Split-virion Inactivated Influenza Vaccine Research Articles

Safety and Immunogenicity of a Carbohydrate Fatty Acid Monosulphate Ester Adjuvant Combined with a Low-Dose Quadrivalent Split-Virion Inactivated Influenza Vaccine: A Randomised, Observer-Blind, Active-Controlled, First-in-Human, Phase 1 Study.

Seasonal influenza vaccine effectiveness is low. Carbohydrate fatty acid monosulphate ester (CMS), a new oil-in-water adjuvant, has proven potency in animal models with suggested capacity for dose-sparing. The objective was to evaluate safety and immunogenicity of CMS when added to a low-dose influenza vaccine (QIV) in humans. In a randomised, double-blind, active-controlled, first-in-human study, sixty participants (18-50 years) received either 0.5 mg CMS or 2 mg CMS with 1/5th dose QIV, or a full dose QIV without CMS. Adverse events (AE) were monitored until 7 days post-vaccination. Haemagglutinin inhibition (HI) titres in serum and CD4+ T cells in PBMCs were determined at day 0, 7, 28, and 180. Mean age was 37.6 (±10.1) years and 42/60 (70.0%) were female. Pain at injection site (42/60, 86.7%) and headache (34/60, 56.7%) were reported most and more frequently in the 2 mg CMS group. HI titres and the frequency of influenza specific CD4+ T cells were equal across strains for the three cohorts on all visits, increased until day 28 and decreased at day 180 to values higher than baseline. CMS was safe in humans. Humoral and cell-mediated immunogenicity was similar across vaccines, even with 1/5th antigen dose. CMS can have beneficial implications in low-resource settings or in a pandemic context.

Immunogenicity and safety of the quadrivalent inactivated split-virion influenza vaccine in populations aged ≥ 3 years: A phase 3, randomized, double-blind, non-inferiority clinical trial

ABSTRACT This study aimed to evaluate the immunogenicity non-inferiority and safety of the quadrivalent inactivated split-virion influenza vaccine in participants ≥ 3 years old. A total of 3,328 participants were enrolled. Participants 3–8 years old were administered one or two doses of the investigational vaccine or one dose of the control vaccine, whereas the other participants were administered only one dose of the investigational or control vaccine. The immunogenicity and occurrence of adverse events (AEs) after 30 days of full-course vaccination and serious adverse events (SAEs) within 6 months after full-course vaccination were assessed. The sero-conversion rates (SCRs) of anti-H1N1, H3N2, B(Y), and B(V) antibodies in the test group were 74.64%, 87.40%, 82.66%, and 78.89%, respectively, and their geometric mean titers were 1:250.13, 1:394.54, 1:200.84, and 1:94.91, respectively, which were non-inferior to those in the control group. The SCRs and sero-protection rates in the two-dose group of participants 3–8 years old were greater than those in the one-dose group. The incidences of total AEs and adverse reactions in the test group were 31.6% and 21.7%, respectively, which were close to those in the control group. In the two-dose group, the incidence of adverse reactions was considerably lower in the second dose (5.5%) than in the first dose (14.7%). Most AEs were grade 1 in severity, and no SAEs were recorded. The investigational vaccine had immunogenicity non-inferior to the control vaccine, and two doses were more effective than one dose in participants 3–8 years old, with a good overall safety. Trial registration: CTR20200715.

Post-Marketing Safety Surveillance of Quadrivalent Influenza Vaccine (VaxigripTetra) in Children Aged 6 to 35Months in South Korea.

The quadrivalent inactivated split-virion influenza vaccine (QIV; VaxigripTetra®) was initially licensed in South Korea in 2017 for immunization against seasonal influenza in those aged ≥ 3years, with the indicated age subsequently lowered to include those aged ≥ 6months in 2018. Here, to comply with South Korean licensure requirements, we undertook a post-marketing surveillance study to assess the safety of QIV in children aged 6-35months (i.e., extension of the previous age indication to include these young children) in routine clinical practice. A multicenter, observational, active safety surveillance of children aged 6-35months who received a single dose of QIV during a routine healthcare visit was undertaken in South Korea from 15June 2018 to 14June 2022. Solicited adverse events (AEs) and unsolicited non-serious AEs were recorded in diary cards, with serious adverse events (SAEs) notified to study investigators. This safety analysis included 676 participants. No AEs led to study termination, and no SAEs were reported. The most frequent solicited injection site reaction was pain in both the ≤ 23-month (12.2% [55/450]) and ≥ 24-month (15.5% [35/226]) age groups. The most frequent solicited systemic reactions were pyrexia and somnolence in the ≤ 23-month age group (6.0% [27/450] each), and malaise (10.6% [24/226]) in the ≥ 24-month age group. Overall, 208 (30.8%) participants experienced 339 unsolicited non-serious AEs, with nasopharyngitis the most common (14.1% [95/676]), and nearly all events (98.8% [335/339]) were considered unrelated to QIV. Grade3 solicited reactions and unsolicited non-serious AEs were reported in five (0.7%) and three (0.4%) participants, respectively, all of whom recovered by day7 after vaccination. This active safety surveillance study confirms that QIV is well tolerated in children aged 6-35months in routine clinical practice in South Korea. There were no safety concerns observed in these young children.

Post-marketing Surveillance of a Quadrivalent Influenza Vaccine (VaxigripTetra) in South Korea.

IntroductionIn 2017, a quadrivalent inactivated split-virion influenza vaccine (QIV; Vaxigrip Tetra®, Sanofi) was licensed in South Korea for active immunization against influenza A and influenza B viruses in individuals aged 3 years or older, which was subsequently extended to individuals aged 6 months or older in 2018. Post-marketing surveillance trials are mandatory in South Korea to retain drug licensure. Here, we assessed the safety of QIV in routine clinical practice in South Korea.MethodsThis was an open, multicenter, observational, active safety surveillance study conducted between 20 June 2017 and 19 June 2021 at 10 study sites in South Korea in individuals aged 3 years or older who received a single dose of QIV during a routine healthcare visit. The participants or their legally acceptable representatives were instructed to record any adverse reactions (solicited events) and unsolicited non-serious adverse events (AE) in diary cards, and notify study investigators in case of serious adverse events (SAE).ResultsOverall, 663 participants were included in this study. There were no AEs leading to study termination, and no SAEs reported. Injection site pain (278 [41.9%]) was the most frequent solicited injection site reaction, with myalgia (250 [37.7%]) and malaise (236 [35.6%]) the most frequent solicited systemic reactions. Grade 3 solicited injection site and systemic reactions were reported by 8 (1.2%) and 13 (2.0%) participants, respectively; most participants with solicited reactions recovered without the need for further action. Overall, 39 (5.9%) participants experienced 49 unsolicited non-serious AEs with the most frequently reported being nasopharyngitis (19 [2.9%]). Grade 3 unsolicited non-serious adverse events were reported in 1 (0.2%) participant. None of the unsolicited non-serious AEs were considered to be related to QIV.ConclusionThis post-marketing surveillance study confirms that QIV is well tolerated and has an acceptable safety profile in routine practice in South Korea. No unexpected safety concerns were identified.Trial RegistrationClinicalTrials.gov identifier NCT05406180.

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 an inactivated SARS-CoV-2 vaccine (Sinopharm BBIBP-CorV) coadministered with quadrivalent split-virion inactivated influenza vaccine and 23-valent pneumococcal polysaccharide vaccine in China: A multicentre, non-inferiority, open-label, randomised, controlled, phase 4 trial

BackgroundThe safety and immunogenicity of the coadministration of an inactivated SARS-CoV-2 vaccine (Sinopharm BBIBP-CorV), quadrivalent split-virion inactivated influenza vaccine (IIV4), and 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults in China is unknown. MethodsIn this open-label, non-inferiority, randomised controlled trial, participants aged ≥ 18 years were recruited from the community. Individuals were eligible if they had no history of SARS-CoV-2 vaccine or any pneumonia vaccine and had not received an influenza vaccine during the 2020–21 influenza season. Eligible participants were randomly assigned (1:1:1), using block randomization stratified, to either: SARS-CoV-2 vaccine and IIV4 followed by SARS-CoV-2 vaccine and PPV23 (SARS-CoV-2 + IIV4/PPV23 group); two doses of SARS-CoV-2 vaccine (SARS-CoV-2 vaccine group); or IIV4 followed by PPV23 (IIV4/PPV23 group). Vaccines were administered 28 days apart, with blood samples taken on day 0 and day 28 before vaccination, and on day 56. ResultsBetween March 10 and March 15, 2021, 1152 participants were recruited and randomly assigned to three groups (384 per group). 1132 participants were included in the per-protocol population (375 in the SARS-CoV-2 + IIV4/PPV23 group, 380 in the SARS-CoV-2 vaccine group, and 377 in the IIV4/PPV23 group). The seroconversion rate (100 % vs 100 %) and GMT (159.13 vs 173.20; GMT ratio of 0.92 [95 % CI 0.83 to 1.02]) of SARS-CoV-2 neutralising antibodies in the SARS-CoV-2 + IIV4/PPV23 group was not inferior to those in the SARS-CoV-2 vaccine group. The SARS-CoV-2 + IIV4/PPV23 group was not inferior to the IIV4/PPV23 group in terms of seroconversion rates and GMT of influenza virus antibodies for all strains except for the seroconversion rate for the B/Yamagata strain. The SARS-CoV-2 + IIV4/PPV23 group was not inferior to the IIV4/PPV23 group regarding seroconversion rates and GMC of Streptococcus pneumoniae IgG antibodies specific to all serotypes. All vaccines were well tolerated. ConclusionsThe coadministration of the inactivated SARS-CoV-2 vaccine and IIV4/PPV23 is safe with satisfactory immunogenicity.This study is registered with ClinicalTrials.gov, NCT04790851.

Immunogenicity of a trivalent influenza vaccine and persistence of induced immunity in adults aged ≥60 years in Taizhou City, Zhejiang Province, China, during the 2018–2019 season

ABSTRACT Yearly administration of influenza vaccine with recommendations can help control seasonal influenza epidemics in adults aged ≥60 years. Here, we describe the results of a prospective study observing the immunogenicity and persistence of induced immunity of a trivalent inactivated split-virion influenza vaccine (TIV) in adults aged ≥60 years during the 2018–2019 season in Taizhou City, Zhejiang Province in China. A total of 422 participants completed the study period. Vaccinated participants (284) received a single dose of TIV, but unvaccinated participants (138) didn’t receive any vaccine. Study participants vaccinated with TIV had significantly higher GMTs of Hemagglutination Inhibition (HI) antibodies against AH1N1, AH2N3, and B/Victoria strains (all p < .0001) at day 30 post-vaccination compared with unvaccinated participants, but the antibody response to the B/Victoria strain was the weakest. Rates of seroprotection and seroconversion were generally higher in the TIV-vaccinated group. At day 180 post-vaccination, the seroconversion rates (95%CI) in the vaccinated group were 99.6% (99.0%–100.3%), 97.9% (96.2%–99.6%), and 68.3% (62.9%–73.8%) for antibodies against three influenza strains, respectively; these rates were significantly different compared with unvaccinated group only for strains AH3N2 and B/Victoria (p = .002 and p < .0001, respectively). These results confirm that in adults aged ≥60 years, a single dose of TIV can induce a protective immune response against influenza, but the protective HI antibody levels induced against strain B/Victoria do not persist through 6 months.

Active-controlled phase III study of an egg-cultivated quadrivalent inactivated split-virion influenza vaccine (GC3110A) in healthy Korean children aged 6–35 months

The inactivated trivalent influenza vaccine (TIV) offers limited protection when two influenza B lineages co-circulate or when there is a vaccine mismatch (i.e., discordance in the predominant circulating B strain and WHO-recommended B strain). Inactivated quadrivalent influenza vaccine (QIV) may reduce the burden of influenza. Here, we report the results of a phase 3 clinical trial that evaluated the immunogenicity and safety of a novel QIV, GC3110A, in Korean children aged 6–35 months, which has been approved and is currently in use in Korea. The study involved two parts. In Part 1, the safety of GC3110A was evaluated in 10 subjects. After none of the subjects reported grade 3 adverse events (AEs), we proceeded to Part 2. Part 2 was a randomized, double-blind, multicenter phase 3 trial wherein we compared the immunogenicity and safety of GC3110A with those of a licensed control TIV. Immunogenicity was evaluated by measuring hemagglutination inhibition titers. The 200 participants enrolled in Part 2 were randomized in a 4:1 ratio to receive GC3110A or control TIV. The study vaccine group met both primary (i.e., the lower limit of 95% confidence interval [CI] of the seroconversion rate exceeds 40% for four strains) and secondary (i.e., the lower limit of 95% CI of the seroprotection rate exceeds 70% for four strains) immunogenicity endpoints. There was no significant between-group difference in the seroconversion rate, seroprotection rate, and geometric mean titer for the shared strains. However, the study vaccine group demonstrated significantly higher immunity for the additional strain B/Yamagata. In the safety analysis, there was no significant between-group difference in the proportion of participants with solicited local AEs, solicited systemic AEs, and unsolicited AEs. In conclusion, the results indicate that GC3110A has comparable immunogenicity and safety to those of TIV.Clinical Trial Registry Number: NCT03285997.

Enhanced passive safety surveillance of the quadrivalent inactivated split-virion influenza vaccine (IIV4) in Finland during the 2019/20 influenza season

Background and aimsThe Enhanced Passive Safety Surveillance is a requirement of the European Medicines Agency (EMA) for seasonal influenza vaccines, aiming to rapidly detect any significant change in frequency or severity of expected reactogenicity or allergic events prior to widespread use of a vaccine in any particular year. The aim of this surveillance was to assess the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunization in Finland, as per the national immunization program for 2019/20. The primary objective was to investigate the suspected adverse drug reactions (ADR) occurring within 7 days following vaccination.MethodsPassive surveillance of individuals vaccinated with IIV4 was conducted within the first 4 to 6 weeks of the influenza season in Finland. Potential ADRs were reported via phone or posted adverse event forms. The vaccinee reporting rate and ADR reporting rate were calculated and compared with the known or expected safety data in order to identify any change which was clinically significant.ResultsData were collected from 939 individuals, with 56 reports received for 163 suspected ADRs. Of these, 38 individuals reported 117 suspected ADRs within 7 days following vaccination, corresponding to an ADR reporting rate of 12.46% (95% CI: 10.41, 14.74%); vaccination-site pain, vaccination-site reaction, and pyrexia were the most frequently reported ADRs. The 18-to-65 years of age category had an ADR reporting rate of 12.56%, the over-65 years of age category had an ADR reporting rate of 16.22%, and no ADRs were reported for individuals aged 6 months to 18 years. No serious suspected ADRs were reported at any time post-vaccination, and the ADR rates were comparable to those reported for IIV4 in the 2018/19 seasonal assessment. The frequency of suspected ADRs was generally aligned with those reported in the Summary of Product Characteristics (SmPC), with the exception of asthenia, somnolence, and erythema, which were slightly higher. No reporting pattern by type, frequency, or severity was identified for the suspected ADRs.ConclusionsNo clinically significant changes in what is known or expected for IIV4 was reported for the 2019/20 season, which supports the overall safety profile.

Safety and immunogenicity of high-dose quadrivalent influenza vaccine in adults ≥65 years of age: A phase 3 randomized clinical trial

BackgroundA high-dose, split-virion inactivated trivalent influenza vaccine (IIV3-HD; Fluzone® High-Dose, Sanofi Pasteur) is available for adults ≥65 years of age. This study examined the safety and immunogenicity of a quadrivalent high-dose split-virion inactivated influenza vaccine (IIV4-HD). MethodsThis was a randomized, modified double-blind, active-controlled, multi-center trial in healthy adults ≥65 years of age. Subjects were randomized in a 4:1:1 ratio to receive a single intramuscular injection of IIV4-HD, the licensed IIV3-HD, or an IIV3-HD containing the alternate B-lineage strain. Hemagglutination inhibition (HAI), seroneutralisation, and anti-neuraminidase antibody titers were measured at baseline and day 28. Solicited reactions were collected for up to 7 days, unsolicited adverse events up to 28 days, and serious adverse events up to 180 days. The primary immunogenicity objective was to demonstrate that IIV4-HD induces HAI geometric mean titers (GMTs) and seroconversion rates that are non-inferior to those induced by IIV3-HD. Secondary objectives were to describe the safety of IIV4-HD and IIV3-HD and to demonstrate that IIV4-HD induces HAI GMTs and seroconversion rates that are superior to those induced by IIV3-HD not containing the same B-lineage strain. ResultsThe study included 2670 adults ≥65 years of age. For all four strains, HAI GMTs and seroconversion rates induced by IIV4-HD were non-inferior to those induced by IIV3-HDs containing the same strains. For both B strains, HAI GMTs and seroconversion rates induced by IIV4-HD were superior to those induced by IIV3-HD not containing the same B–lineage strain. Seroneutralisation and anti-neuraminidase antibody responses, measured in a subset of subjects, were similar. No new safety concerns were identified, and the safety profiles of IIV4-HD and IIV3-HD were similar. ConclusionsAdding a second B strain in IIV4-HD resulted in improved immunogenicity against the added strain without compromising the immunogenicity of the other strains or the vaccine’s tolerability.Clinical trial registration: NCT03282240.

A phase 2/3 double-blind, randomized, placebo-controlled study to evaluate the safety and immunogenicity of a seasonal trivalent inactivated split-virion influenza vaccine (IVACFLU-S) in healthy adults in Vietnam

ABSTRACT Background: Under the WHO’s Global Action Plan for influenza vaccines, we conducted a phase 2–3 study of IVACFLU-S, a trivalent, seasonal inactivated influenza vaccine candidate. Methods: In the phase 2 portion of the study, 252 participants received one dose of 15 mcg hemagglutinin (HA) vaccine per strain or placebo. Following determination of safety, 636 additional participants were randomized in phase 3 to receive vaccine or placebo. Immunogenicity was assessed in a subset of the participants in the phase 3 study. Results: Higher proportion (70%) of participants in the IVACFLU-S arm reported solicited local adverse events (AEs) (p < .0001) as compared to placebo (25%). Mild injection site pain and tenderness were most common AEs seen in 55% and 60% of participants in the vaccine group. The solicited systemic AEs were comparable (p = .4149). The majority of solicited and unsolicited AEs were mild to moderate in severity. In the vaccine arm for the combined age group of 18–60 years of age, seroconversion against antigens A/H1N1, A/H3N2, and B was achieved in 70.3%, 76.1%, and 54.1% of participants respectively; seroprotection against antigens A/H1N1, A/H3N2, and B was achieved in 83.3%, 86.6%, and 60.3% of participants respectively; and the geometric mean fold rise for the hemagglutinin-inhibition (HI) antibody titers against antigen A/H1N1, A/H3N2, and B were 13.15, 11.85, and 5.87, respectively. Conclusion: This study demonstrates the local reactogenicity, other safety, and immunogenicity of IVACFLU-S, first domestically produced influenza vaccine in Vietnam. ClinicalTrials.gov number NCT03095599 (March 29, 2017)

Enhanced passive safety surveillance of three marketed influenza vaccines in the UK and the Republic of Ireland during the 2017/18 season

ABSTRACT Safety surveillance is required for each season’s influenza vaccines to rapidly detect and evaluate potential new safety concerns before the peak period of immunization. Here we report the results of an enhanced passive safety surveillance for a trivalent split-virion inactivated influenza vaccine (IIV3; Vaxigrip®), an intradermal version of this vaccine (IIV3-ID; Intanza® 15 µg), and a recently licensed quadrivalent version (IIV4; VaxigripTetraTM) during the 2017/18 influenza season in the UK and Republic of Ireland. The primary objective was to determine the rates of adverse reactions (ARs) occurring within 7 days following routine vaccination. Between September and November 2017, 979 safety report cards were distributed to vaccinees receiving IIV3-ID, 1005 to those receiving IIV3, and 957 to those receiving IIV4. At least one AR was reported by 28 participants (2.9%) vaccinated with IIV3-ID, 14 participants (1.4%) vaccinated with IIV3, and 20 participants (2.1%) vaccinated with IIV4. The most frequent ARs were injection-site reactions and headache. One participant vaccinated with IIV3-ID reported two suspected serious ARs (dyskinesia and a shock symptom), although these could not be confirmed as vaccine-related. Rates of ARs for IIV3 and IIV3-ID for 2017/18 did not differ from the 2016/17 rates. For IIV4, in its first season since licensure, AR frequencies were similar to those in the Summary of Product Characteristics. In conclusion, no change was found compared to the known or expected AR rates for IIV3, IIV3-ID, or IIV4 during the 2017/18 season.

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.

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.

Efficacy, immunogenicity, and safety of a quadrivalent inactivated influenza vaccine in children aged 6–35 months: A multi-season randomised placebo-controlled trial in the Northern and Southern Hemispheres

BackgroundA quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6–35 months. MethodsThis was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6–35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains. ResultsThe study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36–61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07–81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo. ConclusionsIIV4 was safe and effective for protecting children aged 6–35 months against influenza illness caused by vaccine-similar or any circulating strains. Clinical trial registrationEudraCT no. 2013-001231-51.

Influenza Hemagglutination-inhibition Antibody Titer as a Mediator of Vaccine-induced Protection for Influenza B.

The hemagglutination inhibition (HAI) assay is an established correlate of protection for the inactivated influenza vaccine. However, the proportion of vaccine-induced protection that is mediated by the post-vaccination HAI titer has not been assessed. We used data from a randomized, placebo-controlled trial of a split-virion inactivated influenza vaccine in children aged 6-17 years. Sera were collected before and 30 days after receipt of vaccination or placebo and tested by the HAI assay against B/Brisbane/60/2008-like (B/Victoria lineage). We fitted Cox proportional hazards models to the time to laboratory-confirmed influenza B. We used causal mediation analysis to estimate the proportion of the total effect of vaccination that was mediated by higher HAI titers. We estimated that vaccine efficacy against confirmed B/Victoria infection was 68% (95% confidence interval, 33%, 88%), and post-vaccination HAI titers explained 57% of the effect of vaccination on protection. The majority of the effect of inactivated influenza vaccination in children is mediated by the increased HAI titer after vaccination; however, other components of the immune response to vaccination may also play a role in protection and should be further explored. Causal mediation analysis provides a framework to quantify the role of various mediators of protection.

A novel adjuvant G3 induces both Th1 and Th2 related immune responses in mice after immunization with a trivalent inactivated split-virion influenza vaccine

A preferred adjuvant should promote both Th1 and Th2 responses. However, most adjuvants in common use are biased towards a Th2-driven response. Therefore, the ability of a novel saponin-based adjuvant G3 to inducing balanced Th1 and Th2 responses in BALB/c mice immunized with a split trivalent seasonal influenza vaccine was evaluated in comparison to that of the adjuvant Al(OH)3. Clear differences in the IgG profiles induced by G3, Al(OH)3 or non-adjuvanted vaccine were recorded. Both adjuvants enhanced high and similar levels of the Th2 associated IgG1 subtype compared to mice given vaccine alone. Only G3 enhanced the IgG2a subclass reflecting a Th1 response, whereas Al(OH)3 even abrogated the IgG2a production. Accordingly, G3 enhanced the production of IL-2 and IFN-γ and also of IL-2/IFN-γ double secreting cells, emphasizing the strong Th1 driving effect of G3. Only Al(OH)3 increased splenocyte production of IL-17. Taken together, the results indicate a strong propensity for G3 to induce both Th1 and Th2 driven immune responses.

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.

Immunogenicity and safety of a split-virion quadrivalent influenza vaccine in adults 18–60 years of age in the Republic of Korea

ABSTRACTVaxigripTetra® (Sanofi Pasteur, Lyon, France) is a quadrivalent split-virion inactivated influenza vaccine (IIV4) containing two B-lineage strains approved in the European Union and Taiwan in 2016 for individuals ≥ 3 years of age. Here, we describe an observer-blind, randomized, controlled, multicenter trial study evaluating the immunogenicity and safety of the Northern Hemisphere 2015–2016 formulations of IIV4 and the licensed split-virion trivalent inactivated influenza vaccine (IIV3) in the Republic of Korea (ClinicalTrials.gov no. NCT02550197). The study included 300 Korean adults 18–60 years of age randomized 2:1 to receive a single injection of IIV4 or IIV3. For each of the four vaccine strains in IIV4, 21 days after vaccination, geometric mean post-/pre-vaccination ratios of hemagglutination inhibition titers were ≥ 3.97. Seroconversion/significant increases rates were ≥ 40% for all but the A/H1N1 strain, for which the rate was 39.7%. Results were similar for the three strains in IIV3. For the additional B-lineage strain not in IIV3 (Victoria), hemagglutination inhibition antibody titers were higher for IIV4 than for IIV3. Solicited reactions and adverse events were similar between IIV4 and IIV3, and no serious adverse events or new safety signals were detected. These results confirm the robust immunogenicity and acceptable safety of IIV4 in adults 18–60 years of age and show that including a second B-lineage strain should provide broader protection against B-strain influenza without affecting vaccine safety or the immunogenicity of other three vaccine strains.

Randomized safety and immunogenicity trial of a seasonal trivalent inactivated split virion influenza vaccine (IVACFLU-S) in healthy young Vietnamese adults

BackgroundUnder the auspices of the World Health Organization (WHO) Global Action Plan, PATH supported evaluation of a trivalent, seasonal inactivated influenza vaccine candidate produced by the Institute of Vaccines and Medical Biologicals (IVAC), a Vietnamese manufacturer. MethodsIn 2015, 60 healthy adult subjects 18–45years of age were enrolled in a Phase 1, single center, double blind, randomized, placebo-controlled study conducted at a district health center in Thai Binh Province, Vietnam. The study evaluated the overall safety and immunogenicity of a seasonal, trivalent inactivated split virion influenza vaccine. Volunteers were given either vaccine or placebo in a randomized 1:1 ratio.After undergoing screening, eligible volunteers provided their signed consent and were enrolled in the study. On the first day of immunization, randomly chosen volunteers received IVACFLU-S 15μg (mcg) hemagglutinin of each of the three strains in 0.5mL or placebo by intramuscular injection. All volunteers were monitored for adverse events and underwent blood testing at screening and Day 8 to assess the vaccine candidate’s safety. Sera obtained before and 21days after immunization were tested for influenza antibody titers using the hemagglutination-inhibition (HAI) and microneutralization tests (MNT). ResultsVaccine was well tolerated, and there were no serious adverse events reported. HAI and MNT identified serum antibody responses against the three influenza strains in nearly all volunteers who received the vaccine. Overall, serum HAI responses of fourfold or greater were observed in 93 percent, 83 percent, and 77 percent of H1, H3, and B strains, respectively. Seroprotection rates were also very high. ConclusionsIVAC’s seasonal, trivalent influenza vaccine was safe and well tolerated and induced high levels of seroconversion and seroprotection rates. These clinical data are a first step towards demonstrating the feasibility of producing the vaccine locally and that seasonal vaccine production in Vietnam may be an effective strategy for enhancing the global influenza vaccine supply. ClinicalTrials.gov number NCT02598089, October 15, 2015.