Trivalent Inactivated Influenza Vaccine Research Articles

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.

Comparison of Immunogenicity and Safety between a Single Dose and One Booster Trivalent Inactivated Influenza Vaccination in Patients with Chronic Kidney Disease: A 20-Week, Open-Label Trial

Background: Non-dialysis-dependent chronic kidney disease (CKD-ND) patients are recommended to receive a one-dose influenza vaccination annually. However, studies investigating vaccine efficacy in the CKD-ND population are still lacking. In this study, we aimed to evaluate vaccine efficacy between the one-dose and two-dose regimen and among patients with different stages of CKD throughout a 20-week follow-up period. Methods: We conducted a single-center, non-randomized, open-label, controlled trial among patients with all stages of CKD-ND. Subjects were classified as unvaccinated, one-dose, and two-dose groups (4 weeks apart) after enrollment. Serial changes in immunological parameters (0, 4, 8, and 20 weeks after enrollment), including seroprotection, geometric mean titer (GMT), GMT fold-increase, seroconversion, and seroresponse, were applied to evaluate vaccine efficacy. Results: There were 43, 84, and 71 patients in the unvaccinated, one-dose, and two-dose vaccination groups, respectively. At 4–8 weeks after vaccination, seroprotection rates in the one- and two-dose group for H1N1, H3N2, and B ranged from 82.6–95.8%, 97.4–100%, and 73.9–100%, respectively. The concomitant seroconversion and GMT fold-increases nearly met the suggested criteria for vaccine efficacy for the elderly population. Although the seroprotection rates for all of the groups were adequate, the seroconversion and GMT fold-increase at 20 weeks after vaccination did not meet the criteria for vaccine efficacy. The two-dose regimen had a higher probability of achieving seroprotection for B strains (Odds ratio: 3.5, 95% confidence interval (1.30–9.40)). No significant differences in vaccine efficacy were found between early (stage 1–3) and late (stage 4–5) stage CKD. Conclusions: The standard one-dose vaccination can elicit sufficient protective antibodies. The two-dose regimen induced a better immune response when the baseline serum antibody titer was low. Monitoring change in antibody titers for a longer duration is warranted to further determine the current vaccine strategy in CKD-ND population.

Relative Effectiveness of Adjuvanted Trivalent Inactivated Influenza Vaccine Versus Egg-derived Quadrivalent Inactivated Influenza Vaccines and High-dose Trivalent Influenza Vaccine in Preventing Influenza-related Medical Encounters in US Adults ≥ 65 Years During the 2017–2018 and 2018–2019 Influenza Seasons

BackgroundThe effectiveness of standard, egg-derived quadrivalent influenza vaccines (IIV4) may be reduced in adults ≥65 years of age, largely because of immunosenescence. An MF59-adjuvanted trivalent influenza vaccine (aIIV3) and a high-dose trivalent influenza vaccine (HD-IIV3) offer older adults enhanced protection versus standard vaccines. This study compared the relative effectiveness of aIIV3 with IIV4 and HD-IIV3 in preventing influenza-related medical encounters over 2 US influenza seasons.MethodsThis retrospective cohort study included US patients ≥65 years vaccinated with aIIV3, IIV4, or HD-IIV3. The outcome of interest was the occurrence of influenza-related medical encounters. Data were derived from a large dataset comprising primary and specialty care electronic medical records linked with pharmacy and medical claims. Adjusted odds ratios (OR) were derived from an inverse probability of treatment-weighted sample adjusted for age, sex, race, ethnicity, geographic region, vaccination week, and health status. Relative vaccine effectiveness (rVE) was determined using the formula (% VE = 1 – ORadjusted) × 100.ResultsIn 2017–2018, cohorts included: aIIV3, n = 524 223; IIV4, n = 917 609; and HD-IIV3, n = 3 377 860. After adjustment, 2017–2018 rVE of aIIV3 versus IIV4 was 18.2 (95% confidence interval [CI], 15.8–20.5); aIIV3 vs. HD-IIV3 was 7.7 (95% CI, 2.3–12.8). In 2018–2019, cohorts included: aIIV3, n = 1 031 145; IIV4, n = 915 380; HD-IIV3, n = 3 809 601, with adjusted rVEs of aIIV3 versus IIV4 of 27.8 (95% CI, 25.7–29.9) and vs. HD-IIV3 of 6.9 (95% CI, 3.1–10.6).ConclusionIn the 2017–2018 and 2018–2019 influenza seasons in the United States, aIIV3 demonstrated greater reduction in influenza-related medical encounters than IIV4 and HD-IIV3 in adults ≥65 years.

Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults

Trivalent adjuvanted inactivated influenza vaccine (aIIV3) and trivalent high-dose inactivated influenza vaccine (HD-IIV3) are US-licensed for adults aged 65 years and older. Data are needed on the comparative safety, reactogenicity, and health-related quality of life (HRQOL) effects of these vaccines. To compare safety, reactogenicity, and changes in HRQOL scores after aIIV3 vs HD-IIV3. This randomized blinded clinical trial was a multicenter US study conducted during the 2017 to 2018 and 2018 to 2019 influenza seasons. Among 778 community-dwelling adults aged at least 65 years and assessed for eligibility, 13 were ineligible and 8 withdrew before randomization. Statistical analysis was performed from August 2019 to August 2020. Intramuscular administration of aIIV3 or HD-IIV3 after age-stratification (65-79 years; ≥80 years) and randomization. Proportions of participants with moderate-to-severe injection-site pain and 14 other solicited reactions during days 1 to 8, using a noninferiority test (5% noninferiority margin), and serious adverse events (SAE) and adverse events of clinical interest (AECI), including new-onset immune-mediated conditions, during days 1 to 43. Changes in HRQOL scores before and after vaccination (days 1, 3) were also compared between study groups. A total of 757 adults were randomized, 378 to receive aIIV3 and 379 to receive HD-IIV3. Of these participants, there were 420 women (55%) and 589 White individuals (78%) with a median (range) age of 72 (65-97) years. The proportion reporting moderate-to-severe injection-site pain, limiting or preventing activity, after aIIV3 (12 participants [3.2%]) (primary outcome) was noninferior compared with HD-IIV3 (22 participants [5.8%]) (difference -2.7%; 95% CI, -5.8 to 0.4). Ten reactions met noninferiority criteria for aIIV3; 4 (moderate-to-severe injection-site tenderness, arthralgia, fatigue, malaise) did not. It was inconclusive whether these 4 reactions occurred in higher proportions of participants after aIIV3. No participant sought medical care for a vaccine reaction. No AECI was observed. Nine participants had at least SAE after aIIV3 (2.4%; 95% CI,1.1% to 4.5%); 3 had at least 1 SAE after HD-IIV3 (0.8%; 95% CI, 0.2% to 2.2%). No SAE was associated with vaccination. Changes in prevaccination and postvaccination HRQOL scores were not clinically meaningful and not different between the groups. Overall safety and HRQOL findings were similar after aIIV3 and HD-IIV3, and consistent with prelicensure data. From a safety standpoint, this study's results support using either vaccine to prevent influenza in older adults. ClinicalTrials.gov Identifier: NCT03183908.

LB-2. Relative Effectiveness of aIIV3 versus IIV4 and HD-IIV3 In Preventing Influenza-Related Medical Encounters in Adults ≥65 Years of Age at High Risk for Influenza Complications During the U.S. 2017–2018 and 2018–2019 Influenza Seasons

BackgroundIndividuals with health conditions have shown higher rates of influenza-related morbidity and mortality compared to healthy individuals and are often prioritized for influenza vaccination. However, vaccination with egg-derived standard quadrivalent inactivated influenza vaccines (IIV4) has shown to be less effective in adults ≥65 years of age largely due to immunosenecence. Two enhanced vaccines, the MF59®-adjuvanted trivalent inactivated influenza vaccine (aIIV3) and a high-dose trivalent inactivated influenza vaccine (HD-IIV3), were developed to provide adults ≥65 years with increased protection. The objective of this study was to determine the relative vaccine effectiveness (rVE) of aIIV3 versus IIV4 and HD-IIV3 in preventing influenza-related medical encounters in high-risk adults ≥65 years.MethodsA retrospective cohort study was conducted among adults ≥65 years with ≥1 health condition with a record of receiving either aIIV3, IIV4 or HD-IIV3 in the 2017–18 or 2018–19 influenza seasons. Patient-level electronic medical records linked to pharmacy and medical claims were used to ascertain exposure, outcome and covariate information. The primary outcome was influenza-related medical encounters in primary care and hospital (ICD-10 codes J09*–J11*). Inverse probability of treatment weighting was used to obtain odds ratios (ORs) adjusted for age, sex, race, ethnicity, geographic region, comorbidities and week of vaccination for each health condition. rVE was determined using the formula (1-OR)*100 and reported with 95% confidence intervals (CI).ResultsOverall, 1,755,420 individuals with ≥1 health condition were included for analysis in the 2017–18 season and 2,055,012 individuals in the 2018–19 season. In both seasons, high-risk subjects who received aIIV3 had statistically significantly greater reduction in influenza-related medical encounters as compared to IIV4 (Table 1). Non-statistically significant estimates preclude definitive conclusions for comparisons with HD-IIV3.Table 1. Adjusted relative vaccine effectiveness (rVE) of aIIV3 versus comparators in high-risk patients in the 2017–2018 and 2018–2019 influenza seasons in the U.S. ConclusionThe results of this study support the use of aIIV3 in adults ≥65 years of age at high risk for influenza complications and provides further evidence supporting aIIV3 as an effective public health measure against influenza.Disclosures Lauren Fischer, M.A., Seqirus (Consultant) Dan O'Brien, BA, Seqirus (Consultant) Joseph Vasey, PhD, Seqirus (Consultant) Gregg C. Sylvester, MD, Seqirus (Employee) James A. Mansi, PhD, Seqirus (Employee)

Intersection of Sex and Frailty in Humoral Immune Responses to Influenza Vaccine in Community-Dwelling Older Adults

Older adults bear the highest burden of severe disease and complications associated with seasonal influenza, with annual vaccination serving as the best option for protection. Variability in vaccine efficacy exists, yet the host factors that affect immune responses to inactivated influenza vaccines (IIV) are incompletely understood. We hypothesized that sex and frailty interact to affect vaccine-induced humoral responses among older adults. To test this hypothesis, community-dwelling adults above 75 years of age were recruited yearly, assessed for frailty (as defined by the Cardiovascular Health Study criteria), and vaccinated with the high-dose trivalent IIV. Humoral immune responses were evaluated via hemagglutination inhibition titers. The study began during the 2014-2015 influenza season, with yearly cohorts ranging from 76-163 individuals. A total of 617 vaccinations were delivered from 2014-2019. In preliminary analyses, the outcome of interest was seroconversion, defined as ≥ 4-fold rise in titers. Crude odds ratios suggest that females are more likely to seroconvert to influenza A strains (H1N1: OR = 1.39, (0.98-1.96) ; H3N2: 1.17 (0.85 – 1.62)), while males are more likely to seroconvert to the B strain (OR = 0.85 (0.60 – 1.22)). Furthermore, this sex difference was modified by frailty – for example, the odds of seroconversion to H1N1 were 65% higher for females than males among those who were nonfrail, and only 30% higher among females who were frail. Together, these results suggest that sex and frailty interact to impact immune responses to influenza vaccines. These findings may be leveraged to better protect vulnerable populations.

Effect of High-Dose Trivalent vs Standard-Dose Quadrivalent Influenza Vaccine on Mortality or Cardiopulmonary Hospitalization in Patients With High-risk Cardiovascular Disease

Influenza is temporally associated with cardiopulmonary morbidity and mortality among those with cardiovascular disease who may mount a less vigorous immune response to vaccination. Higher influenza vaccine dose has been associated with reduced risk of influenza illness. To evaluate whether high-dose trivalent influenza vaccine compared with standard-dose quadrivalent influenza vaccine would reduce all-cause death or cardiopulmonary hospitalization in high-risk patients with cardiovascular disease. Pragmatic multicenter, double-blind, active comparator randomized clinical trial conducted in 5260 participants vaccinated for up to 3 influenza seasons in 157 sites in the US and Canada between September 21, 2016, and January 31, 2019. Patients with a recent acute myocardial infarction or heart failure hospitalization and at least 1 additional risk factor were eligible. Participants were randomly assigned to receive high-dose trivalent (n = 2630) or standard-dose quadrivalent (n = 2630) inactivated influenza vaccine and could be revaccinated for up to 3 seasons. The primary outcome was the time to the composite of all-cause death or cardiopulmonary hospitalization during each enrolling season. The final date of follow-up was July 31, 2019. Vaccine-related adverse events were also assessed. Among 5260 randomized participants (mean [SD] age, 65.5 [12.6] years; 3787 [72%] men; 3289 [63%] with heart failure) over 3 influenza seasons, there were 7154 total vaccinations administered and 5226 (99.4%) participants completed the trial. In the high-dose trivalent vaccine group, there were 975 primary outcome events (883 hospitalizations for cardiovascular or pulmonary causes and 92 deaths from any cause) among 884 participants during 3577 participant-seasons (event rate, 45 per 100 patient-years), whereas in the standard-dose quadrivalent vaccine group, there were 924 primary outcome events (846 hospitalizations for cardiovascular or pulmonary causes and 78 deaths from any cause) among 837 participants during 3577 participant-seasons (event rate, 42 per 100 patient-years) (hazard ratio, 1.06 [95% CI, 0.97-1.17]; P = .21). In the high-dose vs standard-dose groups, vaccine-related adverse reactions occurred in 1449 (40.5%) vs 1229 (34.4%) participants and severe adverse reactions occurred in 55 (2.1%) vs 44 (1.7%) participants. In patients with high-risk cardiovascular disease, high-dose trivalent inactivated influenza vaccine, compared with standard-dose quadrivalent inactivated influenza vaccine, did not significantly reduce all-cause mortality or cardiopulmonary hospitalizations. Influenza vaccination remains strongly recommended in this population. ClinicalTrials.gov Identifier: NCT02787044.

Vaccine effectiveness of live attenuated and trivalent inactivated influenza vaccination in 2010/11 to 2015/16: the SIVE II record linkage study.

There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged ≥ 65 years and for those aged < 65 years who are at an increased risk of complications from influenza infection (e.g. people with asthma). To examine the vaccine effectiveness of LAIV and TIV. Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. A total of 1,250,000 people. LAIV for 2- to 11-year-olds and TIV for older people (aged ≥ 65 years) and those aged < 65 years who are at risk of diseases, from 2010/11 to 2015/16. The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2-11 years) for preventing RT-PCR laboratory-confirmed influenza was 21% (95% CI -19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged ≥ 65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged ≥ 65 years (although this was significant in only one season). The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged ≥ 65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. Current Controlled Trials ISRCTN88072400. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 67. See the NIHR Journals Library website for further project information.

A cost-effectiveness analysis of South Africa’s seasonal influenza vaccination programme

BackgroundSeasonal influenza imposes a significant health and economic burden in South Africa, particularly in populations vulnerable to severe consequences of influenza. This study assesses the cost-effectiveness of South Africa’s seasonal influenza vaccination strategy, which involves vaccinating vulnerable populations with trivalent inactivated influenza vaccine (TIV) during routine facility visits. Vulnerable populations included in our analysis are persons aged ≥ 65 years; pregnant women; persons living with HIV/AIDS (PLWHA), persons of any age with underlying medical conditions (UMC) and children aged 6–59 months. MethodWe employed the World Health Organisation’s (WHO) Cost Effectiveness Tool for Seasonal Influenza Vaccination (CETSIV), a decision tree model, to evaluate the 2018 seasonal influenza vaccination campaign from a public healthcare provider and societal perspective. CETSIV was populated with existing country-specific demographic, epidemiologic and coverage data to estimate incremental cost-effectiveness ratios (ICERs) by comparing costs and benefits of the influenza vaccination programme to no vaccination. ResultsThe highest number of clinical events (influenza cases, outpatient visits, hospitalisation and deaths) were averted in PLWHA and persons with other UMCs. Using a cost-effectiveness threshold of US$ 3400 per quality-adjusted life year (QALY), our findings suggest that the vaccination programme is cost-effective for all vulnerable populations except for children aged 6–59 months. ICERs ranged from ~US$ 1 750 /QALY in PLWHA to ~US$ 7500/QALY in children. In probabilistic sensitivity analyses, the vaccination programme was cost-effective in pregnant women, PLWHA, persons with UMCs and persons aged ≥65 years in >80% of simulations. These findings were robust to changes in many model inputs but were most sensitive to uncertainty in estimates of influenza-associated illness burden. ConclusionSouth Africa's seasonal influenza vaccination strategy of opportunistically targeting vulnerable populations during routine visits is cost-effective. A budget impact analysis will be useful for supporting future expansions of the programme.

Influenza vaccine effectiveness against laboratory-confirmed influenza in a vaccine-mismatched influenza B-dominant season

BackgroundThe 2017–2018 influenza season in Israel was characterized by the predominance of influenza B Yamagata, with a lesser circulation of influenza A(H1N1)pdm09 and influenza A(H3N2). We estimated vaccine effectiveness (VE) of the inactivated influenza vaccine which was selected for use that season. MethodsEnd-of-season VE and 95% confidence intervals (CI) against laboratory-confirmed influenza-like illness (ILI) were estimated by means of the test-negative design. Age-specific VE analysis was carried out using a moving age interval. ResultsSpecimen were obtained from 1,453 community ILI patients; 610 (42.0%) were influenza-positive, among which 69.7% were B, 17.2% A(H1N1)pdm09 and 13.4% A(H3N2). A 98.6% of molecularly characterized influenza B belonged to the Yamagata lineage. Of the sampled individuals, 1320 were suitable for VE analysis. Of those vaccinated, 90.6% received the inactivated trivalent influenza vaccine (TIV) containing a Victoria lineage influenza B-like virus. VE against influenza A differed by age, with the highest VE of 72.9% (95%CI 31.9–89.2%) observed in children 0.5–14 years old, while all ages VE was 46.6% (95%CI 10.4–68.2%). All ages VE against influenza B was 23.2% (95%CI −10.1–46.4%) with age-specific analysis showing non-significant VE estimates. Utilizing a moving age interval of 15 years, afforded a detailed age-specific insight into influenza VE against the influenza viruses circulating during the 2017–2018 season. ConclusionsThe moderate-high 2017–2018 influenza A VE among children and adolescents, supports seasonal influenza vaccination at a young age. The low VE against influenza B in Israel, is most likely the result of influenza B/TIV-mismatch.

Evaluating the Effectiveness of Influenza Vaccine in People With At-Risk Medical Conditions: A Test-Negative Design Case-Control Study for the Seasonal Influenza Vaccine Effectiveness II (SIVE II) Project

Background: Seasonal trivalent inactivated influenza (TIV) vaccine effectiveness (VE) against laboratory confirmed influenza in adults with at-risk medical conditions is not well established. Previous studies have been hampered by small sample sizes to assess VE for each at-risk medical condition recommended for vaccination. Larger better powered studies investigating how influenza VE varied in those with specific risk factors associated with poor influenza outcomes is therefore required. Methods: A test-negative design case-control study of influenza VE was carried out in adults with at-risk medical conditions in Scotland between 2010/11 to 2015/16. We used individual patient-level health administrative data from 223 primary care practices linked with hospital and laboratory data (n=10275 swabs from n=9147 individuals). Generalised additive logistic regression was used to provide adjusted VE estimates between adults (aged >18 years) with laboratory-confirmed influenza compared to those with a negative test for influenza. Findings: Significant positive VE was found for all adults with chronic heart disease (31%; 95% confidence interval [CI]: 10 to 48), diabetes (34%; 95%CI: 12 to 51), impaired immune function (51%; 95%CI: 13 to 72), chronic kidney disease (40%; 95%CI: 17 to 57) and Body Mass Index (BMI) >30 to <40 kg/m2 (62%; 95%CI: 26 to 81). Significant VE was demonstrated for impaired immune function amongst most age groups including younger adults (18-54 years; 68%; 95%CI: 17 to 88) and those aged 85 years and over (42%; 95%CI: 4 to 65). The oldest adults aged 85 years and over had a significant positive VE for chronic respiratory disease (20%; 95%CI: 3 to 34), diabetes (34%; 95%CI: 11 to 51), and impaired immune function (42%; 95%CI: 4 to 65). Non-significant VE was found for those with chronic neurological disease (18%; 95%CI: -16 to 43). Interpretation: The amount of vaccine protection against laboratory-confirmed influenza varied amongst adults with at-risk medical conditions in different age groups. Seasonal influenza vaccination programmes should additionally consider those with BMI >30 to <40 kg/m2. Available alternate vaccines which aim to improve immune response should be considered for at-risk groups with consistently low TIV VE (e.g. neurological disease). Funding Statement: National Institute for Health Research Health Technology Assessment Programme (project number 13/34/14), Health Data Research UK, Asthma UK Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The Privacy Advisory Committee of the Information Services Division, NSS, approved the linkage and the statistical analysis of the anonymised data used in this study. Ethical permission was granted from the National Research Ethics Service Committee, West Midlands - Edgbaston [15/WM/0035].

Estimates of Inactivated Influenza Vaccine Effectiveness Among Children in Senegal: Results From 2 Consecutive Cluster-Randomized Controlled Trials in 2010 and 2011.

We report results of years 2 and 3 of consecutive cluster-randomized controlled trials of trivalent inactivated influenza vaccine (IIV3) in Senegal. We cluster-randomized (1:1) 20 villages to annual vaccination with IIV3 or inactivated poliovirus vaccine (IPV) of age-eligible residents (6 months-10 years). The primary outcome was total vaccine effectiveness against laboratory-confirmed influenza illness (LCI) among age-eligible children (modified intention-to-treat population [mITT]). Secondary outcomes were indirect (herd protection) and population (overall community) vaccine effectiveness. We vaccinated 74% of 12 408 age-eligible children in year 2 (June 2010-April 11) and 74% of 11 988 age-eligible children in year 3 (April 2011-December 2011) with study vaccines. Annual cumulative incidence of LCI was 4.7 (year 2) and 4.2 (year 3) per 100 mITT child vaccinees of IPV villages. In year 2, IIV3 matched circulating influenza strains. The total effectiveness was 52.8% (95% confidence interval [CI], 32.3-67.0), and the population effectiveness was 36.0% (95% CI, 10.2-54.4) against LCI caused by any influenza strain. The indirect effectiveness against LCI by A/H3N2 was 56.4% (95% CI, 39.0-68.9). In year 3, 74% of influenza detections were vaccine-mismatched to circulating B/Yamagata and 24% were vaccine-matched to circulating A/H3N2. The year 3 total effectiveness against LCI was -14.5% (95% CI, -81.2-27.6). Vaccine effectiveness varied by type/subtype of influenza in both years. IIV3 was variably effective against influenza illness in Senegalese children, with total and indirect vaccine effectiveness present during the year when all circulating strains matched the IIV3 formulation. NCT00893906.

Induction of Cross-Reactive Hemagglutination Inhibiting Antibody and Polyfunctional CD4+ T-Cell Responses by a Recombinant Matrix-M-Adjuvanted Hemagglutinin Nanoparticle Influenza Vaccine.

BackgroundRecurrent reports of suboptimal influenza vaccine effectiveness have renewed calls to develop improved, broadly cross-protective influenza vaccines. Here, we evaluated the safety and immunogenicity of a novel, saponin (Matrix-M)–adjuvanted, recombinant hemagglutinin (HA) quadrivalent nanoparticle influenza vaccine (qNIV).MethodsWe conducted a randomized, observer-blind, comparator-controlled (trivalent high-dose inactivated influenza vaccine [IIV3-HD] or quadrivalent recombinant influenza vaccine [RIV4]), safety and immunogenicity trial of qNIV (5 doses/formulations) in healthy adults ≥65 years. Vaccine immunogenicity was measured by hemagglutination-inhibition assays using reagents that express wild-type hemagglutination inhibition (wt-HAI) sequences and cell-mediated immune responses.ResultsA total of 1375 participants were randomized, immunized, and followed for safety and immunogenicity. Matrix-M–adjuvanted qNIV induced superior wt-HAI antibody responses against 5 of 6 homologous or drifted strains compared with unadjuvanted qNIV. Adjuvanted qNIV induced post-vaccination wt-HAI antibody responses at day 28 that were statistically higher than IIV3-HD against a panel of homologous or drifted A/H3N2 strains, similar to IIV3-HD against homologous A/H1N1 and B (Victoria) strains and similar to RIV4 against all homologous and drifted strains evaluated. The qNIV formulation with 75 µg Matrix-M adjuvant induced substantially higher post-vaccination geometric mean fold increases of influenza HA-specific polyfunctional CD4+ T cells compared with IIV3-HD or RIV4. Overall, similar frequencies of solicited and unsolicited adverse events were reported in all treatment groups.ConclusionsqNIV with 75 µg Matrix-M adjuvant was well tolerated and induced robust antibody and cellular responses, notably against both homologous and drifted A/H3N2 viruses. Further investigation in a pivotal phase 3 trial is underway.Clinical Trials RegistrationNCT03658629.

Technical guidelines for seasonal influenza vaccination in China (2020-2021)

Influenza virus infection is a respiratory infectious disease that can seriously affect human health. Influenza viruses can have frequent antigenic variation and changes, which can result in rapid and widespread transmission resulting in annual epidemics and outbreaks in places of public gathering such as schools, kindergartens and nursing homes. According to WHO estimation, seasonal influenza epidemics have caused an annually 3 to 5 million severe cases and 290 000 to 650 000 deaths globally. Pregnant women, young children, the elderly, and persons with chronic illnesses are at high risk for severe illness and death associated with influenza virus infection. Especially, COVID-19 pandemic might co-circulate with other respiratory infectious diseases such as influenza in the coming winter-spring season. Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and complications from infection. Currently, China has licensed trivalent inactivated influenza vaccine (IIV3) which includes split-virus influenza vaccine and subunit vaccine, quadrivalent inactivated influenza vaccine (IIV4) which is split, and trivalent live attenuated influenza vaccine (LAIV3) which was newly licensed. Except for a few major cities, influenza vaccine is a category Ⅱ vaccine, which means influenza vaccination is voluntary, and recipients must pay for it. In 2018 and 2019, the China CDC issued the "Technical Guidelines for Seasonal Influenza Vaccination in China" . In the past year, new research evidences home and abroad have been published, and new seasonal influenza vaccine has been licensed in China. To strengthen the technical guidance for prevention and control of influenza and operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC) Influenza Vaccination Technical Working Group (TWG), updated the 2019-2020 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2020-2021)" . The main updates in this version include the following: First, new research evidences especially studies of China, including disease burden, effectiveness, Vaccine-avoidable disease burden, vaccine safety monitoring, and cost-effectiveness and cost-benefit. Second, policies and measures for influenza prevention and control issued by National Health Commission (PRC) in the past year. Thirdly, new type seasonal influenza vaccine licensed and issued in 2020-2021 in China. Fourth, northern hemisphere influenza vaccination composition for the 2020-2021 season which included trivalent and quadrivalent influenza vaccine. Fifth, Influenza vaccination recommendations for 2020-2021 influenza season. The recommendations described in this report include the following: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended, and appropriate product is available. Considering the situation of globally pandemic of COVID-19, to decrease the risk of influenza virus infection and minimize the impact on COVID-19 prevention and control, we recommend the following priority for seasonal influenza vaccination: healthcare workers, including clinical doctors and nurses, public health professionals, quarantine professionals; vulnerable groups living in nursing homes or welfare homes and staffs who take care those vulnerable groups; people work or stay in high population density places, such as teachers and students in kindergartens, primary and secondary school, prisoners and staffs of prisons; other high risk group of influenza, including adults ≥60 years of age, children aged 6-59 months, persons with specific chronic diseases, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to become pregnant during the influenza season. Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. People whoever get IIV or LAIV all apply to the principle. If they were vaccinated in 2019-2020 influenza season or a prior season, 1 dose is recommended. People more than 8 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. For the people unable to be vaccinated before the end of October, influenza vaccination will continue to be offered for the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for use by staff members of the CDCs at all levels who work on influenza control and prevention, PoVs staff members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and staff members of maternity and child care institutions at all levels. These guidelines will be updated periodically as new evidence becomes available.

Technical guidelines for seasonal influenza vaccination in China (2020-2021)

Influenza virus infection is a respiratory infectious disease that can seriously affect human health. Influenza viruses can have frequent antigenic variation and changes, which can result in rapid and widespread transmission resulting in annual epidemics and outbreaks in places of public gathering such as schools, kindergartens and nursing homes. The World Health Organization (WHO) estimated that seasonal influenza epidemics have caused an annual 3 to 5 million severe cases, and 290000 to 650000 deaths globally. Pregnant women, young children, the elderly, and persons with chronic illnesses are at high risk for severe illness and death associated with influenza virus infection. Especially, COVID-19 pandemic might co-circulate with other respiratory infectious diseases such as influenza in the coming winter-spring season. Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and complications from infection. Currently, China has licensed trivalent inactivated influenza vaccine (IIV3) which includes split-virus influenza vaccine and subunit vaccine, quadrivalent inactivated influenza vaccine (IIV4) which is split, and trivalent live attenuated influenza vaccine(LAIV3) which was newly licensed. Except for a few major cities, influenza vaccine is a category Ⅱ vaccine, which means influenza vaccination is voluntary, and recipients must pay for it. In 2018 and 2019, the Chinese Center for Disease Control and Prevention issued the"Technical Guidelines for Seasonal Influenza Vaccination in China". In the past year, new research evidences home and abroad have been published, and new seasonal influenza vaccine has been licensed in China. To strengthen the technical guidance for prevention and control of influenza and operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC) Influenza Vaccination Technical Working Group (TWG), updated the 2019-2020 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2020-2021)". The main updates in this version include the following: First, new research evidences especially studies of China, including disease burden, effectiveness, Vaccine-avoidable disease burden, vaccine safety monitoring, and cost-effectiveness and cost-benefit. Second, policies and measures for influenza prevention and control issued by National Health Commission(PRC)in the past year. Thirdly, new type seasonal influenza vaccine licensed and issued in 2020-2021 in China. Fourth, northern hemisphere influenza vaccination composition for the 2020-2021 season which included trivalent and quadrivalent influenza vaccine. Fifth, Influenza vaccination recommendations for 2020-2021 influenza season. The recommendations described in this report include the following: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended, and appropriate product is available. Considering the situation of globally pandemic of COVID-19, to decrease the risk of influenza virus infection and minimize the impact on COVID-19 prevention and control, we recommend the following priority for seasonal influenza vaccination: (1) healthcare workers, including clinical doctors and nurses, public health professionals, quarantine professionals; (2) Vulnerable groups living in nursing homes or welfare homes and staffs who take care those vulnerable groups; (3) People in some key places, such as teachers and students in kindergartens, primary and secondary school, prisoners and staffs of prisons; (4) Other high risk group of influenza, including adults ≥60 years of age, children aged 6-59 months, persons with specific chronic diseases, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to become pregnant during the influenza season. Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. People whoever get IIV or LAIV all apply to the principle. If they were vaccinated in 2019-2020 influenza season or a prior season, 1 dose is recommended. People more than 8 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. For the people unable to be vaccinated before the end of October, influenza vaccination will continue to be offered for the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for use by staff members of the Centers for Disease Control and Prevention at all levels who work on influenza control and prevention, PoVs staff members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and staff members of maternity and child care institutions at all levels. These guidelines will be updated periodically as new evidence becomes available.

Artificial Intelligence Applied to in vitro Gene Expression Testing (IVIGET) to Predict Trivalent Inactivated Influenza Vaccine Immunogenicity in HIV Infected Children.

The number of patients affected by chronic diseases with special vaccination needs is burgeoning. In this scenario, predictive markers of immunogenicity, as well as signatures of immune responses are typically missing even though it would especially improve the identification of personalized immunization practices in these populations. We aimed to develop a predictive score of immunogenicity to Influenza Trivalent Inactivated Vaccination (TIV) by applying deep machine learning algorithms using transcriptional data from sort-purified lymphocyte subsets after in vitro stimulation. Peripheral blood mononuclear cells (PBMCs) collected before TIV from 23 vertically HIV infected children under ART and virally controlled were stimulated in vitro with p09/H1N1 peptides (stim) or left unstimulated (med). A multiplexed-qPCR for 96 genes was made on fixed numbers of 3 B cell subsets, 3 T cell subsets and total PBMCs. The ability to respond to TIV was assessed through hemagglutination Inhibition Assay (HIV) and ELIspot and patients were classified as Responders (R) and Non Responders (NR). A predictive modeling framework was applied to the data set in order to define genes and conditions with the higher predicted probability able to inform the final score. Twelve NR and 11 R were analyzed for gene expression differences in all subsets and 3 conditions [med, stim or Δ (stim-med)]. Differentially expressed genes between R and NR were selected and tested with the Adaptive Boosting Model to build a prediction score. The score obtained from subsets revealed the best prediction score from 46 genes from 5 different subsets and conditions. Calculating a combined score based on these 5 categories, we achieved a model accuracy of 95.6% and only one misclassified patient. These data show how a predictive bioinformatic model applied to transcriptional analysis deriving from in-vitro stimulated lymphocytes subsets may predict poor or protective vaccination immune response in vulnerable populations, such as HIV-infected individuals. Future studies on larger cohorts are needed to validate such strategy in the context of vaccination trials.

Immunogenicity of seasonal inactivated influenza and inactivated polio vaccines among children in Senegal: Results from a cluster-randomized trial

Data on influenza vaccine immunogenicity in children are limited from tropical developing countries. We recently reported significant, moderate effectiveness of a trivalent inactivated influenza vaccine (IIV) in a controlled, cluster-randomized trial in children in rural Senegal during 2009, a year of H3N2 vaccine mismatch (NCT00893906). We report immunogenicity of IIV3 and inactivated polio vaccine (IPV) from that trial. We evaluated hemagglutination inhibition (HAI) and polio antibody titers in response to vaccination of three age groups (6 through 35 months, 3 through 5 years, and 6 through 8 years). As all children were IIV naïve, each received two vaccine doses, although titers were assessed after only the first dose for subjects aged 6 through 8 years. Seroconversion rates (4-fold titer rise or increase from <1:10 to ≥1:40) were 74–87% for A/H1N1, 76–87% for A/H3N2, and 54–79% for B/Yamagata. Seroprotection rates (HAI titer ≥ 1:40) were 79–88% for A/H1N1, 88–96% for A/H3N2, and 52–74% for B/Yamagata. IIV responses were lowest in the youngest age group, and they were comparable between ages 3 through 5 years after two doses and 6 through 8 years after one dose. We found that baseline seropositivity (HAI titer ≥ 1:10) was an effect modifier of IIV response. Using a seroprotective titer (HAI titer ≥ 1:160) recommended for IIV evaluation in children, we found that among subjects who were seropositive at baseline, 69% achieved seroprotection for both A/H1N1 and A/H3N2, while among those who were seronegative at baseline, seroprotection was achieved in 11% for A/H1N1 and 22% for A/H3N2. The IPV group had high baseline polio antibody seropositivity and appropriate responses to vaccination. Our data emphasize the importance of a two-dose IIV3 series in vaccine naïve children. IIV and IPV vaccines were immunogenic in Senegalese children.

Summary of the NACI Supplemental Statement on Mammalian Cell Culture-Based Influenza Vaccines.

Mammalian cell culture-based technology is an innovative technique for influenza vaccine manufacturing that may be a valuable alternative to overcome some of the problems and vulnerabilities associated with conventional egg-based influenza vaccine production. Flucelvax® Quad (Seqirus, Inc.) is the first and only mammalian cell culture-based quadrivalent inactivated, subunit influenza vaccine (IIV4-cc) authorized for adult and pediatric use in Canada. The National Advisory Committee on Immunization (NACI) has not previously made a recommendation on cell culture-based influenza vaccines in any population. To review the available evidence for the efficacy, effectiveness, immunogenicity, and safety of IIV4-cc, and to summarize the NACI recommendation regarding the use of Flucelvax Quad in Canada in adults and children. A systematic literature review on the vaccine efficacy, effectiveness, immunogenicity and safety of IIV4-cc in persons four years of age and older was performed. The systematic review's methodology was specified a priori in a written protocol. The NACI evidence-based process was used to assess the quality of eligible studies, summarize and analyze the findings, and develop a recommendation regarding the use of Flucelvax Quad in adults and children. The proposed recommendation was then considered and approved by NACI in light of the available evidence. Thirteen eligible studies were included in the evidence synthesis. In the four observational studies that assessed vaccine effectiveness of IIV4-cc, there were some data indicating potentially improved protection against influenza compared to conventional egg-based quadrivalent inactivated influenza vaccines (IIV4) or trivalent inactivated influenza vaccine (IIV3), particularly against A(H3N2) virus infection. There was also some evidence that IIV4-cc may be more effective than egg-based trivalent or quadrivalent influenza vaccines against non-laboratory confirmed influenza-related outcomes, but there is insufficient evidence for laboratory-confirmed outcomes. Two randomized controlled trials assessed the immunogenicity and safety of IIV4-cc compared with mammalian cell culture-based trivalent inactivated, subunit influenza vaccine (IIV3-cc). The IIV4-cc was well-tolerated and the reported solicited local and systemic adverse events were generally mild to moderate in intensity, self-limited and did not precipitate sequelae. One clinical review of cases and six peer-reviewed randomized controlled trials (four in adults and two in children) that reported on the safety of IIV3-cc were included in the review. The evidence on immunogenicity and safety was consistent across these studies and showed that there was no significant difference in adults and children four years of age and older who had received IIV3-cc or an egg-based IIV3. NACI concluded that there is fair evidence (Grade B Evidence) that Flucelvax Quad is effective, safe, and has non-inferior immunogenicity to comparable vaccines, based on direct evidence in adults and children nine years of age and older. NACI recommends that Flucelvax Quad may be considered among the IIV4 offered to adults and children nine years of age and older (Discretionary NACI Recommendation).

Enhanced passive safety surveillance of a trivalent and a quadrivalent influenza vaccine in Denmark and Finland during the 2018/2019 season

ABSTRACT The European Medicines Agency requires Enhanced Passive Safety Surveillance (EPSS) for all seasonal influenza vaccines. Here, we report the EPSS results for the trivalent inactivated influenza vaccine (IIV3; Vaxigrip®) and the quadrivalent inactivated influenza vaccine (IIV4; VaxigripTetraTM) during the 2018/19 influenza season in Denmark and Finland. The primary objective was to estimate the rates of suspected adverse reactions (ARs) occurring within 7 days following routine vaccination. Between October and November 2018, 1000 safety report cards (SRCs) for IIV3 were distributed in Denmark, and 996 SRCs for IIV4 were distributed in Finland. Participants were instructed to report any ARs by telephone or e-mail using the information provided on the SRC. All participants vaccinated with IIV3 were aged ≥18 years. Most participants vaccinated with IIV4 (95.5%) were aged 18 − 65 years, 2.2% were aged 6 months to 17 years, and 2.3% were aged >65 years. Fifty-five ARs were reported by 12 participants (1.2%) vaccinated with IIV3 and 162 ARs were reported by 53 participants (5.3%) vaccinated with IIV4. The most frequent ARs were vaccination site pain and fever for IIV3, and vaccination site pain, vaccination site inflammation, myalgia, and headache for IIV4. The 2018/19 AR rates for IIV3 were comparable to 2017/18 rates. The 2018/19 AR rates for IIV4 were higher than those in 2017/18 but were still lower than the expected AR rates listed in the IIV4 Summary of Product Characteristics. In conclusion, the 2018/19 EPSS showed no clinically significant change from the expected safety profiles of IIV3 and IIV4 vaccines.

Relative effectiveness of high dose versus standard dose influenza vaccines in older adult outpatients over four seasons, 2015–16 to 2018–19

BackgroundNew influenza vaccine formulations are designed to improve vaccine effectiveness and protect those most vulnerable to infection. High dose trivalent inactivated influenza vaccine (HD-IIV3), licensed for ages ≥65 years, produces greater antibody responses and efficacy in clinical trials, but post-licensure vaccine effectiveness (VE) compared to standard dose (SD-IIV3/4) vaccine remains an open question. MethodsUsing a test-negative, case control design and propensity analyses to adjust for confounding, US Influenza VE Network data from the 2015–2016 through 2018–2019 seasons were analyzed to determine relative VE (rVE) between HD-IIV3 and SD-IIV3/4 among outpatients ≥65 years old presenting with acute respiratory illness. Influenza vaccination status was derived from electronic medical records and immunization registries. ResultsAmong 3861 enrollees, 2993 (78%) were vaccinated; 1573 (53%) received HD-IIV3 and 1420 (47%) received SD-IIV3/4. HD-IIV3 recipients differed from SD-IIV3/4 recipients by race, previous vaccination, number of outpatient visits in the previous year and timing of vaccination, and were balanced in the propensity model except the timing of vaccination. Compared with no vaccination, significant protection against any influenza A was observed from both HD-IIV3 (VE = 29%; 95%CI = 10%, 44%) and SD-IIV3/4 (VE = 24%; 95%CI = 5%, 39%); rVE = 18% (95%CI = 0%, 33%, SD as referent). When stratified by virus type, against A/H1N1, HD-IIV3 VE was 30% (95%CI = −7%, 54%), SD-IIV3/4 VE was 40% (95%CI = 10%, 61%), and rVE = −32%; (95%CI = −94%, 11%); Against A/H3N2, HD-IIV3 VE was 31% (95%CI = 9%, 47%), SD-IIV3/4 VE was 19% (95%CI = −5%, 37%), and rVE = 27%; (95% CI = 9%, 42%). ConclusionsAmong adults ≥65 years of age, recipients of standard and high dose influenza vaccines differed significantly in their characteristics. After adjusting for these differences, high dose vaccine offered more protection against A/H3N2 and borderline significant protection against all influenza A requiring outpatient care during the 2015–2018 influenza seasons.