High-dose Trivalent Influenza Vaccine Research Articles

Immunogenicity and Safety of Alternative Influenza Vaccination Strategies in Repeated Seasons in Pediatric Hematopoietic-Cell Transplant Recipients

Abstract Background Pediatric hematopoietic cell transplant (HCT) recipients are at increased risk for morbidity and mortality from influenza infection. Annual influenza vaccination is recommended; however, HCT recipients have diminished immune responses to vaccination. Our recent trial demonstrated that two doses of high-dose trivalent influenza vaccine (HD-TIV) given four weeks apart post-HCT were more immunogenic than two doses of standard dose quadrivalent influenza vaccine (SD-QIV). We assessed the impact of this strategy in a consecutive season post-HCT. Methods The initial trial was a multi-center double-blinded phase II randomized controlled trial comparing two doses of HD-TIV to two doses of SD-QIV in children 3-17 years old given 3-35 months post-allogeneic HCT. Participants completing the initial trial could re-enroll the subsequent influenza season to receive the same two-dose vaccine formulation. Hemagglutinin inhibition (HAI) titers were measured at baseline and 28-42 days following each dose. Injection-site and systemic adverse events were assessed. The immunogenicity endpoints were the post-dose 1 and post-dose 2 geometric mean HAI titers (GMTs) in the second year of participation. Results A total of 170 participants were enrolled in the initial trial, with 65 re-enrolling for a second year (n=33 SD-QIV and n=32 HD-TIV). Post-dose 1 and 2 GMTs were higher for both the SD-QIV and HD-TIV groups in the second year compared the first year (Table 1). In year two, the adjusted geometric mean ratio (aGMR) comparing HD-TIV to SD-QIV was higher post-dose 1 for A/H1N1 (aGMR=1.99, 95% CI:[1.07, 3.68]). The HD-TIV group demonstrated a higher frequency of four-fold titer rise after a single dose compared to two doses of SD-QIV for A/H3N2 (61% vs. 48%) and B/Victoria (77% vs. 65%). Frequency of injection site and systemic reactions were similar between the HD-TIV and SD-QIV groups in year two. Conclusions The post-dose 1 and 2 GMTs were consistently higher for HD-TIV compared to SD-QIV in year two, and aGMR reached statistical significance after a single dose of HD-TIV for A/H1N1. Year two reactogenicity was comparable for both vaccination strategies. Further studies with larger numbers of participants are needed to demonstrate if one or two doses of HD-TIV are needed in subsequent influenza seasons post-HCT when a two-dose vaccination series is given in the first post-HCT season. Table 1. Point estimates and 95% CIs for geometric mean HAI titer, titer ≥1:40, and proportion with ≥4-fold rise from baseline for each vaccine regimen, stratified for each antigen. Also included is the ratio of the observed values (n) to the number of evaluable subjects (N) at each visit. Baseline titers are measured prior to first vaccine dose, post-dose 1 titers are measured 28-42 days following first dose (prior to the second dose), post-dose 2 titers are measured 28-42 days following second dose. Table 1 Note: If 100% achieved seroprotection or seroconversion, “n/a” was entered as a two-sided 95% CI could not be calculated.

Temporal Association Among Influenza-Like Illness, Cardiovascular Events, and Vaccine Dose in Patients With High-Risk Cardiovascular Disease

Influenza-like illness (ILI) activity has been associated with increased risk of cardiopulmonary (CP) events during the influenza season. High-dose trivalent influenza vaccine was not superior to standard-dose quadrivalent vaccine for reducing these events in patients with high-risk cardiovascular (CV) disease in the Influenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated Heart Failure (INVESTED) trial. To evaluate whether high-dose trivalent influenza vaccination is associated with benefit over standard-dose quadrivalent vaccination in reducing CP events during periods of high, local influenza activity. This study was a prespecified secondary analysis of INVESTED, a multicenter, double-blind, active comparator randomized clinical trial conducted over 3 consecutive influenza seasons from September 2016 to July 2019. Follow-up was completed in July 2019, and data were analyzed from September 21, 2016, to July 31, 2019. Weekly Centers for Disease Control and Prevention (CDC)-reported, state-level ILI activity was ascertained to assess the weekly odds of the primary outcome. The study population included 3094 patients with high-risk CV disease from participating centers in the US. Participants were randomized to high-dose trivalent or standard-dose quadrivalent influenza vaccine and revaccinated for up to 3 seasons. The primary outcome was the time to composite of all-cause death or CP hospitalization within each season. Additional measures included weekly CDC-reported ILI activity data by state. Among 3094 participants (mean [SD] age, 65 [12] years; 2309 male [75%]), we analyzed 129 285 person-weeks of enrollment, including 1396 composite primary outcome events (1278 CP hospitalization, 118 deaths). A 1% ILI increase in the prior week was associated with an increased risk in the primary outcome (odds ratio [OR], 1.14; 95% CI, 1.07-1.21; P < .001), CP hospitalization (OR, 1.13; 95% CI, 1.06-1.21; P < .001), and CV hospitalization (OR, 1.12; 95% CI, 1.04-1.19; P = .001), after adjusting for state, demographic characteristics, enrollment strata, and CV risk factors. Increased ILI activity was not associated with all-cause death (OR, 1.00; 95% CI, 0.88-1.13; P > .99). High-dose compared with standard-dose vaccine did not significantly reduce the primary outcome, even when the analysis was restricted to weeks of high ILI activity (OR, 0.88; 95% CI, 0.65-1.20; P = .43). Traditionally warmer months in the US were associated with lower CV risk independent of local ILI activity. In this secondary analysis of a randomized clinical trial, ILI activity was temporally associated with increased CP events in patients with high-risk CV disease, and a higher influenza vaccine dose did not significantly reduce temporal CV risk. Other seasonal factors may play a role in the coincident high rates of ILI and CV events. ClinicalTrials.gov Identifier: NCT02787044.

25. Relative Effectiveness of Adjuvanted Trivalent Influenza Vaccine Compared to Egg-Based Trivalent High-Dose Influenza Vaccine among U.S. Older Adults during 2019-20 Influenza Season

BackgroundAccording to the Centers for Disease Control and Prevention (CDC), during the 2019-20 U.S. influenza season, influenza resulted in almost 180,000 hospitalizations and over 13,000 deaths in adults ≥ 65 years. The current study evaluated the relative vaccine effectiveness (rVE) of adjuvanted trivalent influenza vaccine (aTIV) compared to high-dose trivalent influenza vaccine (TIV-HD), against influenza-related hospitalizations/emergency room (ER) visits, all-cause hospitalizations and hospitalizations/ER visits for cardio-respiratory disease (CRD) among adults ≥65 years for the 2019-20 influenza season.MethodsA retrospective cohort analysis of older adults (≥ 65 years) was conducted using IQVIA’s professional fee, prescription claims and hospital charge master data in the U.S. Baseline characteristics included age, gender, payer type, geographic region, Charlson Comorbidity Index (CCI), comorbidities, indicators of frail health status, and pre-index hospitalization rates. To avoid any influenza outcome misclassification with COVID-19 infection, the study period ended March 7, 2020. Adjusted analyses were conducted through inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted pairwise rVE against influenza-related hospitalizations/ER visits, all-cause hospitalizations and any hospitalization/ER visit for CRD. An unrelated negative control outcome, urinary tract infection (UTI) hospitalization was included.ResultsDuring the 2019-20 influenza season, following IPTW, 798,987 recipients of aTIV and 1,655,979 recipients of TIV-HD were identified. After IPTW adjustment and Poisson regression, aTIV was statistically comparable to TIV-HD for prevention of influenza-related hospitalizations/ER visits (3.1%; 95% CI: -2.8%-8.6%) and all-cause hospitalizations (-0.7%; 95% CI: -1.6%-0.3%). Similar comparable outcomes were found for reduction of any hospitalization/ER visit for CRD (0.9%; 95% CI: 0.0%-1.7%). No treatment effect was identified for the negative control outcome. ConclusionaTIV and TIV-HD demonstrated comparable reductions in influenza-related hospitalizations/ER visits, all-cause hospitalizations and hospitalizations/ER visits for CRD.Disclosures myron J. levin, MD, GSK group of companies (Employee, Research Grant or Support) Victoria Divino, PhD, Seqirus (Consultant) Stephen I. Pelton, MD, Seqirus (Consultant) Maarten Postma, Dr., Seqirus (Consultant) Drishti Shah, PhD, Seqirus (Consultant) Joaquin F. Mould-Quevedo, PhD, Seqirus (Employee) Mitchell DeKoven, PhD, Seqirus (Consultant)

Comparing the Clinical and Economic Outcomes Associated with Adjuvanted versus High-Dose Trivalent Influenza Vaccine among Adults Aged ≥ 65 Years in the US during the 2019-20 Influenza Season-A Retrospective Cohort Analysis.

The burden of influenza is disproportionally higher among older adults. We evaluated the relative vaccine effectiveness (rVE) of adjuvanted trivalent (aIIV3) compared to high-dose trivalent influenza vaccine (HD-IIV3e) against influenza and cardio-respiratory disease (CRD)-related hospitalizations/ER visits among adults ≥65 years during the 2019–2020 influenza season. Economic outcomes were also compared. A retrospective cohort analysis was conducted using prescription, professional fee claims, and hospital data. Inverse probability of treatment weighting (IPTW) was used to adjust for confounding. IPTW-adjusted Poisson regression was used to evaluate the adjusted rVE of aIIV3 versus HD-IIV3e. All-cause and influenza-related healthcare resource utilization (HCRU) and costs were examined post-IPTW. Recycled predictions from generalized linear models were used to estimate adjusted costs. Adjusted analysis showed that aIIV3 (n = 798,987) was similarly effective compared to HD-IIV3e (n = 1,655,979) in preventing influenza-related hospitalizations/ER visits (rVE 3.1%; 95% CI: −2.8%; 8.6%), hospitalizations due to any cause (−0.7%; 95% CI: −1.6%; 0.3%), and any CRD-related hospitalization/ER visit (0.9%; 95% CI: 0.01%; 1.7%). Adjusted HCRU and annualized costs were also statistically insignificant between the two cohorts. The adjusted clinical and economic outcomes evaluated in this study were comparable between aIIV3 and HD-IIV3e during the 2019–2020 influenza season.

Clinical efficacy and safety of high dose trivalent influenza vaccine in adults and immunosuppressed populations – A systematic review and meta-analysis

ObjectivesInfluenza is associated with significant morbidity and mortality, especially in older and immunocompromised patients. Few data are available on the clinical benefit of high dose trivalent influenza vaccine (TIV). We aimed to assess the clinical efficacy and safety of high dose TIV. MethodsWe conducted a systematic review and meta-analysis of randomized controlled trials (RCTs), evaluating high dose versus standard dose TIV for prevention of seasonal influenza in adult population. Primary outcome was laboratory-confirmed influenza. Subgroups analyses included older adults and immunocompromised patients. ResultsWe included 16 trials, 47,857 patients; 10 included older adults and three immunocompromised patients. Laboratory confirmed influenza was significantly reduced with high dose TIV (relative risk 0.76, 95% confidence interval 0.64 to 0.9). This outcome stemmed mainly from one trial in older adults. Specifically, A(H3N2) laboratory confirmed influenza, but not A(H1N1) or B lineages, was reduced. No difference in mortality or hospitalizations was demonstrated. Immunological response was significantly higher with high dose vaccine. Serious adverse events were significantly less common in the high dose group. ConclusionsHigh dose TIV lowers the rates of laboratory confirmed influenza, mainly A (H3N2), in older adults vs. standard dose. Further studies should address immunocompromised patients and report clinical outcomes.

A retrospective cohort study assessing relative effectiveness of adjuvanted versus high-dose trivalent influenza vaccines among older adults in the United States during the 2018–19 influenza season

PurposeTo evaluate the relative vaccine effectiveness (rVE) against influenza-related hospitalizations/emergency room (ER) visits, influenza-related office visits, and cardio-respiratory disease (CRD)-related hospitalizations/ER visits and compare all-cause and influenza-related costs associated with two vaccines specifically indicated for older adults (≥65 years), adjuvanted (aTIV) and high-dose trivalent influenza vaccine (TIV-HD), for the 2018–19 influenza season. MethodsA retrospective analysis of older adults was conducted using claims and hospital data in the United States. For clinical evaluations, adjusted analyses were conducted following inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted rVE against influenza-related hospitalizations/ER visits, influenza-related office visits, and any CRD-related hospitalizations/ER visits. For the economic evaluation, treatment selection bias was adjusted through 1:1 propensity score matching (PSM). All-cause and influenza-related costs associated with hospitalizations/ER, physician office and pharmacy visits were adjusted using generalized estimating equation (GEE) models. ResultsAfter IPTW and Poisson regression, aTIV (n = 561,315) was slightly more effective in reducing influenza-related office visits compared to TIV-HD (n = 1,672,779) (6.6%; 95% CI: 2.8–10.3%). aTIV was statistically comparable to TIV-HD (2.0%; 95% CI: −3.7%-7.3%) in preventing influenza-related hospitalizations/ER visits but more effective in reducing hospitalizations/ER visits for any CRD (2.6%; 95% CI: 2.0–3.2%). In the PSM-adjusted cohorts (n = 561,243 pairs), following GEE adjustments, predicted mean annualized all-cause and influenza-related total costs per patient were statistically similar between aTIV and TIV-HD (US$9676 vs. US$9625 and US$18.74 vs. US$17.28, respectively; both p > 0.05). Finally, influenza-related pharmacy costs were slightly lower for aTIV as compared to TIV-HD ($1.75 vs $1.85; p < 0.0001). ConclusionsDuring the 2018–19 influenza season, influenza-related hospitalization/ER visits and associated costs among people aged ≥ 65 were comparable between aTIV and TIV-HD. aTIV was slightly more effective in preventing influenza-related office visits and any CRD event as compared to TIV-HD in this 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.

The humoral immune response to high-dose influenza vaccine in persons with monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL)

BackgroundLimited data are available regarding the immunogenicity of high-dose influenza vaccine among persons with chronic lymphocytic leukemia (CLL) and monoclonal B cell lymphocytosis (MBL). MethodsA prospective pilot study of humoral immune responses to 2013–2014 and 2014–2015 high-dose trivalent influenza vaccine (HD IIV; Fluzone® High-Dose; Sanofi Pasteur) was conducted among individuals with MBL and previously untreated CLL. Serum hemagglutination inhibition (HAI) antibody titers were measured at baseline and Day 28 after vaccination; seroprotection and seroconversion rates were determined. Memory B cell responses were assessed by B-cell enzyme-linked immune absorbent spotassays. ResultsThirty subjects (17 CLL and 13 MBL) were included. Median age was 69.5 years. Day 28 seroprotection rates for the cohort were 19/30 (63.3%) for A/H1N1; 21/23 (91.3%) for A/H3N2; and 13/30 (43.3%) for influenza B. Those with MBL achieved higher day 28 HAI geometric mean titers (54.1 [4.9, 600.1] vs. 12.1 [1.3, 110.1]; p = 0.01) and higher Day 28 seroprotection rates (76.9% vs. 17.6%; p = 0.002) against the influenza B-vaccine strain virus than those with CLL. ConclusionsImmunogenicity of the HD IIV3 in patients with CLL and MBL is lower than reported in healthy adults. Immunogenicity to influenza B was greater in those with MBL than CLL.

Cost-effectiveness of high dose versus adjuvanted trivalent influenza vaccines in England and Wales

Aims High dose trivalent influenza vaccine (HD TIV) and adjuvant TIV (aTIV) have been developed specifically for adults aged 65 and older (65+) who are at high risk of life-threatening complications. However, there is a scarcity of evidence comparing the clinical and cost-effectiveness of HD TIV and aTIV. The aim of this study was to determine the cost-effectiveness of HD TIV versus aTIV in the England and Wales 65+ population. Methods A cost-utility analysis was conducted using a decision tree with two influenza related outcomes: Laboratory confirmed cases that could result in GP consultation, and hospitalizations that may result in premature mortality. Due to a lack of comparative evidence, the effectiveness of HD TIV versus aTIV was calculated indirectly, based on relative effectiveness estimates for each vaccine versus a common comparator, standard dose (SD) TIV. The primary analysis included hospitalizations explicitly due to influenza/pneumonia. Cost-effectiveness was established for three scenarios applying differing relative effectiveness estimates for aTIV versus SD TIV. Uncertainty was analysed in one-way deterministic sensitivity analyses. A secondary analysis included hospitalizations due to any respiratory illness. Results The minimum population impact of vaccination with HD TIV rather than aTIV was 13,092 fewer influenza cases, 1,109 fewer influenza related deaths, 4,673 fewer hospitalizations, and 3,245 fewer GP appointments. HD TIV was cost-effective versus aTIV for all three effectiveness scenarios, with incremental cost-effectiveness ratios (ICER) equal to £1,932, £4,181, and £8,767 per quality adjusted life year. Results were consistent across the secondary analysis and deterministic sensitivity analyses. Limitations The analysis was limited by a lack of robust and consistent effectiveness data for aTIV. Conclusion HD TIV is cost-effective versus aTIV in people aged 65+ in England and Wales. Use of HD TIV over aTIV could increase clinical benefits and reduce the public health and economic burden of influenza.

6. MF59 ASSURANCE 2: A Real-world Study to Estimate the Relative Vaccine Effectiveness of Adjuvanted Trivalent Influenza Vaccine Compared to Egg-based Trivalent High-dose Among U.S. Older Adults During 2018–19 Influenza Season

BackgroundIn the 2018–19 influenza season, influenza resulted in almost 280,000 hospitalizations and over 25,000 deaths in U.S. adults > 65 years. This study aimed to evaluate the relative vaccine effectiveness (rVE) of adjuvant trivalent influenza vaccine (aTIV) compared to high-dose trivalent influenza vaccine (TIV-HD), against influenza-related hospitalizations/emergency room (ER) visits, office visits and hospitalization/ER visit for cardio-respiratory disease (CRD) among older adults for the 2018–19 flu season.MethodsA retrospective cohort analysis of older adults (> 65 years) was conducted using professional fee, prescription claims and hospital charge master data in the U.S. Baseline characteristics included age, gender, payer type, region, Charlson Comorbidity Index (CCI), comorbidities, indicators of frail health status, and pre-index hospitalization rates. Adjusted analyses were conducted through inverse probability of treatment weighting (IPTW) to control for selection bias. Poisson regression was used to estimate the adjusted pairwise rVE against influenza-related hospitalizations/ER visits and office visits and any hospitalization/ER visit for CRD (based on diagnoses codes). An unrelated outcome, urinary tract infection (UTI) hospitalization, was assessed.ResultsDuring 2018–19 flu season, following IPTW analyses, 561,315 recipients of aTIV and 1,672,779 of TIV-HD were identified. After IPTW adjustment and Poisson regression, aTIV was more effective in reducing influenza-related office visits compared to TIV-HD (6.6%; 95% CI: 2.8%-10.3%). aTIV was statistically comparable to TIV-HD (2.0%; 95% CI: -3.7%-7.3%) for prevention of influenza-related hospitalizations/ER visits but more effective than TIV-HD (2.6%; 95% CI: 2.0%-3.2%) in reducing hospitalizations/ER visits for CRD. No treatment effect was identified for control condition (UTI hospitalization).ConclusionIn adjusted analyses, aTIV reduced influenza-related office visits and CRD hospitalizations/ER visits compared to TIV-HD. aTIV and TIV-HD demonstrated comparable reductions in influenza-related hospitalizations/ER visits.Disclosures Stephen I. Pelton, MD, Merck vaccine (Consultant, Grant/Research Support)Pfizer (Consultant, Grant/Research Support)Sanofi Pasteur (Consultant, Other Financial or Material Support, DSMB)Seqirus Vaccine Ltd. (Consultant) Maarten Postma, Dr., IQVIA (Consultant) Victoria Divino, PhD, Seiqrus Vaccines Ltd. (Consultant) Drishti Shah, PhD, Seqirus Vaccines Ltd. (Consultant) Joaquin F. Mould-Quevedo, PhD, Seqirus Vaccines Ltd. (Employee, Shareholder) Mitchell DeKoven, PhD, Seqirus Vaccines Ltd. (Consultant) Girishanthy Krishnarajah, PhD, Seqirus Vaccines Ltd. (Employee, Shareholder)

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.

High-dose trivalent influenza vaccine: safety and immunogenicity

RESUMENLas personas mayores son uno de los colectivos que más sufren los efectos de la gripe estacional. Aunque la vacuna antigripal es efectiva a la hora de prevenir la infección por el virus de la gripe y sus complicaciones, no resulta tan efectiva en personas de edad avanzada debido al fenómeno de inmunosenescencia asociado a la edad. Desde 2009 existe en EE. UU. una vacuna antigripal trivalente de alta dosis aprobada para la inmunización de personas ≥ 65 años con una concentración de antígeno cuatro veces mayor que la vacuna estándar. Múltiples ensayos clínicos llevados a cabo a lo largo de distintas temporadas, y mediante diferentes metodologías, han demostrado que la vacuna antigripal trivalente de alta dosis no solo es más efectiva, sino que además presenta un perfil de seguridad similar y es más inmunogénica que la vacuna de dosis estándar en la prevención de la gripe y sus complicaciones en personas de avanzada edad. En este documento se hace una revisión de la evidencia científica actual sobre la seguridad e inmunogenicidad de la vacuna antigripal de alta dosis en personas ≥ 65 años, y se incluye información de ensayos clínicos aleatorizados, estudios observacionales con datos de práctica clínica real y revisiones sistemáticas y metaanálisis.

High-dose trivalent influenza vaccine. Efficacy and effectiveness

RESUMENLa gripe estacional es un importante problema de salud pública, particularmente en las personas mayores. La vacuna antigripal es la forma más efectiva de prevenir la infección por el virus de la gripe y sus complicaciones, pero debido al fenómeno de inmunosenescencia asociado a la edad, las personas mayores no responden eficientemente a la inmunización. En 2009 se aprobó en EE. UU. una vacuna antigripal trivalente de alta dosis (IIV3-HD), con una concentración cuatro veces mayor de antígeno que la vacuna estándar, para la inmunización de personas ≥ 65 años. En numerosos ensayos clínicos llevados a cabo en diferentes temporadas, y utilizando diferentes metodologías, se ha demostrado que la vacuna IIV3-HD es, además de segura, más inmunogénica y más efectiva que la vacuna de dosis estándar previniendo la gripe y sus complicaciones en personas mayores. En este trabajo se hace una revisión de la evidencia científica disponible sobre la eficacia y efectividad de la vacuna antigripal de alta dosis en personas ≥ 65 años, incluyendo información de ensayos clínicos aleatorizados, estudios observacionales de práctica clínica real y revisiones sistemáticas y meta-análisis.

High dose trivalent influenza vaccine compared to standard dose vaccine in patients with rheumatoid arthritis receiving TNF-alpha inhibitor therapy and healthy controls: Results of the DMID 10-0076 randomized clinical trial

IntroductionSubjects with rheumatoid arthritis (RA) receiving tumor necrosis factor-inhibiting (TNFi) therapies are at risk for severe influenza, and may respond less well to influenza vaccine. We examined the safety and immunogenicity of high dose influenza vaccine (HD) compared to standard dose vaccine (SD) in participants with RA receiving stable TNFi. MethodsA randomized, double-blinded, Phase II study was conducted in adults with RA receiving TNFi, and healthy, gender and age-matched control subjects. Participants were immunized with HD (Sanofi Pasteur Fluzone High Dose [60 mcg × 3 strains]) or SD (Sanofi Pasteur Fluzone® [15 mcg × 3 strains]) intramuscularly (IM). A self-administered memory aid recorded temperature and systemic and local adverse events (AEs) for 8 days, and safety was evaluated and serum obtained to measure HAI activity on days 7, 21 and 180 days following vaccination. ResultsA greater proportion of RA subjects who received HD seroconverted at day 21 compared to SD, although this was not statistically significant. GMT antibody responses in RA subjects who received HD compared to SD were greater for all strains on day 21, and this was significant for H1N1. Seroconversion rates and GMT values were not different between RA subjects and control subjects. There were no safety concerns for HD or SD in RA subjects, and RA-related symptoms did not differ between SD and HD recipients by a RA-symptom questionnaire (RAPID 3). ConclusionsTNF-inhibitor therapy in people with RA did not appear to influence the immunogenicity of either SD or HD. Influenza seroconversion and GMT values were higher among RA subjects receiving HD compared to SD; however, differences were small and a larger study is needed to validate these findings. Given the apparent risk of increased influenza-related morbidity and mortality among immune compromised subjects, the higher GMT values generated by HD may be beneficial.

Cost Benefit of High-Dose vs Standard-Dose Influenza Vaccine in a Long-Term Care Population During an A/H1N1-Predominant Influenza Season

ObjectivesInfluenza is a leading cause of avoidable admissions for nursing home (NH) residents. We previously evaluated the effectiveness of a high-dose trivalent influenza vaccine (HD) compared to a standard-dose influenza vaccine (SD) through a cluster-randomized trial of NH residents. Fewer residents from facilities randomized to HD were hospitalized. In this article, we extend our analyses to consider direct medical care costs relative to vaccine costs for HD ($31.82/dose) as compared to SD ($12.04/dose). DesignPost hoc, cost-benefit analysis. Setting and participantsFrom the participating NH facilities (n = 817), we identified Medicare fee-for-service enrollees who were long-stay residents (>100 days) at the start of the 2013-2014 influenza season (November 1–May 31). The intervention was residence in a facility randomized to HD or SD influenza vaccine. MethodsWe summed expenditures from long-stay NH residents' Medicare Part A, B, and D fee-for-service claims and compared person-level expenditures between residents of facilities offering HD vs SD. Expenditures were adjusted for clustering of residents within NHs, person-time, and prespecified covariates using 2-part, generalized linear models with bootstrapped standard errors. We examined the incremental cost-benefit of HD vs SD vaccines from a payer perspective. ResultsThere were 18,605 and 18,658 Medicare fee-for-service long-stay residents in facilities offering HD and SD, respectively. Person- and facility-adjusted total expenditures differed by $546 (P = .006). The $20 incremental cost of HD to SD offset adjusted expenditures for a net benefit of $526 per NH resident and a financial return on investment of 546/20 = 27:1. Conclusions/implicationsThe use of HD influenza vaccine in long-stay NH residents reduced total health care expenditures for a net benefit despite HD being more expensive per dose. These cost offsets applied to Medicare beneficiaries residing in NHs could result in important savings to the Medicare program.

Post-licensure surveillance of trivalent adjuvanted influenza vaccine (aIIV3; Fluad), Vaccine Adverse Event Reporting System (VAERS), United States, July 2016–June 2018

BackgroundTrivalent adjuvanted influenza vaccine (aIIV3; Fluad®) was approved in the United States (U.S.) in 2015 for adults aged ≥65 years and has been in use since the 2016–17 influenza season. MethodsWe analyzed U.S. reports for aIIV3 submitted from July 1, 2016 through June 30, 2018 to the Vaccine Adverse Event Reporting System (VAERS), a national spontaneous reporting system. Medical records were reviewed for serious reports. Among individuals ≥65 years of age, the relative frequency of the most commonly reported adverse events (AEs) after aIIV3 were compared with non-adjuvanted inactivated influenza vaccines given to adults aged ≥65 years, high-dose trivalent influenza vaccine (IIV3-HD) and trivalent or quadrivalent vaccines (IIV3/IIV4). Data mining analyses were undertaken to identify whether AEs for aIIV3 occurred disproportionately more than expected compared to all influenza vaccines. ResultsVAERS received 630 reports after aIIV3, of which 521 (83%) were in adults aged ≥65 years; 79 (13%) in persons <65 years and in 30 (5%) reports age was missing; 19 (3%) reports were serious, including two deaths (0.4%) related to myocardial infarction and Sjogren’s syndrome. The most common AEs reported in adults aged ≥65 years were injection site pain (21%) and erythema (18%), with similar proportions reported for IIV3-HD (17% and 19%, respectively) and for IIV3/IIV4 (15%, each). Except for reports related to vaccination of inappropriate age (n = 79) and syringe malfunction (n = 6), data mining did not identify other disproportionately reported AEs. ConclusionsAlthough our review of aIIV3 in VAERS did not identify any unexpected health conditions of concern, we observed more than twice the expected number of reports with administration of the vaccine to persons outside of the age range for which the vaccine is approved in the U.S. Health care providers should be educated on the age groups for whom aIIV3 is recommended.

High-Dose Seasonal Influenza Vaccine in Patients Undergoing Dialysis.

High-dose influenza vaccine, which contains fourfold more antigen than standard dose, is associated with fewer cases of influenza and less influenza-related morbidity in the elderly general population. Whether the high-dose influenza vaccine benefits patients on dialysis, whose immune response to vaccination is less robust than that of healthy patients, is uncertain. We compared hospitalizations and deaths during the 2015-2016 and 2016-2017 influenza seasons by vaccine type (standard trivalent, standard quadrivalent, and high-dose trivalent influenza vaccine) administered within a national dialysis organization. The association of vaccine type with outcomes was estimated using Cox proportional hazards regression with adjustment for patient factors and "center effect." Analyses were stratified by age and dialysis modality. Between September 1 and December 31, 2015, standard dose trivalent, standard dose quadrivalent, and high-dose trivalent influenza vaccines were administered to 3057 (31%), 5981 (61%), and 805 (8%) patients, respectively. The adjusted rates of first hospitalizations by vaccine type during the influenza season were 8.43, 7.88, and 7.99 per 100 patient-months, respectively, and the adjusted rates of death were 1.00, 0.97, and 1.04, respectively. These differences were not significant. In 2016, 3614 (39%) received quadrivalent vaccine, and 5700 (61%) received high-dose trivalent vaccine. The adjusted rates of first hospitalization by vaccine type were 8.71 and 8.04 per 100 patient-months, respectively, and the adjusted rates of death were 0.98 and 1.02, respectively. Receipt of high dose was associated with a significant reduction in hospitalization (hazard ratio, 0.93; 95% confidence interval, 0.86 to 1.00; P=0.04); there was no significant association with death. There was no significant heterogeneity of either association by age group or dialysis modality. Receipt of high-dose compared with standard dose influenza vaccine in 2016-2017 was associated with lower rates of hospitalization in patients on dialysis, although that was not seen in 2015-2016.

Seasonal influenza immunisation: Strategies for older adults.

Adults over the age of 60-65years suffer disproportionally from seasonal influenza, experiencing high rates of complications, exacerbation of underlying medical comorbidities, and excess mortality. Thus, older adults are an important priority for influenza immunisation campaigns. Unfortunately, older adults generally display lower immune responses to standard influenza vaccines because of immunosenescence, with resulting suboptimal vaccine effectiveness. Thus, the development of improved vaccines that heighten immune responses and improve effectiveness is an important medical need. To this end, enhanced influenza vaccines specifically targeting this age group have been developed, which seek to overcome the inherent limitations in the immune responses of older adults. Both the licensed high-dose trivalent influenza vaccine (hdTIV) containing fourfold higher antigen contents than standard vaccine, and the MF59® -adjuvanted trivalent influenza vaccine (aTIV) have been proven to be safe and well-tolerated while enhancing the immune response. Healthcare providers for populations of older adults should be advised to routinely use these enhanced influenza vaccines in seasonal immunisation campaigns to provide improved immunity against influenza and its consequences in this particularly susceptible age group.

Potential Cost-Effectiveness of a Universal Influenza Vaccine in Older Adults.

Background and Objectives“Universal” vaccines that could have multistrain and multiyear effectiveness are being developed. Their potential cost-effectiveness in geriatric populations is unknown.Research Design and MethodsA Markov model estimated effects of a theoretical universal influenza vaccine compared with available seasonal vaccines in hypothetical cohorts of U.S. 65+-year olds followed over a 5-year time horizon to capture potential multiyear protection. Outcomes included costs per quality-adjusted life-year gained and influenza cases avoided.ResultsUsing hypothetical universal vaccine parameter values (cost $100, vaccine effectiveness 39%, uptake 64%, effectiveness duration 5 years), universal vaccine was less costly than seasonal influenza vaccination strategies. High-dose trivalent influenza vaccine, compared with universal vaccine, gained 0.0028 quality-adjusted life-years and cost $82 more, or $28,700 per quality-adjusted life-year gained. Other seasonal vaccines were not favorable economically. Five-year influenza risk with universal vaccination was 32.3% under base case assumptions, compared with <30% with adjuvanted or high-dose vaccine use. In sensitivity analyses, universal vaccine was favored when uptake or vaccine effectiveness was greater than standard-dose influenza vaccine. If absolute universal vaccine effectiveness was 10% less than standard-dose vaccine, universal vaccine could be cost-saving but not more effective than other strategies. Universal vaccine was not favored if its effectiveness duration was <3 years.Discussion and ImplicationsUniversal vaccine use in older persons could be either cost effective or cost saving when universal vaccine parameters are within plausible ranges. However, if its effectiveness is substantially less than current vaccines, its use would probably not be favored in geriatric populations.

High-dose influenza vaccine to reduce clinical outcomes in high-risk cardiovascular patients: Rationale and design of the INVESTED trial

BackgroundInfluenza leads to significant cardiopulmonary morbidity and mortality—particularly in patients with cardiovascular disease—that may be prevented with a standard influenza vaccine. However, patients with cardiovascular conditions have a reduced immune response to influenza vaccine, potentially resulting in reduced effectiveness for preventing clinical events. High-dose vaccine augments immune response in cardiac patients, suggesting that a high-dose influenza vaccination strategy may further reduce morbidity and mortality. Alternatively, broader coverage with an influenza vaccine containing an increased number of viral strains is an alternative strategy without direct evaluation. Research design and methodsINfluenza Vaccine to Effectively Stop Cardio Thoracic Events and Decompensated heart failure (INVESTED) is a pragmatic, randomized, double-blind, parallel-group, active-controlled trial comparing the effectiveness of an annual vaccination strategy of high-dose trivalent versus standard-dose quadrivalent influenza vaccine in patients with a history of recent heart failure or myocardial infarction hospitalization. The trial will enroll approximately 9,300 patients over 4 influenza seasons. The primary hypothesis is that high-dose influenza vaccine will reduce the composite outcome of all-cause mortality and hospitalization from a cardiovascular or pulmonary cause compared with standard-dose influenza vaccine within each enrolling season. Approximately 1,300 primary outcome events will provide >90% power to detect an 18% relative risk reduction at a 2-sided α level of .05. ConclusionINVESTED is the largest and longest study to assess whether high-dose influenza vaccine is superior to standard-dose influenza vaccine in reducing cardiopulmonary events in a high-risk cardiovascular population (ClinicalTrials.gov Identifier: NCT02787044).