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Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines.

ABSTRACT: BACKGROUND:Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates. OBJECTIVES: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. METHODS: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. RESULTS: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. CONCLUSIONS: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.

SUBMITTER: Butler AM

PROVIDER: S-EPMC7310582 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines.

Butler Anne M AM Layton J Bradley JB Krueger Whitney S WS Kshirsagar Abhijit V AV McGrath Leah J LJ

Medical care 20190101 1

<h4>Background</h4>Estimating influenza vaccine effectiveness using an unvaccinated comparison group may result in biased effect estimates.<h4>Objectives</h4>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.<h4>Methods</h4>Using Medicare data from the United States end-stage renal disease program (2009-2013), we compared the risk of all-cause mortality among recip ...[more]

PMID: 30422840

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Project description:Abstract Background More effective influenza vaccines are needed to prevent influenza and its complications. Recombinant influenza vaccines may offer better protection than traditional egg-based vaccines. Using a cluster randomized design to estimate the relative vaccine effectiveness (rVE) of Flublok Quadrivalent recombinant influenza vaccine (RIV4) vs. standard dose inactivated influenza vaccine (SD-IIV4), we separately reported that RIV4 provided significantly better protection against primary outcome of confirmed influenza in adults 50–64 yrs in the 2018–20 moderately severe influenza seasons. Here we report the rVE against the secondary and exploratory outcomes of hospitalized influenza-related outcomes. Methods We randomized 66 facilities within Kaiser Permanente Northern California (KPNC) to routinely administer RIV4 or SD-IIV4 to adults, alternating vaccine formulations weekly by facility during the influenza season (ClinicalTrials.gov NCT03694392). Hospitalized cases of PCR-confirmed influenza, community-acquired pneumonia, and cardio-respiratory events were prespecified as secondary in 50–64 yrs and exploratory in 18–49 yrs. We estimated the relative hazard ratio (rHR) using Cox regression on a calendar timeline, adjusting for age, sex, and race, using facility-specific stabilized propensity scores. We calculated rVE as (1–rHR) x 100%. Results During the 2018–19 and 2019–20 seasons, the study consisted of 1,630,328 vaccinees 18–64 yrs (RIV4=632,962; SD-IIV4=997,366), and included 95 hospitalized influenza cases after RIV4 and 153 after SD-IIV4 among 50–64 yrs (Table 1). RIV4 vs. SD-IIV4 was not significantly more protective against hospitalized influenza-related outcomes in adults 50–64 yrs or 18–49 yrs. Conclusion While this large cluster randomized study found that RIV4 vs. SD-IIV4 reduced the risk of lab-confirmed influenza in adults 50–64 yrs across 2 influenza seasons, RIV4 and SD-IIV4 performed similarly against hospitalized influenza-related outcomes. Evaluating influenza-related hospitalizations during influenza seasons when more hospital outcomes occur may help to better understand the relative effectiveness of recombinant versus standard inactivated influenza vaccines against severe disease. Disclosures All Authors: No reported disclosures.

Project description:Rationale & objectiveStudies 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.Study designCohort study using data from the US Renal Data System.Setting & participants507,552 adults undergoing in-center maintenance hemodialysis between the 2010 to 2011 and 2014 to 2015 influenza seasons.ExposuresSDV and HDV.OutcomesAll-cause mortality, hospitalization due to influenza or pneumonia, and influenza-like illness during the influenza season.Analytic approachPatients 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.ResultsWithin 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.LimitationsResidual confounding and outcome misclassification.ConclusionsThe 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.

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

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Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines.

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Assessing Residual Bias in Estimating Influenza Vaccine Effectiveness: Comparison of High-dose Versus Standard-dose Vaccines.

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