Relative vaccine effectiveness of MF59-adjuvanted vs high-dose trivalent inactivated influenza vaccines for prevention of test-confirmed influenza hospitalizations during the 2017-2020 influenza seasons.

OBJECTIVES: This study evaluated relative vaccine effectiveness (rVE) of MF59-adjuvanted trivalent inactivated influenza vaccine (aTIV) vs high-dose trivalent inactivated influenza vaccine (HD-TIV) for prevention of test-confirmed influenza emergency department visits and/or inpatient admissions ("ED/IP") and for IP admissions alone pooled across the 2017-2020 influenza seasons. Exploratory individual season analyses were also performed. METHODS: This retrospective test-negative design study included United States (US) adults age ≥65 years vaccinated with aTIV or HD-TIV who presented to an ED or IP setting with acute respiratory or febrile illness during the 2017-2020 influenza seasons. Test-positive cases and test-negative controls were grouped by vaccine received. The rVE of aTIV vs HD-TIV was evaluated using a combination of inverse probability of treatment weighting and logistic regression to adjust for potential confounders. RESULTS: Pooled analyses over the three seasons found no significant differences in the rVE of aTIV vs HD-TIV for prevention of test-confirmed influenza ED/IP (-2.5% [-19.6, 12.2]) visits and admissions or IP admissions alone (-1.6% [-22.5, 15.7]). The exploratory individual season analyses also showed no significant differences. CONCLUSIONS: Evidence from the 2017-2020 influenza seasons indicates aTIV and HD-TIV are comparable for prevention of test-confirmed influenza ED/IP visits in US adults age ≥65 years.

The relative vaccine effectiveness of high-dose vs standard-dose influenza vaccines in preventing hospitalization and mortality: A meta-analysis of evidence from randomized trials.

OBJECTIVES: To summarize current evidence of high-dose influenza vaccine (HD-IV) vs standard-dose (SD-IV) regarding severe clinical outcomes. METHODS: A prespecified meta-analysis was conducted to assess relative vaccine effectiveness (rVE) of HD-IV vs SD-IV in reducing the rates of (1) pneumonia and influenza (P&I) hospitalization, (2) all hospitalizations, and (3) all-cause death in adults ≥ 65 years in randomized controlled trials. Pooled effect sizes were estimated using fixed-effects models with the inverse variance method. RESULTS: Five randomized trials were included encompassing 105,685 individuals. HD-IV vs SD-IV reduced P&I hospitalizations (rVE: 23.5 %, [95 %CI: 12.3 to 33.2]). HD-IV vs SD-IV also reduced rate of all-cause hospitalizations (rVE: 7.3 %, [95 %CI: 4.5 to 10.0]). No significant differences were observed in death rates (rVE = 1.6 % ([95 %CI: -2.0 to 5.0]) in HD-IV vs SD-IV. Sensitivity analyses omitting trials with participants sharing the same comorbidity, trials with ≥ 100 events, and random-effects models provided comparable estimates for all outcomes. CONCLUSIONS: HD-IV reduced the incidence of P&I and all-cause hospitalization vs SD-IV in adults ≥ 65 years in randomized trials, through no significant difference was observed in all-cause death rates. These findings, supported by evidence from several randomized studies, can benefit from replication in a fully powered, individually randomized trial.

Relative Effectiveness of the MF59®-Adjuvanted Influenza Vaccine Versus High-Dose and Non-Adjuvanted Influenza Vaccines in Preventing Cardiorespiratory Hospitalizations During the 2019-2020 US Influenza Season.

BACKGROUND: Adults ≥ 65 years of age have suboptimal influenza vaccination responses compared to younger adults due to age-related immunosenescence. Two vaccines were specifically developed to enhance protection: MF59-adjuvanted trivalent influenza vaccine (aIIV3) and high-dose egg-based trivalent influenza vaccine (HD-IIV3e). METHODS: In a retrospective cohort study conducted using US electronic medical records linked to claims data during the 2019-2020 influenza season, we compared the relative vaccine effectiveness (rVE) of aIIV3 with HD-IIV3e and a standard-dose non-adjuvanted egg-based quadrivalent inactivated influenza vaccine (IIV4e) for the prevention of cardiorespiratory hospitalizations, including influenza hospitalizations. We evaluated outcomes in the "any" diagnosis position and the "admitting" position on the claim. A doubly robust methodology using inverse probability of treatment weighting and logistic regression was used to adjust for covariate imbalance. rVE was calculated as 100 * (1 - ORadjusted). RESULTS: The study included 4,299,594 adults ≥ 65 years of age who received aIIV3, HD-IIV3e, or IIV4e. Overall, aIIV3 was associated with lower proportions of cardiorespiratory hospitalizations with diagnoses in any position compared to HD-IIV3e (rVE = 3.9% [95% CI, 2.7-5.0]) or IIV4e (9.0% [95% CI, 7.7-10.4]). Specifically, aIIV3 was more effective compared with HD-IIV3e and IIV4e in preventing influenza hospitalizations (HD-IIV3e: 9.7% [95% CI, 1.9-17.0]; IIV4e: 25.3% [95% CI, 17.7-32.2]). Consistent trends were observed for admitting diagnoses. CONCLUSION: Relative to both HD-IIV3e and IIV4e, aIIV3 provided improved protection from cardiorespiratory or influenza hospitalizations.

Immunogenicity of Enhanced Influenza Vaccines Against Mismatched Influenza Strains in Older Adults: A Review of Randomized Controlled Trials.

Antigenic drift is a major driver of viral evolution and a primary reason why influenza vaccines must be reformulated annually. Mismatch between vaccine and circulating viral strains negatively affects vaccine effectiveness and often contributes to higher rates of influenza-related hospitalizations and deaths, particularly in years dominated by A(H3N2). Several countries recommend enhanced influenza vaccines for older adults, who are at the highest risk of severe influenza complications and mortality. The immunogenicity of enhanced vaccines against heterologous A(H3N2) strains has been examined in nine studies to date. In six studies, an enhanced, licensed MF59-adjuvanted trivalent inactivated influenza vaccine (aIIV3) consistently increased heterologous antibody titers relative to standard influenza vaccine, with evidence of a broad heterologous immune response across multiple genetic clades. In one study, licensed high-dose trivalent inactivated influenza vaccine (HD-IIV3) also induced higher heterologous antibody titers than standard influenza vaccine. In a study comparing a higher dose licensed quadrivalent recombinant influenza vaccine (RIV4) with HD-IIV3 and aIIV3, no significant differences in antibody titers against a heterologous strain were observed, although seroconversion rates were higher with RIV4 versus comparators. With the unmet medical need for improved influenza vaccines, the paucity of studies especially with enhanced vaccines covering mismatched strains highlights a need for further investigation of cross-protection in older adults.

Regional Disparities in the Uptake of Differentiated Influenza Vaccines in the United States.

Significant racial/ethnic inequities in the uptake of differentiated influenza vaccines (DIVs) have been previously reported, though less is known about regional disparities. We conducted a retrospective longitudinal study (2014/15-2017/18 influenza seasons) among privately insured adults aged 65 + years in the US. The exposure was the beneficiary's area of residence (US Census Bureau division) and the outcome was the type of influenza vaccine: differentiated (high-dose [HDV], adjuvanted, recombinant, and cell-based) versus conventional standard-dose egg-based. Multilevel logistic regression modeling, guided by a causal diagram, was used to assess the influence of socio-demographics, medical, healthcare utilization, community, and vaccinator characteristics in confounding or mediating regional disparities. Among those vaccinated in physician offices, beneficiaries in the East North Central region were twice as likely to receive a DIV vs those in the South Atlantic, whereas those in the East and West South Central were least likely. Disparities became more pronounced in models adjusted for individual and community characteristics, suggesting that crude uptake estimates understate the true magnitude of disparities. A vaccinator's previous HDV use was most influential in explaining regional differences. Similar but less pronounced patterns emerged for vaccinations in pharmacies/facilities. Regional disparities remained even in fully adjusted models, pointing to currently poorly understood factors that may include quality of healthcare, client health literacy and engagement, and other political and cultural factors.

Rollout of the 2022/2023 Seasonal Influenza Vaccination and Correlates of the Use of Enhanced Vaccines among Italian Adults.

In Italy, several types of seasonal influenza vaccines (SIVs) are available for older adults, but for the 2022/2023 season there were no guidelines on their specific use. This cross-sectional study assessed the frequency and determinants of the use of enhanced (adjuvanted and high-dose) SIVs in Italian older adults, as compared to standard-dose non-adjuvanted formulations. Of 1702 vaccines administered to a representative outpatient sample of adults aged ≥ 60 years and residing in Genoa, 69.5% were enhanced SIVs. Older age (adjusted odds ratio (aOR) for each 1-year increase 1.10; p < 0.001), and the presence of cardiovascular disease (aOR 1.40; p = 0.011) and diabetes (aOR 1.62; p = 0.005) were associated with the use of enhanced vaccines. Compared with the adjuvanted SIV, subjects immunized with the high-dose vaccine were older (aOR for each 1-year increase 1.05; p < 0.001) and had higher prevalence of respiratory diseases (aOR 1.85; p = 0.052). Moreover, usage of the enhanced SIVs was driven by the period of immunization campaign, place of vaccination and physician. Despite their superior immunogenicity and effectiveness, the adoption of enhanced SIVs in Italy is suboptimal, and should be increased. Enhanced formulations are mostly used in the oldest, and in subjects with some co-morbidities.

Estimated health and economic impact of using high-dose influenza vaccine on respiratory and circulatory plus respiratory hospitalizations of older adults in Australia.

Background: Standard dose influenza vaccine provides moderate protection from infection, but with lower effectiveness among the elderly. High dose and adjuvanted vaccines (HD-TIV and aTIV) were developed to address this. This study aims to estimate the incremental health and economic impact of using HD-TIV (high dose trivalent vaccine) instead of aTIV (adjuvanted trivalent vaccine) on respiratory and circulatory plus respiratory hospitalizations of older people (≥65 years) in Australia. Methods: This is a modelling study comparing predicted hospitalization outcomes in people receiving HD-TIV or aTIV during an average influenza season in Australia. Hospitalization records of Australian adults ≥65 years of age from 01 April to 30 November during 15 influenza seasons (2002-2017 excluding 2009, which was a pandemic) were extracted from the Australian Institute of Health and Welfare [AIHW] and used to calculate hospitalisation rates during an average season. Relative vaccine effectiveness data for aTIV and HD-TIV were used to estimate morbidity burden related to influenza. Results: Between 2002 and 2017, the average respiratory hospitalization rate among older people during influenza season (April-November) was 3,445/100,000 population-seasons, with an average cost of AU$ 7,175 per admission. The average circulatory plus respiratory hospitalization rate among older Australian people during that time was 10,393/100,000 population-seasons, with an average cost of AU$ 7829 per admission. For older Australians, HD-TIV may avert an additional 6,315-9,410 respiratory admissions each year, with an incremental healthcare cost saving of AU$ 15.9-38.2 million per year compared to aTIV. Similar results were also noted for circulatory plus respiratory hospitalizations. Conclusions: From the modelled estimations, HD-TIV was associated with less economic burden and fewer respiratory, and circulatory plus respiratory hospitalizations than aTIV for older Australians.

Immunogenicity of adjuvanted versus high-dose inactivated influenza vaccines in older adults: a randomized clinical trial.

BACKGROUND: Adjuvanted inactivated influenza vaccine (aIIV) and high-dose inactivated influenza vaccine (HD-IIV) are U.S.-licensed for adults aged ≥ 65 years. This study compared serum hemagglutination inhibition (HAI) antibody titers for the A(H3N2) and A(H1N1)pdm09 and B strains after trivalent aIIV3 and trivalent HD-IIV3 in an older adult population. RESULTS: The immunogenicity population included 342 participants who received aIIV3 and 338 participants who received HD-IIV3. The proportion of participants that seroconverted to A(H3N2) vaccine strains after allV3 (112 participants [32.8%]) was inferior to the proportion of participants that seroconverted after HD-IIV3 (130 participants [38.5%]) at day 29 after vaccination (difference, - 5.8%; 95%CI, - 12.9% to 1.4%). There were no significant differences between the vaccine groups in percent seroconversion to A(H1N1)pdm09 or B vaccine strains, in percent seropositivity for any of the strains, or in post-vaccination GMT for the A(H1N1)pdm09 strain. The GMTs for the post-vaccination A(H3N2) and B strains were higher after HD-IIV than after aIIV3. CONCLUSIONS: Overall immune responses were similar after aIIV3 and HD-IIV3. For the primary outcome, the aIIV3 seroconversion rate for H3N2 did not meet noninferiority criteria compared with HD-IIV3, but the HD-IIV3 seroconversion rate was not statistically superior to the aIIV3 seroconversion rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03183908.

High-dose influenza vaccine in older adults by age and seasonal characteristics: Systematic review and meta-analysis update.

This updated systematic review and meta-analysis of randomized and observational studies published up to April 2023 assessed the relative performance of high-dose inactivated influenza vaccine (HD-IIV) and standard-dose influenza vaccines (SD-IIV) against influenza-associated outcomes in older adults (≥65 years). The analysis included studies conducted over 12 influenza seasons (2009/2010 to 2019/2020, 2021/2022), including over 45 million individuals aged ≥ 65 years, and showed that HD-IIV provided significantly better protection than SD-IIV against influenza-like illness and influenza-related hospitalizations, as well as cardiovascular, cardiorespiratory, and all-cause hospitalizations. Subgroup analyses showed HD-IIV consistently provided better protection than SD-IIV against influenza outcomes across the age range (65+, 75+ 85+ years), and regardless of the predominantly circulating influenza strain and vaccine antigenic match/mismatch. Randomized studies continue to drive high-quality evidence on the effectiveness of high-dose inactivated influenza vaccine relative to SD-IIV against severe influenza outcomes in adults aged ≥ 65 years, supported by observational data.

High-Dose Influenza Vaccine Is Associated With Reduced Mortality Among Older Adults With Breakthrough Influenza Even When There Is Poor Vaccine-Strain Match.

BACKGROUND: High-dose (HD) influenza vaccine offers improved protection from influenza virus infection among older adults compared with standard-dose (SD) vaccine. Here, we explored whether HD vaccine attenuates disease severity among older adults with breakthrough influenza. METHODS: This was a retrospective cohort study of US claims data for influenza seasons 2016-2017, 2017-2018, and 2018-2019, defined as 1 October through 30 April, among adults aged ≥65 years. After adjusting the different cohorts for the probability of vaccination conditional on patients' characteristics, we compared 30-day mortality rate post-influenza among older adults who experienced breakthrough infection after receipt of HD or SD influenza vaccines and among those not vaccinated (NV). RESULTS: We evaluated 44 456 influenza cases: 23 109 (52%) were unvaccinated, 15 037 (33.8%) received HD vaccine, and 6310 (14.2%) received SD vaccine. Significant reductions in mortality rates among breakthrough cases were observed across all 3 seasons for HD vs NV, ranging from 17% to 29% reductions. A significant mortality reduction of 25% was associated with SD vaccination vs NV in the 2016-2017 season when there was a good match between circulating influenza viruses and selected vaccine strains. When comparing HD vs SD cohorts, mortality reductions were higher among those who received HD in the last 2 seasons when mismatch between vaccine strains and circulating H3N2 viruses was documented, albeit not significant. CONCLUSIONS: HD vaccination was associated with lower post-influenza mortality among older adults with breakthrough influenza, even during seasons when antigenically drifted H3N2 circulated. Improved understanding of the impact of different vaccines on attenuating disease severity is warranted when assessing vaccine policy recommendations.

Cost-effectiveness of influenza vaccination with a high dose quadrivalent vaccine of the elderly population in Belgium, Finland, and Portugal.

BACKGROUND: Seasonal influenza may result in severe outcomes, resulting in a significant increase of hospitalizations during the winter. To improve the protection provided by the standard dose influenza quadrivalent vaccine (SDQIV), a high-dose vaccine (HDQIV) has been developed specifically for adults aged 60 and older who are at higher risk of life-threatening complications. OBJECTIVES: The aim of this study was to determine the cost-effectiveness of HD QIV vs. SD-QIV in the recommended population of three European countries: Belgium, Finland and Portugal. METHODS: A cost-utility analysis comparing HDQIV vs. SDQIV was conducted using a decision tree estimating health outcomes conditional on influenza: cases, general practitioner and emergency department visits, hospitalizations and deaths. To account for the full benefit of the vaccine, an additional outcome-hospitalizations attributable to influenza-was also evaluated. Demographic, epidemiological and economic inputs were based on the respective local data. HDQIV relative vaccine efficacy vs. SDQIV was obtained from a phase IV efficacy randomized clinical trial. The incremental cost-effectiveness ratios (ICER) were computed for each country, and a probabilistic sensitivity analysis (1,000 simulations per country) was performed to assess the robustness of the results. RESULTS: In the base case analysis, HDQIV resulted in improved health outcomes (visits, hospitalizations, and deaths) compared to SDQIV. The ICERs computed were 1,397, 9,581, and 15,267 €/QALY, whereas the PSA yielded 100, 100, and 84% of simulations being cost-effective at their respective willingness-to-pay thresholds, for Belgium, Finland, and Portugal, respectively. CONCLUSION: In three European countries with different healthcare systems, HD-QIV would contribute to a significant improvement in the prevention of influenza health outcomes while being cost-effective.

High-dose influenza vaccines for the prevention of hospitalization due to cardiovascular events in older adults in the nursing home: Post-hoc analysis of a cluster-randomized trial.

Older adults are at high risk of major acute cardiovascular events (MACE) linked to influenza illness andpreventable by influenza vaccination. It is unknown whether high-dose vaccine might incrementally reduce the risk of MACE.We conducted a post-hoc analysis of data collected from a pragmatic cluster randomized study of 823 nursing homes (NH) randomized to standard-dose (SD) or high-dose (HD) influenza vaccine in the 2013-14 season. Adults age 65 year or older who are Medicare-enrolled long-stay residents were included in the analysis.There were no statistically significant differences in hospitalization for MACE, acute coronary syndromes (ACS), stroke or heart failure between the HD and SD arms. However, in the fee-for-service group, participants in the HD arm had significantly decreased risk of hospitalization for respiratory problems, which was not observed in the Medicare Advantage group.High-dose influenza vaccine was not shown to be incrementally protective against MACE relative to standard-dose vaccine.

What explains racial/ethnic inequities in the uptake of differentiated influenza vaccines?

We investigated the role of individual, community and vaccinator characteristics in mediating racial/ethnic disparities in the uptake of differentiated influenza vaccines (DIVs; including high-dose, adjuvanted, recombinant and cell-based vaccines). We included privately-insured (commercial and Medicare Advantage) ≥65 years-old community-dwelling health plan beneficiaries in the US with >1 year of continuous coverage and who received ≥1 influenza vaccine during the study period (July 2014-June 2018). Of 2.8 million distinct vaccination claims, 60% were for DIVs; lower if received in physician offices (49%) compared to pharmacies/facilities (74%). Among those vaccinated in physician offices, non-whites had lower odds of receiving a DIV if they lived in a non-minority county (0.77;95%CI 0.75-0.80) and even lower odds if they lived in a minority county (0.62;0.60-0.63). Differences in education, household income, medical history, community and vaccinator characteristics did not fully explain the disparities. Similar patterns emerged for vaccinations in pharmacies/facilities, although disparities disappeared altogether after controlling for socio-economic and vaccinator characteristics. When vaccinated in physician offices, minority county residents were less likely to receive a DIV, especially for non-whites (0.72;0.67-0.78). These disparities disappeared for whites, but not for non-whites, after controlling for community and vaccinator characteristics. We found an alarming level of inequity in DIV vaccine uptake among fully insured older adults that could not be fully explained by differences in sociodemographic, medical, community, and vaccinator characteristics. New strategies are urgently needed to address these inequities.

Comparative effectiveness of adjuvanted versus high-dose seasonal influenza vaccines for older adults: a systematic review and meta-analysis.

OBJECTIVES: MF59-adjuvanted standard-dose and nonadjuvanted high-dose seasonal influenza vaccines have been developed to protect the elderly at high risk of severe complications. This study aimed to summarize the available evidence on the comparative efficacy/effectiveness of these two vaccines. METHODS: A systematic literature review of experimental and observational studies were conducted according to the preferred reporting items for systematic reviews and meta-analyses guidelines. When possible, the extracted effect sizes were pooled in random-effects meta-analyses. RESULTS: Ten studies were identified. Of these, no head-to-head randomized controlled trials were identified. All available studies had retrospective cohort design and large sample sizes, were conducted in the United States between the 2016-2017 and 2019-2020 seasons, and were at moderate risk of bias. Relative effectiveness estimates were limited to nonlaboratory-confirmed clinical end points, such as medical encounters including hospitalizations. Although most pooled relative effectiveness estimates were close to null, few statistically significant pooled effect sizes were small in magnitude, moved in opposite directions, and depended on the study sponsor and specificity of influenza-related outcomes. CONCLUSION: At present, MF59-adjuvanted standard-dose and nonadjuvanted high-dose vaccines appear to have similar effectiveness in preventing seasonal influenza in the elderly, and no conclusive recommendations on the preference of one vaccine over another could be drawn.

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

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

Comparative efficacy and safety of vaccines to prevent seasonal influenza: A systematic review and network meta-analysis.

Background: Influenza is one of the most common respiratory viral infections worldwide. Numerous vaccines are used to prevent influenza. Their selection should be informed by the best available evidence. We aimed to estimate the comparative efficacy and safety of seasonal influenza vaccines in children, adults and the elderly. Methods: We conducted a systematic review and network meta-analysis (NMA). We searched the Cochrane Library Central Register of Controlled Trials, MEDLINE and EMBASE databases, and websites of regulatory agencies, through December 15th, 2020. We included placebo- or no vaccination-controlled, and head-to-head randomized clinical trials (RCTs). Pairs of reviewers independently screened the studies, abstracted the data, and appraised the risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions. The primary outcome was laboratory-confirmed influenza. We also synthesized data for hospitalization, mortality, influenza-like illness (ILI), pneumonia or lower respiratory-tract disease, systemic and local adverse events (AEs). We estimated summary risk ratios (RR) using pairwise and NMA with random effects. This study is registered with PROSPERO, number CRD42018091895. Findings: We identified 13,439 citations. A total of 231 RCTs were included after screening: 11 studies did not provide useful data for the analysis; 220 RCTs [100,677 children (< 18 years) and 329,127 adults (18-60 years) and elderly (≥ 61 years)] were included in the NMA. In adults and the elderly, all vaccines, except the trivalent inactivated intradermal vaccine (3-IIV ID), were more effective than placebo in reducing the risk of laboratory-confirmed influenza, with a RR between 0.33 (95% credible interval [CrI] 0.21-0.55) for trivalent inactivated high-dose (3-IIV HD) and 0.56 (95% CrI 0.41-0.74) for trivalent live-attenuated vaccine (3-LAIV). In adults and the elderly, compared with trivalent inactivated vaccine (3-IIV), no significant differences were found for any, except 3-LAIV, which was less efficacious [RR 1.41 (95% CrI 1.04-1.88)]. In children, compared with placebo, RR ranged between 0.13 (95% CrI 0.03-0.51) for trivalent inactivated vaccine adjuvanted with MF59/AS03 and 0.55 (95% CrI 0.36-0.83) for trivalent inactivated vaccine. Compared with 3-IIV, 3-LAIV and trivalent inactivated adjuvanted with MF59/AS03 were more efficacious [RR 0.52 (95% CrI 0.32-0.82) and RR 0.23 (95% CrI 0.06-0.87)] in reducing laboratory-confirmed influenza. With regard to safety, higher systemic AEs rates after vaccination with 3-IIV, 3-IIV HD, 3-IIV ID, 3-IIV MF59/AS03-adj, quadrivalent inactivated (4-IIV), quadrivalent adjuvanted (4-IIV MF59/AS03-adj), quadrivalent recombinant (4-RIV), 3-LAIV or quadrivalent live attenuated (4-LAIV) vaccines were noted in adults and the elderly [RR 1.5 (95% CrI 1.18-1.89) to 1.15 (95% CrI 1.06-1.23)] compared with placebo. In children, the systemic AEs rate after vaccination was not significantly higher than placebo. Interpretation: All vaccines cumulatively achieved major reductions in the incidence of laboratory-confirmed influenza in children, adults, and the elderly. While the live-attenuated was more efficacious than the inactivated vaccine in children, many vaccine types can be used in adults and the elderly. Funding: The directorate general of welfare, Lombardy region.

Immunogenicity and safety of a quadrivalent high-dose inactivated influenza vaccine compared with a standard-dose quadrivalent influenza vaccine in healthy people aged 60 years or older: a randomized Phase III trial.

A quadrivalent high-dose inactivated influenza vaccine (IIV4-HD) is licensed for adults ≥65 y of age based on immunogenicity and efficacy studies. However, IIV4-HD has not been evaluated in adults aged 60-64 y. This study compared immunogenicity and safety of IIV4-HD with a standard-dose quadrivalent influenza vaccine (IIV4-SD) in adults aged ≥60 y. This Phase III, randomized, modified double-blind, active-controlled study enrolled 1,528 participants aged ≥60 y, randomized 1:1 to a single injection of IIV4-HD or IIV4-SD. Hemagglutination inhibition (HAI) geometric mean titers (GMTs) were measured at baseline and D 28 and seroconversion assessed. Safety was described for 180 d after vaccination. The primary immunogenicity objective was superiority of IIV4-HD versus IIV4-SD, for all four influenza strains 28 d post vaccination in participants aged 60-64 and ≥65 y. IIV4-HD induced a superior immune response versus IIV4-SD in terms of GMTs in participants aged 60-64 y and those aged ≥65 y for all four influenza strains. IIV4-HD induced higher GMTs in those aged 60-64 y than those aged ≥65 y. Seroconversion rates were higher for IIV4-HD versus IIV4-SD in each age-group for all influenza strains. Both vaccines were well tolerated in participants ≥60 y of age, with no safety concerns identified. More solicited reactions were reported with IIV4-HD than with IIV4-SD. IIV4-HD provided superior immunogenicity versus IIV4-SD and was well tolerated in adults aged ≥60 y. IIV4-HD is assumed to offer improved protection against influenza compared with IIV4-SD in adults aged ≥60 y, as was previously assessed for adults aged ≥65 y.

Economic evaluation of high-dose inactivated influenza vaccine in adults aged ≥65 years: A systematic literature review.

INTRODUCTION: Due to waning immunity, adults aged ≥65 years are at increased risk of seasonal influenza infection and its complications. Adding to this risk, older adults have reduced responses to influenza vaccines. A high-dose trivalent inactivated influenza vaccine (Fluzone High-Dose, Sanofi Pasteur) (IIV3-HD) was developed to improve protection against influenza in adults aged ≥65 years and has been licensed in the US since 2009 and in Canada since 2015. Post-licensure studies have shown that IIV3-HD is more effective than standard-dose trivalent inactivated influenza vaccine (IIV3-SD) at protecting against influenza infection in this population. Here, we performed a systematic review of economic analyses of IIV3-HD in adults aged ≥65 years. METHODS: On June 9, 2019, using the Ovid search platform, we searched Econlit, Embase, and Ovid MEDLINE® for original studies published in peer-reviewed journals examining the economics or cost-effectiveness of IIV3-HD in adults aged ≥65 years. Two reviewers independently selected studies and assessed their quality. RESULTS: Seven studies were selected, all performed in the US or Canada. Five studies were funded by IIV3-HD manufacturer, and the remaining two by the US National Institute of General Medical Sciences. In all studies, IIV3-HD reduces healthcare resource utilization and is cost-effective or cost-saving compared to IIV3-SD. The main driver is reduced hospitalizations for cardiorespiratory events. CONCLUSION: IIV3-HD is cost-saving or cost-effective versus IIV3-SD in adults aged ≥65 years. Reduced cardiorespiratory complications are an important driver of these economic benefits. A video summary of the article can be accessed via the Supplementary data link at the end of this article.

Influenza vaccination in immunocompromised populations: Strategies to improve immunogenicity.

Immunocompromised individuals are at high risk of severe illness and complications from influenza infection. For this reason, immunization using inactivated influenza vaccines is recommended for transplant patients, individuals receiving immunosuppressant treatments, and other persons with immunodeficiency. However, these immunocompromised populations are more likely to have lower and non-protective responses to annual vaccination with a standard influenza vaccine. Here, we review strategies aimed to improve the immunogenicity of influenza vaccines in immunocompromised populations. The different strategies employed have included adjuvanted vaccines, high-dose vaccines, booster doses, intradermal vaccination, and temporary discontinuation of immunosuppressant treatment regimens. High-dose trivalent, inactivated, split-virus influenza vaccine (IIV3-HD) is so far one of the leading strategies for improving vaccine responses in HIV patients, transplant patients, and persons receiving immunosuppressant therapies for inflammatory diseases. Several studies in these populations have shown stronger humoral responses with IIV3-HD than existing standard-dose trivalent vaccine, and comparable safety. Accordingly, some scientific societies have stated that high-dose influenza vaccine could be a preferred option for immunocompromised patients. However, larger randomized controlled studies are needed to validate relative immunogenicity and safety of IIV3-HD and other enhanced vaccines and vaccination strategies in immunocompromised individuals.

Efficacy and effectiveness of high-dose influenza vaccine in older adults by circulating strain and antigenic match: An updated systematic review and meta-analysis.

BACKGROUND: Influenza vaccine efficacy/effectiveness can vary from season to season due in part to the dominant circulating strains and antigenic matching. This study reviews the relative vaccine efficacy/effectiveness (rVE) of high-dose inactivated trivalent influenza vaccine (HD-IIV3) compared to standard-dose influenza vaccines (SD-IIV) in adults aged ≥ 65 years against influenza-associated outcomes. Additional sub-analyses of HD-IIV3 rVE were performed by the predominantly circulating influenza strain and the antigenic match or mismatch of the vaccine against the predominant circulating strains. METHODS: An updated systematic review and meta-analysis was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults aged ≥ 65 years. Results from individual seasons were extracted from the studies, and viral surveillance data were used to determine the dominant circulating strains and antigenic match for each season. Results were then stratified based on clinical outcomes and seasonal characteristics and meta-analyzed to estimate pooled rVEs of HD-IIV3. RESULTS: 15 publications were meta-analyzed after screening 1,293 studies, providing data on 10 consecutive influenza seasons and over 22 million individuals receiving HD-IIV3 in randomized and observational settings. Across all influenza seasons, HD-IIV3 demonstrated improved protection against ILI compared to SD-IIV (rVE = 15.9%, 95% CI: 4.1-26.3%). HD-IIV3 was also more effective at preventing hospital admissions from all-causes (rVE = 8.4%, 95% CI: 5.7-11.0%), as well as influenza (rVE = 11.7%, 95% CI: 7.0-16.1%), pneumonia (rVE = 27.3%, 95% CI: 15.3-37.6%), combined pneumonia/influenza (rVE = 13.4%, 95% CI: 7.3-19.2%) and cardiorespiratory events (rVE = 17.9%, 95% CI: 15.0-20.8%). Reductions in mortality due to pneumonia/influenza (rVE = 39.9%, 95% CI: 18.6-55.6%) and cardiorespiratory causes (rVE = 27.7%, 95% CI: 13.2-32.0%) were also observed. Similar pooled rVEs were observed in both matched and mismatched seasons and in seasons where A/H3N2 or A/H1N1 strains were predominantly circulating. CONCLUSIONS: Evidence over 10 consecutive influenza seasons and in more than 34 million individuals aged ≥ 65 years suggests that HD-IIV3 is consistently more effective than SD-IIV at reducing influenza cases as well as influenza-associated clinical complications irrespective of circulating strain and antigenic match. A video summary of the article can be accessed via the Supplementary data link at the end of this article.