and the use of AERCs allowed rapid monitoring and analysis of reported AEs.Trial RegistrationClinicalTrials.gov identifier, NCT03688620.FundingGlaxoSmithKline Biologicals SA.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01105-2) contains supplementary material, which is available to authorized users.

Immunogenicity and safety of a quadrivalent inactivated influenza vaccine in pregnant women: a randomized, observer-blind trial

ABSTRACT Vaccination against influenza during pregnancy provides direct protection to pregnant women and indirect protection to their infants. Trivalent inactivated influenza vaccines (IIV3s) are safe and effective during pregnancy, but quadrivalent inactivated influenza vaccines (IIV4s) have not been evaluated in pregnant women and their infants. Here, we report the results of a randomized phase IV study to evaluate the immunogenicity and safety of IIV4 vs. IIV3 in pregnant women. Participants aged ≥18 years at weeks 20 to 32 of gestation were randomly assigned in a 2:1 ratio to receive a single dose of IIV4 (n = 230) or IIV3 (n = 116). Between baseline and 21 days after vaccination, hemagglutination inhibition (HAI) antibody titers increased in both groups by similar magnitudes for the two influenza A strains and single B strain common to IIV4 and IIV3. For the additional B strain in IIV4, HAI titers were higher in IIV4 recipients than IIV3 recipients (post-/pre-vaccination geometric mean titer ratio, 6.3 [95% CI: 5.1 − 7.7] vs. 3.4 [95% CI: 2.7 − 4.3]). At delivery, in both groups, HAI antibody titers for all strains were 1.5 − 1.9-fold higher in umbilical cord blood than in maternal blood, confirming active transplacental antibody transfer. Rates of solicited and unsolicited vaccine-related adverse events in mothers were similar between the two groups. Live births were reported for all participants and there were no vaccine-related adverse events in newborns. These results suggest IIV4 is as safe and immunogenic as IIV3 in pregnant women, and that maternal immunization with IIV4 should protect newborns against influenza via passively acquired antibodies.

A phase IIb study to determine the safety and efficacy of candidate INfluenza Vaccine MVA-NP+M1 in combination with licensed Ina CTivated infl Uenza vaccine in adult S aged 65 years and above (INVICTUS): a study protocol

Seasonal influenza has a significant annual global impact. Current influenza vaccines work by inducing strain-specific antibodies against the highly polymorphic surface proteins of the influenza virus and need to be redesigned every year, increasing their cost and limiting availability. There is a demand for a more efficacious vaccine, particularly in older adults in which the current vaccines show poor efficacy. The aim is to investigate a novel vaccine, MVA-NP+M1, which targets T cell responses to the nucleoprotein and matrix 1 core proteins of the influenza virus A, which are highly conserved, and therefore may provide long protection against a broad range of influenza strains. INVICTUS is a phase IIb study to determine the safety and efficacy of candidate INfluenza Vaccine MVA-NP+M1 in combination with licensed Ina CTivated infl Uenza vaccine in adult S aged 65 years and above is a randomised, participant-blinded, placebo-controlled, multi-centre phase IIb efficacy study planned for 2030 volunteers aged 65 and over, in primary care. The primary objective is to assess the efficacy of MVA-NP+M1 co-administered with licensed inactivated quadrivalent influenza vaccine in adults ≥65 years. Participants complete daily diaries to record solicited and unsolicited events in the first four weeks post vaccination, and influenza-like illness (ILI) symptoms and severity throughout the influenza season. We hypothesise an improvement in the primary outcome, a reduction in the average number of days spent with moderate or severe influenza-like illness during periods of influenza circulation, in the group administered with MVA-NP+M1, compared to those in the control group. Registration: ClinicalTrials.gov identifier NCT03300362. Protocol version: INVICTUS Protocol v3.0, 08 June06 2018.

Effects of probiotic administration on immune responses of children and adolescents with type 1 diabetes to a quadrivalent inactivated influenza vaccine

ABSTRACTThis study was planned to evaluate whether a 3-month treatment with Lactobacillus rhamnosus GG (LGG) can modify immune system functions in children and adolescents with type 1 diabetes (T1D), leading to an increased immune response to an injectable quadrivalent inactivated influenza vaccine (QIV). A total of 87 pediatric patients with T1D were screened, although 34 patients in the Probiotic group and 30 in the Control group accepted to be vaccinated with QIV and completed the study. Vaccine immunogenicity and safety and the inflammatory cytokine response were studied. Results showed that QIV was immunogenic and safe in T1D pediatric patients and pre-administration of LGG for three months did not substantially modify the QIV humoral immunity. The combination of QIV and LGG reduced inflammatory responses (i.e., IFN-γ, IL17A, IL-17F, IL-6, and TNF-α) from activated PBMCs of pediatric patients with T1D, without dampening the production of seroprotective antibodies. In conclusion, QIV is associated with an adequate immunogenicity in children and adolescents with T1D in presence of a good safety profile. Although a systematic administration of LGG did not result in an improvement of humoral responses to an influenza vaccine, the probiotic did induce important anti-inflammatory effects.

Randomized, single-blind, active-controlled phase I clinical trial to evaluate the immunogenicity and safety of GC3114 (high-dose, quadrivalent influenza vaccine) in healthy adults

Influenza is a major medically attended respiratory illness. The impact of influenza on morbidity and mortality is particularly high in the elderly. Immunosenescence attenuates the immune response of influenza vaccine in the elderly. High-dose influenza vaccine contains 60 μg of hemagglutinin per strain, four times more compared with standard-dose (SD) influenza vaccine. This study is a phase I clinical trial investigating the immunogenicity and safety of the GC3114, high-dose, quadrivalent inactivated influenza vaccine (HD-QIV) in healthy adults aged 19–64 years during the 2017–2018 season. Seroprotection rates of HD-QIV were 100.0% for A/H1N1, 96.67% for A/H3N2, 83.33% for B/Yamagata, and 96.67% for B/Victoria. Seroconversion rate for A/H1N1, A/H3N2, B/Yamagata, and B/Victoria strains were 86.67%, 90.0%, 53.33%, and 53.33%, respectively, in the HD-QIV group. The post-/pre-vaccination geometric mean titer ratio (GMTR) was 15.28 for A/H1N1, 8.19 for A/H3N2, 3.56 for B/Yamagata, and 3.03 for B/Victoria in the HD-QIV group. Seroconversion rate and post-/pre-vaccination GMTR for A/H3N2 were significantly higher in the HD-QIV group than in the SD-QIV group (control). No serious adverse events were reported. In conclusion, GC3114 was safe, well-tolerated, and immunogenic in healthy adults. Clinical Trials Identifier: NCT03357263.

Recommended immunization schedule for children and adolescents: Committee on Infectious Diseases of the Korean Pediatric Society, 2018.

The Committee on Infectious Diseases of the Korean Pediatric Society recommended immunization schedule for children and adolescents aged 18 years or younger in the 9th (2018) edition of Immunization guideline. This report provides the revised recommendations made by the committee and summarizes several changes from the 2015 guideline. National immunization program (NIP) launched a human papillomavirus (HPV) immunization for girls aged 12 years in 2016. NIP has also expanded age indication for inactivated influenza vaccine (IIV) to 12 years of age in the 2018-2019 season. Quadrivalent IIVs with a full dose (0.5 mL) are approved for all children of 6 months or older. Recommendations of live attenuated influenza vaccine were removed. For inactivated Japanese encephalitis vaccine, first 2 doses are considered as the primary series. Recommendations for use of newly introduced vaccines (diphtheria-tetanus-acellular pertussis/inactivated poliovirus/Haemophilus influenzae type b, 9-valent HPV, new varicella vaccine, new quadrivalent IIV, and attenuated oral typhoid vaccine) were added. Lastly, monitoring system for adverse events following immunization was updated. Other changes can be found in the 9th edition of Immunization guideline in detail.

The Effect of Influenza Vaccination History on Changes in Hemagglutination Inhibition Titers After Receipt of the 2015-2016 Influenza Vaccine in Older Adults in Hong Kong.

Immune responses to influenza vaccination can be weaker in older adults than in other age groups. We hypothesized that antibody responses would be particularly weak among repeat vaccinees when the current and prior season vaccine components are the same. An observational study was conducted among 827 older adults (aged ≥75 years) in Hong Kong. Serum samples were collected immediately before and 1 month after receipt of the 2015-2016 quadrivalent inactivated influenza vaccine. We measured antibody titers with the hemagglutination inhibition assay and compared the mean fold rise from prevaccination to postvaccination titers and the proportions with postvaccination titers ≥40 or ≥160. Participants who reported receipt of vaccination during either of the previous 2 years had a lower mean fold rise against all strains than with those who did not. Mean fold rises for A(H3N2) and B/Yamagata were particularly weak after repeated vaccination with the same vaccine strain, but we did not generally find significant differences in the proportions of participants with postvaccination titers ≥40 and ≥160. Overall, we found that reduced antibody responses in repeat vaccinees were particularly reduced among older adults who had received vaccination against the same strains in preceding years.

Summary of the NACI Seasonal Influenza Vaccine Statement for 2019-2020.

Many different influenza vaccines are authorized for use in Canada and new evidence on influenza and vaccines is continually emerging. The National Advisory Committee on Immunization (NACI) provides annual recommendations regarding the use of seasonal influenza vaccines to the Public Health Agency of Canada (PHAC) for the upcoming influenza season. To summarize NACI recommendations regarding the use of seasonal influenza vaccines for the 2019-2020 influenza season, including conclusions from reviews of evidence on 1) a new split virus quadrivalent inactivated influenza vaccine and 2) the comparative effectiveness and immunogenicity of subunit and split virus inactivated influenza vaccines in adults 65 years of age and older. For both topics, the NACI Influenza Working Group developed a predefined search strategy to identify all eligible studies, assessed their quality, summarized and analyzed the findings and, according to the NACI evidence-based process, proposed recommendations and identified the grade of evidence that supported them. In light of the evidence, the recommendations were then considered and approved by NACI. NACI concluded that the new split virus quadrivalent inactivated influenza vaccine has a safety and immunogenicity profile comparable to the quadrivalent inactivated influenza vaccines already authorized for adults and children 5 years of age and older (Grade B Evidence). Therefore, NACI recommended that this new vaccine may be considered among the quadrivalent inactivated influenza vaccines offered to adults and children five years of age and older (Discretionary NACI Recommendation). However, NACI concluded that the evidence is not sufficient (Grade I Evidence) to support specific recommendations on the differential use of subunit and split virus inactivated influenza vaccines in adults 65 years of age and older. NACI continues to recommend that an age-appropriate influenza vaccine should be offered annually to anyone six months of age and older who does not have contraindications to the vaccine, with focus on the groups for whom influenza vaccination is particularly recommended. This includes people at high risk of influenza-related complications or hospitalization, people capable of transmitting influenza to those at high risk, people who provide essential community services and people in direct contact with poultry infected with avian influenza during culling operations.

Influenza vaccination in the elderly: 25 years follow-up of a randomized controlled trial. No impact on long-term mortality.

Influenza vaccination is proven effective in preventing influenza. However, long-term effects on mortality have never been supported by direct evidence. In this study we assessed the long-term outcome of influenza vaccination on mortality in the elderly by conducting a 25-year follow-up study of a RCT on the efficacy of influenza vaccination as baseline. The RCT had been conducted in the Netherlands 5 years before vaccination was recommended for those aged >65 and 17 years before recommending it for those aged >60. The RCT included 1838 community-dwelling elderly aged ≥ 60 that had received an intramuscular injection with the inactivated quadrivalent influenza vaccine (n = 927) or placebo (n = 911) during the 1991/1992 winter. In our follow-up study, outcomes included all-cause mortality, influenza-related mortality and seasonal mortality. Unadjusted and adjusted hazard ratios (HRs) were estimated by Cox regression and sub-hazard ratios (SHRs) by competing risk models. Secondary analyses included subgroup analyses by age and disease status. The vital status up to January 1, 2017 was provided in 1800/1838 (98%) of the cases. Single influenza vaccination did not reduce all-cause mortality when compared to placebo (adjusted HR 0.95, 95% CI 0.85−1.05). Also, no differences between vaccination and placebo group were shown for underlying causes of death or seasonal mortality. In those aged 60–64, median survival increased with 20.1 months (95% CI 2.4–37.9), although no effects on all-cause mortality (adjusted HR 0.86, 95% CI 0.72−1.03) could be demonstrated in survival analysis. In conclusion, this study did not demonstrate a statistically significant effect following single influenza vaccination on long-term mortality in community-dwelling elderly in general. We propose researchers designing future studies on influenza vaccination in the elderly to fit these studies for longer-term follow-up, and suggest age-group comparisons in observational research.Clinical trial registry number: NTR6179.

Modification of the vaccine manufacturing process improves the pyrogenicity profile of inactivated influenza vaccines in young children

BackgroundThere were increased reports of fevers and febrile reactions in young children (particularly children aged <5 years) receiving the Seqirus/CSL Southern Hemisphere 2010 trivalent inactivated influenza vaccine (IIV3). Modifying the vaccine manufacturing process by increasing the minimum concentration of splitting agent (sodium taurodeoxycholate [TDOC]) from 0.5% w/v to 1.5% w/v for all strains resolved this issue. The current analysis compared fever rates in three pediatric studies of Seqirus IIV3 (S-IIV3) or quadrivalent inactivated influenza vaccine (S-IIV4), prepared using the modified manufacturing process, with fever rates in three pediatric studies of historical (pre-2010) IIV3 formulations. The historical IIV3 formulations, S-IIV3, and S-IIV4 had 0/3, 2/3, and 4/4 vaccine strains split at 1.5% TDOC, respectively. MethodsFor each study, fever rates (any grade and severe) were determined for the following age subgroups (as applicable), using the fever intensity grading system used in the S-IIV3/S-IIV4 studies: 6 months to <3 years; 3 to <5 years; 5 to <9 years; and 9 to <18 years. ResultsFor each age subgroup, the any grade and severe fever rates were lower in the S-IIV3/S-IIV4 studies than in the historical IIV3 formulation studies, with the greatest differences in fever rates observed in the youngest age groups. In the 6 months to <3 years group, the any grade fever rate was 7.0% (severe fever: 2.5%) in one S-IIV4 study compared with 38.7% to 40.0% (severe fever: 9.6% to 17.8%) in the historical IIV3 formulation studies. In the 3 to <5 years subgroup, the any grade fever rate was 4.9% (severe fever: 1.2%) in one S-IIV4 study compared with 34.1% to 36.0% (severe fever: 6.3% to 16.5%) in the historical IIV3 formulation studies. ConclusionThis analysis provides clinical evidence that the modified manufacturing process improved the fever profile across all pediatric age groups, in particular, in children aged <5 years.

Immunogenicity and safety of an intramuscular split-virion quadrivalent inactivated influenza vaccine in individuals aged ≥ 6 months in India

ABSTRACT A quadrivalent split-virion inactivated influenza vaccine (IIV4; Fluzone® Quadrivalent, Sanofi Pasteur) has been available in the US since 2013 for individuals aged ≥ 6 months. Here, we describe the results of an open-label, multicenter trial (WHO Universal Trial Number U1111-1143–8370) evaluating the immunogenicity and safety of IIV4 in Indian children aged 6–35 months and 3–8 years, adolescents aged 9–17 years, and adults aged ≥ 18 years (n = 100 per group). Post-vaccination hemagglutination inhibition titers for all strains in all age groups were ≥ 8 fold higher than at baseline (range, 8–51). At least 70% of participants in all age groups seroconverted or had a significant increase in titer for each strain. The most common solicited reactions were injection-site pain and tenderness, plus fever in participants 6–23 months and myalgia in older children and adolescents. All injection-site reactions and most systemic reactions were grade 1 or 2 and resolved within 3 days. Only three vaccine-related unsolicited adverse events were reported, all of which were grade 1 or 2 and transient. No immediate adverse events, adverse events leading to study discontinuation, adverse events of special interest, or serious adverse events were reported. This study showed that IIV4 was well tolerated and highly immunogenic in all age groups. This adds important data on the safety, tolerability, and immunogenicity of influenza vaccines in India.

Effect of Previous-Season Influenza Vaccination on Serologic Response in Children During 3 Seasons, 2013-2014 Through 2015-2016.

BackgroundThe effects of repeated influenza vaccination in children are not well understood. In this study, we evaluated previous vaccination effects on antibody response after vaccination with trivalent inactivated influenza vaccine (IIV) or quadrivalent live-attenuated influenza vaccine (LAIV) among school-aged children (5–17 years) across 3 seasons.MethodsChildren were enrolled in the fall of 2013, 2014, and 2015. The participants received IIV or LAIV according to parent preference (2013–2014) or our randomization scheme (2014–2015). All study children received IIV in 2015–2016. Hemagglutination-inhibition assays measured antibody response to egg-grown vaccine strains from prevaccination and postvaccination serum samples. Geometric mean titers (GMTs) and increases in GMTs from before to after vaccination (geometric mean fold rise [GMFR]) were estimated from repeated-measures linear mixed models.ResultsWe enrolled 161 children in 2013–2014, 128 in 2014–2015, and 126 in 2015–2016. Among the IIV recipients, responses to the influenza A(H1N1)pdm09 and B vaccine strains were lowest among children who had received a previous-season IIV. The GMFRs for strains A(H1N1)pdm09 and B were 1.5 to 2.3 for previous-season IIV and 4.3 to 12.9 for previous-season LAIV or no previous vaccine. GMFRs were lower for strain A(H3N2), and differences according to previous-season vaccination history were smaller and not significant in most seasons. Most children had a post-IIV vaccination titer of ≥40 for vaccine strains in all seasons, regardless of previous-season vaccination history. Little to no increase in antibody levels was observed after vaccination with LAIV.ConclusionsSerologic response to vaccination was greatest for IIV, but previous-season vaccination modified IIV response to A(H1N1)pdm09 and B. Influenza A(H3N2) responses were low in all groups, and LAIV generated minimal serologic response against all strains.

Impact of a quadrivalent inactivated influenza vaccine on influenza-associated complications and health care use in children aged 6 to 35 months: Analysis of data from a phase III trial in the Northern and Southern Hemispheres

BackgroundA multi-season phase III trial conducted in the Northern and Southern Hemispheres demonstrated the efficacy of a quadrivalent split-virion inactivated influenza vaccine (IIV4) in children 6–35 months of age. MethodsData collected during the phase III trial were analysed to examine the vaccine efficacy (VE) of IIV4 in preventing laboratory-confirmed influenza in age subgroups and to determine the relative risk for IIV4 vs. placebo for severe outcomes, healthcare use, and parental absenteeism from work associated with laboratory-confirmed influenza. ResultsVE (95% confidence interval [CI]) to prevent laboratory-confirmed influenza due to any A or B strain was 54.76% (40.24–66.03%) for participants aged 6–23 months and 46.91% (23.57–63.53%) for participants aged 24–35 months. VE (95% CI) to prevent laboratory-confirmed influenza due to vaccine-similar strains was 74.51% (53.55–86.91%) for participants aged 6–23 months and 59.78% (19.11–81.25%) for participants aged 24–35 months. Compared to placebo, IIV4 reduced the risk (95% CI) by 31.28% (8.96–89.34%) for acute otitis media, 21.76% (6.46–58.51%) for acute lower respiratory infection, 40.80% (29.62–55.59%) for healthcare medical visits, 29.71% (11.66–67.23%) for parent absenteeism from work, and 39.20% (26.89–56.24%) for antibiotic use. ConclusionIn children aged 6–35 months, vaccination with IIV4 reduces severe outcomes of influenza as well as the associated burden for their parents and the healthcare system. In addition, vaccination with IIV4 is effective at preventing against influenza in children aged 6–23 and 24–35 months.Trial registration: EudraCT no. 2013-001231-51.

Effectiveness of the quadrivalent inactivated influenza vaccine in Japan during the 2015–2016 season: A test-negative case-control study comparing the results by real time PCR, virus isolation

BackgroundWe estimated influenza vaccine effectiveness (VE) in 2015–2016 season against medically attended, laboratory-confirmed influenza, when quadrivalent inactivated vaccine (IIV4) was first introduced in Japan, using test-negative case-control design. Influenza A(H1N1)pdm09 cocirculated with B/Yamagata and B/Victoria during the study period in Japan. MethodWe based our case definition on two laboratory tests, real-time reverse transcription polymerase chain reaction (RT PCR), and virus isolation and compared VEs based on these tests. In addition, VE was evaluated by rapid diagnostic test (RDT). Nasopharyngeal swabs were collected from outpatients who visited clinics with influenza-like illness (ILIs) in Hokkaido, Niigata, Gunma and Nagasaki prefectures. ResultsAmong 713 children and adults enrolled in this study, 578 were influenza positive by RT PCR including, 392 influenza A and 186 influenza B, while 135 were tested negative controls. The adjusted VE by RT PCR for all ages against any influenza was low protection of 36.0% (95% confidence interval [CI], 3.1% to 58.6%), for influenza A was 30.0% (95% CI: −10.0% to 55.5%), and influenza B was moderate 50.2% (95% CI: 13.3% to 71.4%). Adjusted VE for virus isolation for A(H1N1)pdm09 was 37.1% (95% CI: 1.7% to 59.7%), Yamagata lineage 51.3% (95% CI: 6.4% to 74.7%) and Victoria lineage 21.3% (95% CI: −50.0% to 58.9%). VE was highest and protective in 0–5 years old group against any influenza and influenza A and B/Yamagata, but the protective effect was not observed for other age groups and B/Victoria. RDT demonstrated concordant results with RT PCR and virus isolation. Sequencing of hemagglutinin gene showed that all A(H1N1)pdm09 belong to clade 6B including 31 strains (88.6%), which belong to clade 6B.1 possessing S162N mutations that may alter antigenicity and affect VE for A(H1N1)pdm09. ConclusionsIIV4 influenza vaccine during 2015–2016 was effective against A(H1N1)pdm09 and the two lineages of type B. Younger children was more protected than older children and adults by vaccination.

Flucelvax Tetra: a surface antigen, inactivated, influenza vaccine prepared in cell cultures

On 18 October 2018, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion on the inactivated cell-based quadrivalent influenza vaccine Flucelvax Tetra for the use in adults and in children aged 9 years and above.1 Influenza is a major cause of illness and mortality worldwide. Clinical attack rates often range from 10% to 20% in the general community during epidemics and can be as high as 50% in closed populations, such as schools or nursing homes.2 According to the WHO, influenza causes annually three to five million cases of severe respiratory tract infections and is estimated to result in 290 000–650 000 respiratory deaths per year globally.3 During pandemics, such as the 1918 pandemic, the death toll has been estimated to be as high as 40 million.2 Vaccination against influenza does not confer complete protection but it has been consistently shown to have an important impact on morbidity and has therefor become an important public health intervention to protect vulnerable patient populations. Since many years several commercial influenza vaccine products are available in Europe, so that one have to ask what are the advantages of the latest registered influenza vaccine …