Standard-dose Influenza Vaccine Research Articles

Comparative safety of high-dose versus standard-dose influenza vaccination in patients with end-stage renal disease

BackgroundHigh-dose influenza vaccine (HDV) is an alternative vaccination strategy in patients with end-stage renal disease (ESRD), though the safety of HDV has not been evaluated in this population. The objective of this study was to estimate the relative occurrence of adverse vaccine reactions in patients with ESRD following vaccination with HDV compared with standard-dose influenza vaccine (SDV). MethodsUsing data from the United States Renal Data System, we identified patients with ESRD aged ≥ 65 years at influenza vaccination during yearly influenza seasons from 2010 through 2016. Patients were followed after vaccination to observe serious (anaphylaxis, angioedema, seizure, encephalopathy, Guillain-Barré syndrome [GBS], and short-term, all-cause mortality) and milder (urticaria/hives, rash, pain in limb, cellulitis, myalgia/myositis, fever, nausea and vomiting, diarrhea, and syncope) adverse events. Propensity score-weighted hazard ratios (HRs) and 95% confidence intervals (CIs) for HDV versus SDV were estimated with Cox proportional hazards models. ResultsOf 520,876 vaccinations observed (mean age = 74.7 years at vaccination; 63% white race), 7.4% were HDV. For serious events, the weighted HRs were null for seizure, encephalopathy, and mortality and inestimable due to too few cases for anaphylaxis, angioedema, and GBS. For milder vaccine reactions, the weighted HRs demonstrated generally increased risks in the HDV group, including rash (HR = 1.86; 95% CI, 1.34–2.57), diarrhea (HR = 1.26; 95% CI, 1.07–1.50), pain in limb (HR = 1.23; 95% CI, 1.12–1.34), and myalgia/myositis (HR = 1.16; 95% CI, 1.04–1.30). ConclusionsThe risks of serious adverse events were low and similar between treatment groups; however, HDV recipients had increased risks of several milder adverse events compared with SDV recipients, consistent with clinical trial findings in the general population of older adults. These results add important information to inform the risk-benefit tradeoff of the use of HDV versus SDV in patients with ESRD.

High-dose influenza vaccination and mortality among predominantly male, white, senior veterans, United States, 2012/13 to 2014/15.

IntroductionIt is unclear whether high-dose influenza vaccine (HD) is more effective at reducing mortality among seniors.AimThis study aimed to evaluate the relative vaccine effectiveness (rVE) of HD. MethodsWe linked electronic medical record databases in the Veterans Health Administration (VHA) and Medicare administrative files to examine the rVE of HD vs standard-dose influenza vaccines (SD) in preventing influenza/pneumonia-associated and cardiorespiratory mortality among VHA-enrolled veterans 65 years or older during the 2012/13, 2013/14 and 2014/15 influenza seasons. A multivariable Cox proportional hazards model was performed on matched recipients of HD vs SD, based on vaccination time, location, age, sex, ethnicity and VHA priority level. ResultsAmong 569,552 person-seasons of observation, 207,574 (36%) were HD recipients and 361,978 (64%) were SD recipients, predominantly male (99%) and white (82%). Pooling findings from all three seasons, the adjusted rVE estimate of HD vs SD during the high influenza periods was 42% (95% confidence interval (CI): 24–59) against influenza/pneumonia-associated mortality and 27% (95% CI: 23–32) against cardiorespiratory mortality. Residual confounding was evident in both early and late influenza periods despite matching and multivariable adjustment. Excluding individuals with high 1-year predicted mortality at baseline reduced the residual confounding and yielded rVE of 36% (95% CI: 10–62) and 25% (95% CI: 12–38) against influenza/pneumonia-associated and cardiorespiratory mortality, respectively. These were confirmed by results from two-stage residual inclusion estimations.DiscussionThe HD was associated with a lower risk of influenza/pneumonia-associated and cardiorespiratory death in men during the high influenza period.

Frailty Is Associated With Increased Hemagglutination-Inhibition Titers in a 4-Year Randomized Trial Comparing Standard- and High-Dose Influenza Vaccination.

BackgroundAlthough high-dose (HD) vaccines have been reported to stimulate higher antibody responses compared with standard-dose (SD) influenza vaccines, there have been limited studies on the impact of frailty on such responses.MethodsWe conducted a randomized, double-blind trial (2014/2015 to 2017/2018) of SD versus HD trivalent split-virus vaccine (Fluzone) in 612 study participants aged 65+ over 4 influenza seasons. Hemagglutination inhibition antibody titers for influenza H1N1, H3N2, and B vaccine subtypes were measured at baseline and at 4, 10, and 20 weeks postvaccination and frailty was measured using a validated frailty index.ResultsGeometric mean antibody titers were significantly higher in HD compared with SD vaccine recipients for all influenza subtypes at all time points postvaccination. However, frailty was positively correlated with 4-week titers and was associated with increased odds of being a vaccine responder. For influenza A subtypes, this was mostly limited to HD recipients.ConclusionsFrailty was associated with higher titers and increased antibody responses at 4 weeks after influenza vaccination, which was partially dependent on vaccine dosage. Chronic inflammation or dysregulated immunity, both of which are commonly observed with frailty, may be responsible, but it requires further investigation.

Relative and Absolute Effectiveness of High-Dose and Standard-Dose Influenza Vaccine Against Influenza-Related Hospitalization Among Older Adults-United States, 2015-2017.

Seasonal influenza causes substantial morbidity and mortality in older adults. High-dose inactivated influenza vaccine (HD-IIV), with increased antigen content compared to standard-dose influenza vaccines (SD-IIV), is licensed for use in people aged ≥65 years. We sought to evaluate the effectiveness of HD-IIV and SD-IIV for prevention of influenza-associated hospitalizations. Hospitalized patients with acute respiratory illness were enrolled in an observational vaccine effectiveness study at 8 hospitals in the United States Hospitalized Adult Influenza Vaccine Effectiveness Network during the 2015-2016 and 2016-2017 influenza seasons. Enrolled patients were tested for influenza, and receipt of influenza vaccine by type was recorded. Effectiveness of SD-IIV and HD-IIV was estimated using a test-negative design (comparing odds of influenza among vaccinated and unvaccinated patients). Relative effectiveness of SD-IIV and HD-IIV was estimated using logistic regression. Among 1487 enrolled patients aged ≥65 years, 1107 (74%) were vaccinated; 622 (56%) received HD-IIV, and 485 (44%) received SD-IIV. Overall, 277 (19%) tested positive for influenza, including 98 (16%) who received HD-IIV, 87 (18%) who received SD-IIV, and 92 (24%) who were unvaccinated. After adjusting for confounding variables, effectiveness of SD-IIV was 6% (95% confidence interval [CI] -42%, 38%) and that of HD-IIV was 32% (95% CI -3%, 54%), for a relative effectiveness of HD-IIV versus SD-IIV of 27% (95% CI -1%, 48%). During 2 US influenza seasons, vaccine effectiveness was low to moderate for prevention of influenza hospitalization among adults aged ≥65 years. High-dose vaccine offered greater effectiveness. None of these findings were statistically significant.

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccine Among Patients Receiving Maintenance Hemodialysis

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccine Among Patients Receiving Maintenance Hemodialysis

EFFECT OF INFLUENZA VACCINE ON TWEAK LEVELS IN THE ELDERLY: IMPLICATION IN CARDIOVASCULAR PROTECTION

Substantial evidence suggests a protective effect of annual influenza immunization on cardiovascular diseases (CVD). The inflammatory mediator TNF-related weak inducer of apoptosis (TWEAK) is thought to be involved in the pathogenesis of CVD. We previously showed that administration of a standard-dose influenza vaccine reduced circulating TWEAK levels. This study aimed to test the hypothesis that a high-dose vaccine would have greater impact on TWEAK levels than the standard-dose. Two groups of participants matched on age and sex were included in the study. One group (n=25) received standard-dose vaccine during 2008-2009 season, the other group (n=25) received high-dose vaccine during 2014-2015 season. Soluble TWEAK (sTWEAK) levels were assessed using ELISA in serum samples collected immediately before vaccination and during the 4th week after vaccination. Vaccine-induced strain specific antibody titers were measured by hemagglutination inhibition assay. The participants had a mean age 86 years and 68% were women. Our preliminary results thus far demonstrated no statistically significant change in sTWEAK levels after vaccination in either group (Wilcoxon matched-pairs signed rank test: standard-dose group: median change [interquartile range]=11.2 [-92.2–197.1] pg/mL, p=0.72; high-dose group: -24.8 [-58.9–87.3] pg/mL, p=0.70). Pre-vaccination sTWEAK levels tended to be negatively associated with age (unadjusted linear regression of log2(x) transformed TWEAK levels on age: estimate [±SE]=-4.6% [±2.7%] change in TWEAK level per year, p=0.08). We continue to evaluate more pre- and post-vaccination samples. We have also begun exploring TWEAK expression by circulating immune cells (T and B lymphocytes and monocytes) and potential impact of influenza immunization in older adults.

PIN29 PUBLIC HEALTH AND ECONOMIC IMPACT OF VACCINATION OF SENIORS WITH A HIGH DOSE TRIVALENT INFLUENZA VACCINE IN BRAZILIAN PRIVATE HEALTH CARE SYSTEM

Older adults are particularly vulnerable to influenza and are susceptible to serious complications after an influenza infection, which frequently lead to hospitalizations. Standard-dose influenza vaccines have proven to be beneficial to older patients, however presenting suboptimal efficacy due to immunosenescence. A large randomized controlled trial (FIM12) and several real world studies have shown trivalent influenza vaccine high dose (TIV-HD) to be more effective than standard dose trivalent influenza vaccine (TIV-SD) in terms of reducing influenza cases and hospitalizations, including serious cardio-respiratory events, in the elderly population. In 2018, TIV-HD has been licensed in Brazil. The objective is to assess the impact of switching from TIV-SD to TIV-HD for adults aged ≥65 years in Brazilian private health care system. A flexible age structured decision tree model was used and two classes of events were considered: cases of laboratory confirmed influenza, and hospitalizations due to conditions known to be related to influenza. Three alternative definitions of hospitalization were provided: influenza/pneumonia, any respiratory illness, or all serious cardiorespiratory events. The model was populated with clinical data from FIM12 and demographic and economic inputs appropriate to the Brazilian private setting. Switching from TIV-SD to TIV-HD for adults aged ≥65 years in Brazilian private sector was estimated to lead to an incremental annual reduction from 10,000 to 20,000 influenza-related hospitalization (where 14,000 were respiratory-related hospitalization and 6,000 were cardiovascular-related hospitalization), from 900 to 1800 influenza-related deaths, and 11,000 influenza-related general practitioner visits, corresponding to avoided costs from USD111 million (BRL454M) to USD219 million (BRL890M), depending on the hospitalization definition. Hospitalization avoided costs represented 99% of the total avoided costs. Switching to TIV-HD would significantly reduce the burden of influenza especially by reducing hospitalizations that represent the most important source of cost for private market.

2745. Efficacy and Effectiveness of High-Dose Influenza Vaccine for Older Adults by Circulating Strain and Antigenic Match: A Systematic Review and Meta-Analysis

BackgroundInfluenza 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 with standard-dose influenza vaccines (SD-IIV3) in adults ≥65 years against influenza-associated outcomes across all influenza seasons, during seasons where A/H3N2 or A/H1N1 strains predominantly circulated, and where there was an antigenic match or mismatch of the vaccine and circulating strains.MethodsA systematic review was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults ≥65 years. Results from individual seasons were extracted from the identified studies, and surveillance data from each season were used to determine the dominant circulating strains and antigenic match. Results were then stratified based on clinical outcomes and seasonal characteristics and meta-analyzed to estimate pooled rVEs of HD-IIV3.Results11 studies were meta-analyzed after screening 1,018 studies, providing data on 9 consecutive influenza seasons and over 12 million individuals receiving HD-IIV3. Across all influenza seasons, HD-IIV3 demonstrated improved protection against ILI compared with SD-IIV3 (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 = 16.1%, 95% CI: 7.4–24.1%), pneumonia (rVE = 27.3%, 95% CI: 15.3–37.6%), pneumonia/influenza (rVE = 13.4%, 95% CI: 7.3–19.2%) and cardiorespiratory events (rVE = 17.9%, 95% CI: 15.0–20.8%). Some numerical differences were observed in the pooled rVE of outcomes in matched and mismatched seasons and in seasons where A/H3N2 or A/H1N1 strains were predominantly circulating (Table 1).ConclusionEvidence over 9 influenza seasons suggest that HD-IIV3 is consistently more effective than SD-IIV3 at reducing the clinical outcomes associated with influenza infection irrespective of circulating strain and antigenic match. This study was funded by sanofi pasteur. Disclosures All authors: No reported disclosures.

Erratum to: Effect of Age on Relative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries Aged ≥65 Years.

BACKGROUND Studies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries. METHODS A 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations. RESULTS The study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012-2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%-28.3%), 2013-2014 (RVE, 15.3%; 95% CI, 7.8%-22.3%), 2014-2015 (RVE, 8.9%; 95% CI, 5.6%-12.1%), and 2016-2017 (RVE, 12.6%; 95% CI, 6.3%-18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays. CONCLUSIONS The RVE of high-dose versus standard-dose influenza vaccines increases with age.

Comparative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccine Among Patients Receiving Maintenance Hemodialysis

Studies of patients on maintenance dialysis therapy suggest that standard-dose influenza vaccine (SDV) may not prevent influenza-related outcomes. Little is known about the comparative effectiveness of SDV versus high-dose influenza vaccine (HDV) in this population. Cohort study using data from the US Renal Data System. 507,552 adults undergoing in-center maintenance hemodialysis between the 2010 to 2011 and 2014 to 2015 influenza seasons. SDV and HDV. All-cause mortality, hospitalization due to influenza or pneumonia, and influenza-like illness during the influenza season. Patients were eligible for inclusion in multiple yearly cohorts; thus, our unit of analysis was the influenza patient-season. To examine the relationship between vaccine dose and effectiveness outcomes, we estimated risk differences and risk ratios using propensity score weighting of Kaplan-Meier functions, accounting for a wide range of patient- and facility-level characteristics. For nonmortality outcomes, we used competing-risk methods to account for the high mortality rate in the dialysis population. Within 225,215 influenza patient-seasons among adults 65 years and older, 97.4% received SDV and 2.6% received HDV. We observed similar risk estimates for HDV and SDV recipients for mortality (risk difference,-0.08%; 95% CI,-0.85% to 0.80%), hospitalization due to influenza or pneumonia (risk difference, 0.15%; 95% CI,-0.69% to 0.93%), and influenza-like illness (risk difference, 0.00%; 95% CI,-1.50% to 1.08%). Our findings were similar among adults younger than 65 years, as well as within other subgroups defined by influenza season, age group, dialysis vintage, month of influenza vaccination, and vaccine valence. Residual confounding and outcome misclassification. The HDV does not appear to provide additional protection beyond the SDV against all-cause mortality or influenza-related outcomes for adults undergoing hemodialysis. The additional cost and side effects associated with HDV should be considered when offering this vaccine. Future studies of HDV and other influenza vaccine strategies are warranted.

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

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

Effect of Age on Relative Effectiveness of High-Dose Versus Standard-Dose Influenza Vaccines Among US Medicare Beneficiaries Aged ≥65 Years.

Studies have found that the high-dose influenza vaccine has a higher relative vaccine effectiveness (RVE) versus standard-dose vaccines in some seasons. We evaluated the effect of age on the RVE of high-dose versus standard-dose influenza vaccines among Medicare beneficiaries. A 6-season retrospective cohort study from 2012 to 2018 among Medicare beneficiaries aged ≥65 years was performed. Poisson regression was used to evaluate the effect of age on the RVE of high-dose versus standard-dose influenza vaccines in preventing influenza-related hospitalizations. The study included >19 million vaccinated beneficiaries in a community pharmacy setting. The Poisson models indicated a slightly increasing trend in RVE with age in all seasons. The high-dose vaccine was more effective than standard-dose vaccines in preventing influenza-related hospital encounters (ie, influenza-related inpatient stays and emergency department visits) in the 2012-2013 (RVE, 23.1%; 95% confidence interval [CI], 17.6%-28.3%), 2013-2014 (RVE, 15.3%; 95% CI, 7.8%-22.3%), 2014-2015 (RVE, 8.9%; 95% CI, 5.6%-12.1%), and 2016-2017 (RVE, 12.6%; 95% CI, 6.3%-18.4%) seasons and was at least as effective in all other seasons. We also found that the high-dose vaccine was consistently more effective than standard-dose vaccines across all seasons for people aged ≥85 years. Similar trends were observed for influenza-related inpatient stays. The RVE of high-dose versus standard-dose influenza vaccines increases with age.

Economic assessment of a high-dose versus a standard-dose influenza vaccine in the US Veteran population: Estimating the impact on hospitalization cost for cardio-respiratory disease

ObjectiveTo compare the economic impact of high-dose trivalent (HD) versus standard-dose trivalent (SD) influenza vaccination on direct medical costs for cardio-respiratory hospitalizations in adults aged 65 years or older enrolled in the United States (US) Veteran’s Health Administration (VHA). MethodsLeveraging a relative vaccine effectiveness study of HD versus SD over five respiratory seasons (2010/11 through 2014/15), we collected cost data for healthcare provided to the same study population both at VHA and through Medicare services. Our economic assessment compared the costs of vaccination and hospital care for patients experiencing acute cardio-vascular or respiratory illness. ResultsWe analyzed 3.5 million SD and 158,636 HD person-seasons. The average cost of HD and SD vaccination was $23.48 (95% CI: $21.29 - $25.85) and $12.21 (95% CI: $11.49 - $13.00) per recipient, respectively, while the hospitalization rates for cardio-respiratory disease in HD and SD recipients were 0.114 (95% CI: 0.108–0.121) and 0.132 (95% CI: 0.132–0.133) per person-season, respectively. Attributing the average cost per hospitalization of $11,796 (95% CI: $11,685 - $11,907) to the difference in hospitalization rates, we estimated savings attributable to HD to be $202 (95% CI: $115 – $280) per vaccinated recipient. ConclusionsFor the five-season period of 2010/11 through 2014/15, HD influenza vaccination was associated with net cost savings due to fewer hospitalizations, and therefore lower direct medical costs, for cardio-respiratory disease as compared to SD influenza vaccination in the senior US VHA population.

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.

Analysis of relative effectiveness of high-dose versus standard-dose influenza vaccines using an instrumental variable method

BackgroundObservational studies of the relative effectiveness of influenza vaccines are essential for public health decision making. Their estimates, however, are subject to bias due to unmeasured confounders. Instrumental variable (IV) methods can control for observed and unobserved confounders. MethodsWe used linked electronic medical record databases in the Veterans Health Administration (VHA) as well as Medicare administrative files to examine the relative vaccine effectiveness (rVE) of high-dose influenza vaccine (HD) versus standard-dose influenza vaccines (SD) in preventing hospitalizations among VHA-enrolled Veterans ≥65 years of age during 5 influenza seasons (2010–2011 through 2014–2015). Using multivariable IV Poisson regression modeling to address unmeasured confounding and bias, we analyzed the data by each season and through longitudinal analysis of all five seasons. FindingsWe included 3,638,924 person–influenza seasons of observation where 158,636 (4%) were among HD vaccine recipients and 3,480,288 (96%) were among SD vaccine recipients. Of the 1,728,562 Veterans, 1,702,824 (98.5%) were male and 1,299,412 (75%) were non-Hispanic white. Based on the longitudinal analysis of all five seasons, the IV-adjusted rVE estimate of HD vs. SD was 10% (95% CI, 8–12%) against all-cause hospitalization; 18% (95% CI, 15–21%) against cardiorespiratory-associated hospitalization; and 14% (95% CI, 6–22%) against influenza/pneumonia-associated hospitalization. The findings by season were similar. InterpretationOur analysis of VHA clinical data collected from approximately 1.7 million Veterans 65 years and older during five seasons demonstrates that high-dose influenza vaccine is more effective than standard-dose influenza vaccines in preventing influenza- or pneumonia-associated hospitalizations, cardiorespiratory hospitalizations, and all-cause hospitalizations.

Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness

Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates. To explore the reduction of confounding bias in an active comparison of high-dose versus standard-dose influenza vaccines, as compared with vaccinated versus unvaccinated comparisons. Using Medicare data from the United States end-stage renal disease program (2009-2013), we compared the risk of all-cause mortality among recipients of high-dose vaccine (HDV) versus standard-dose vaccine (SDV), HDV versus no vaccine, and SDV versus no vaccine. To quantify confounding bias, analyses were restricted to the preinfluenza season, when the protective effect of vaccination should not yet be observed. We estimated the standardized mortality ratio-weighted cumulative incidence functions using Kaplan-Meier methods and calculated risk ratios (RRs) and risk differences between groups. Among 350,921 eligible patients contributing 825,642 unique patient preinfluenza seasons, 0.8% received HDV, 70.5% received SDV, and 28.7% remained unvaccinated. Comparisons with unvaccinated patients yielded spurious decreases in mortality risk during the preinfluenza period, for HDV versus none [RR, 0.60; 95% confidence interval (CI), 0.51-0.70)] and SDV versus none (RR, 0.72; 95% CI, 0.70-0.75). The effect estimate was attenuated in the HDV versus SDV comparison (RR, 0.89; 95% CI, 0.77-1.03). Estimates on the absolute scale followed a similar pattern. The HDV versus SDV comparison yielded less-biased estimates of the all-cause mortality before influenza season compared to those with nonuser comparison groups. Vaccine effectiveness and safety researchers should consider the active comparator design to reduce bias due to differences in underlying health status between vaccinated and unvaccinated individuals.

150. Relative Effectiveness of High-Dose and Standard-Dose Influenza Vaccine Against Influenza-Related Hospitalization Among Older Adults—United States, 2015–2017

BackgroundSeasonal influenza causes substantial morbidity and mortality, and older adults are disproportionately affected. Newer vaccines have been developed for use in people 65 years and older, including a trivalent inactivated vaccine with a 4-fold higher dose of antigen (IIV-HD). In recent years, the use of IIV-HD has increased sufficiently to evaluate its effectiveness compared with standard-dose inactivated influenza vaccines (IIV-SD).MethodsHospitalized patients with acute respiratory illness were enrolled in an observational vaccine effectiveness study at 8 hospitals in 4 states participating in the United States Hospitalized Adult Influenza Vaccine Effectiveness Network during the 2015–2016 and 2016–2017 influenza seasons. Predominant influenza A virus subtypes were H1N1 and H3N2, respectively, during these seasons. All enrolled patients were tested for influenza virus with polymerase chain reaction. Receipt and type of influenza vaccine was determined from electronic records and chart review. Odds of laboratory-confirmed influenza were compared among vaccinated and unvaccinated patients. Relative odds of laboratory-confirmed influenza were determined for patients who received IIV-HD or IIV-SD, and adjusted for potential confounding variables via logistic regression.ResultsAmong 1,744 enrolled patients aged ≥ 65 years, 1,105 (63%) were vaccinated; among those vaccinated, 621 (56%) received IIV-HD and 484 (44%) received IIV-SD. Overall, 315 (18%) tested positive for influenza, including 97 (6%) who received IIV-HD, 86 (5%) who received IIV-SD, and 132 (8%) who were unvaccinated. Controlling for age, race, sex, enrollment site, date of illness, index of comorbidity, and influenza season, the adjusted odds of influenza among patients vaccinated with IIV-HD vs. IIV-SD were 0.72 (P = 0.06, 95% CI: 0.52 to 1.01).ConclusionComparison of high-dose vs. standard-dose vaccine effectiveness during 2 recent influenza seasons (1 H1N1 and 1 H3N2-predominant) suggested relative benefit (nonsignificant) of high-dose influenza vaccine in protecting against influenza-associated hospitalization among persons aged 65 years and older; additional years of data are needed to confirm this finding.Disclosures H. K. Talbot, sanofi pasteur: Investigator, Research grant. Gilead: Investigator, Research grant. MedImmune: Investigator, Research grant. Vaxinnate: Safety Board, none. Seqirus: Safety Board, none.

1953. Comparative Effectiveness of High- vs. Standard-Dose Influenza Vaccine on Hospitalization for Acute Myocardial Infarction in Nursing-Home Residents: A Post-hoc Analysis From a Large Cluster-Randomized Trial

BackgroundThere is growing evidence supporting the role of influenza vaccine in decreasing the risk of cardiovascular (CV) events, including acute myocardial infarction. The development of vaccines targeting older adults, such as high-dose (HD) and adjuvanted formulations, offers the promise of enhanced CV protection in this high-risk group. We evaluated whether a HD trivalent vaccine was associated with a reduced incidence of acute CV events (ACE) among nursing home (NH) residents, compared with a standard-dose trivalent vaccine (SD).MethodsThis is a secondary analysis of data from a single-blind, pragmatic, cluster-randomized comparative effectiveness trial. We recruited and randomized Medicare-certified NHs located within 50 miles of a CDC influenza reporting city to facility-wide standard of care for the residents to either HD or SD as the vaccine offered for the 2013–2014 influenza season. Long-stay residents 65 and older in a fee-for-service Medicare plan were eligible for the study. Study staff were masked to NH allocations and raw data access to minimize bias. Outcome data of interest were obtained from the Centers for Medicare and Medicaid Services (CMS). The primary outcome was hospitalization for an acute cardiovascular event (ACE), defined as acute myocardial infarction, atrial fibrillation or heart failure between November 2013 and May 2014. Hazard ratios were estimated from cox-proportional hazard models with facility random effects to account for clustering. We conducted stratified analyses by gender and baseline cardiovascular disease. All models were adjusted for individual and facility level baseline characteristics.ResultsA total of 823 facilities with 38,672 eligible residents were randomized into balanced groups. Facility and resident characteristics were comparable. The incidence of hospitalization for ACE was significantly lower in HD than SD facilities (10.1% vs. 11.0%; adjusted HR 0.92; 95% CI 0.85–0.95; P-value 0.015). Figure 1 shows adjusted HR for each outcome; selected subgroups are presented in Figure 2. ConclusionHigh-dose flu vaccine reduces the risk of hospitalization for ACE in long-term care residents by 8% relative to standard-dose vaccine. Registration NCT01815268. Funding sanofi pasteur.Disclosures E. Saade, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. N. Joyce, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. J. Ogarek, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. H. E. Davidson, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. D. Canaday, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. A. Yasin, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. T. Shireman, Sanofi-Pasteur: Grant Investigator, Grant recipient. V. Mor, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support. S. Gravenstein, sanofi pasteur: Collaborator, Research support. Seqirus: Collaborator, Research support.

LB14. Safety and Immunogenicity of High-Dose Quadrivalent Influenza Vaccine Administered by Intramuscular Route in Subjects Aged 65 Years and Older

BackgroundOlder adults (≥65 years of age) remain at increased risk of influenza because they do not respond to standard dose influenza vaccines as well as younger adults. A high dose, inactivated trivalent influenza vaccine, IIV3-HD, containing four times the antigen content (60 µg hemagglutinin per influenza strain) of standard-dose influenza vaccines has been available in the United States since 2010. Two distinct B influenza lineages (Victoria and Yamagata) have co-circulated for over a decade, making it difficult to predict which will predominate the next season. IIV4-HD has been developed to address the frequent influenza B strain mismatches by incorporating a strain from each B lineage. This pivotal Phase III study evaluated the safety and immunogenicity of IIV4-HD as compared with two IIV3-HD vaccines.MethodA randomized, modified double-blind, multicenter study (NCT03282240) was conducted in 2670 healthy subjects in the United States, who were randomly assigned to receive IIV4-HD, a licensed IIV3-HD, or an IIV3-HD with the alternate B influenza strain. Using the hemagglutinin inhibition (HAI) assay at baseline and 28 days after vaccination, post-vaccination geometric mean titers and seroconversion rates were measured. Safety data were collected through 6 months post-vaccination.ResultIIV4-HD was noninferior to the licensed IIV3-HD and the investigational IIV3-HD (containing the alternate B strain) for all four influenza strains as assessed by HAI GMTs and seroconversion rates. Moreover, IIV4-HD induced a superior immune response (HAI GMTs and seroconversion rates) compared with the immune response induced by the IIV3-HD that does not contain the corresponding B strain. Reactogenicity profiles were comparable across all study groups. Most unsolicited adverse events were of Grade 1 or Grade 2 intensity. One serious adverse event considered related by the Investigator was reported in the IIV4-HD group.ConclusionVaccination of adults 65 years of age and older with IIV4-HD was found to be noninferior to two IIV3-HD vaccines with a similar safety profile. The addition of a second B lineage strain does not adversely affect the safety or immunogenicity profile of IIV4-HD compared with IIV3-HD.Disclosures L. J. Chang, Sanofi Pasteur: Employee, Salary. Y. Meng, Sanofi Pasteur: Employee, Salary. H. Janosczyk, Sanofi Pasteur: Employee, Salary. V. Landolfi, Sanofi Pasteur: Employee, Salary. H. K. Talbot, Sanofi Pasteur: Investigator, Research grant. Gilead: Investigator, Research grant. MedImmune: Investigator, Research grant. Vaxinnate: Safety Board, none. Seqirus: Safety Board, none.

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.