Relative Vaccine Efficacy of High-Dose Versus Standard-Dose Influenza Vaccines in Preventing Probable Influenza in a Medicare Fee-for-Service Population

Abstract Background Older 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. Method A 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. Result IIV4-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. Conclusion Vaccination 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.

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2747. Relative Vaccine Efficacy of High-Dose vs. Standard Dose Influenza Vaccines in Preventing Probable Influenza in a US Medicare Fee-for-Service Population

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2424 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S967-S967

Author(s):

Misti Paudel ◽

Salah Mahmud ◽

Ami R Buikema ◽

Stephanie Korrer ◽

Van Voorhis Damon ◽

...

Keyword(s):

Outpatient Clinic ◽

Clinical Judgment ◽

Standard Dose ◽

High Dose ◽

Fee For Service ◽

Subdistribution Hazard ◽

Risk Of Death ◽

Test Culture ◽

Lower Treatment ◽

And Gender

Abstract Background High dose (HD) influenza vaccine has been shown to be more efficacious than standard dose (SD) vaccine in multiple randomized trials. HD is currently the most commonly used vaccine in US seniors (≥65 years of age). In this study, we evaluated the real-world relative vaccine effectiveness (rVE) of HD vs SD over 3 influenza seasons. Methods This study includes a cohort of Medicare fee-for-service enrollees during influenza seasons 2011–2012 to 2013–2014 who received either HD or SD at a pharmacy or an outpatient clinic. HD recipients were matched 1:1 to SD recipients based on location, date of vaccination, age, and gender. Fine-Gray subdistribution hazard models with competing risk of death were used to adjust for residual confounding. The study outcome of probable influenza was defined as any inpatient stay with an influenza diagnosis on the claim, or an outpatient medical encounter with a rapid influenza test/culture followed by an antiviral prescription. Analyses were stratified based on vaccination location (clinic vs pharmacy) as it is expected that physicians carrying both vaccines may prioritize HD to frailer patients, while pharmacists may not exercise clinical judgment. Results Over the influenza seasons 2011–2012, 2012/–2013, and 2013–2014, 1.6–2.2 million seniors were immunized at a pharmacy; and 3.3–3.5 million at a clinic. After matching, there were 535,598; 1,017,552; and 1,548,164 in the pharmacy cohort, and 821,662; 1,151,080; and 1,559,488 in the clinic cohort, across study years. The rVE over 2011/12, 2012/13, and 2013/14 during peak influenza circulation was 21.8% (95% CI: −5.9%, 42.3%), 14.8% (9.3%,19.9%), and 16.9% (9.2%, 23.9%), respectively, in the pharmacy cohort; and 16.5% (−5.9%, 34.2%), 15.1% (10.9%, 19.1%), 10.0% (2.9%, 16.6%), respectively, in the clinic cohort. Conclusion HD was consistently associated with better protection against probable influenza events requiring outpatient or inpatient care. The slightly lower treatment effects observed in the outpatient clinic cohort could be a result of confounding by indication due to physicians triaging HD to frailer patients. Disclosures All authors: No reported disclosures.

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Providing Additional “Muscle” for Older Adults Through Optimal Influenza Vaccine Selection

Annals of Pharmacotherapy ◽

10.1177/1060028018772579 ◽

2018 ◽

Vol 52 (9) ◽

pp. 936-941 ◽

Cited By ~ 2

Author(s):

John A. Dougherty ◽

Elias B. Chahine

Keyword(s):

Older Adults ◽

Influenza Vaccine ◽

Disease Control ◽

Older Patients ◽

Standard Dose ◽

Influenza Vaccines ◽

High Dose ◽

Control And Prevention ◽

Reasonable Evidence ◽

Age Appropriate

Immunization is the best strategy to protect individuals from influenza; however, older adults tend to respond less favorably to vaccines because of immunosenescence. The Centers for Disease Control and Prevention states that any licensed, recommended, and age-appropriate influenza vaccine may be used in older adults despite reasonable evidence suggesting that the high-dose and, to a lesser extent, the adjuvanted and recombinant influenza vaccines provide better protection than the standard-dose vaccines in this vulnerable population. In this era of precision medicine, clinicians can preferentially recommend these contemporary vaccines to equip their older patients with the best possible protection against influenza.

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Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial

Clinical and Vaccine Immunology ◽

10.1128/cvi.00604-15 ◽

2016 ◽

Vol 23 (3) ◽

pp. 228-235 ◽

Cited By ~ 31

Author(s):

Andrew J. Dunning ◽

Carlos A. DiazGranados ◽

Timothy Voloshen ◽

Branda Hu ◽

Victoria A. Landolfi ◽

...

Keyword(s):

Influenza Vaccine ◽

Vaccine Efficacy ◽

Standard Dose ◽

The Elderly ◽

High Dose ◽

Efficacy Trial ◽

Correlates Of Protection ◽

Immune Correlates ◽

Immunologic Assays ◽

Dose Vaccine

ABSTRACTAlthough a number of studies have investigated and quantified immune correlates of protection against influenza in adults and children, data on immune protection in the elderly are sparse. A recent vaccine efficacy trial comparing standard-dose with high-dose inactivated influenza vaccine in persons 65 years of age and older provided the opportunity to examine the relationship between values of three immunologic assays and protection against community-acquired A/H3N2 influenza illness. The high-dose vaccine induced significantly higher antibody titers than the standard-dose vaccine for all assays. For the hemagglutination inhibition assay, a titer of 40 was found to correspond with 50% protection when the assay virus was antigenically well matched to the circulating virus—the same titer as is generally recognized for 50% protection in younger adults. A dramatically higher titer was required for 50% protection when the assay virus was a poor match to the circulating virus. With the well-matched virus, some protection was seen at the lowest titers; with the poorly matched virus, high levels of protection were not achieved even at the highest titers. Strong associations were also seen between virus neutralization test titers and protection, but reliable estimates for 50% protection were not obtained. An association was seen between titers of an enzyme-linked lectin assay for antineuraminidase N2 antibodies and protection; in particular, the proportion of treatment effect explained by assay titer in models that included both this assay and one of the other assays was consistently higher than in models that included either assay alone. (This study has been registered at ClinicalTrials.gov under registration no. NCT01427309.)

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Relative effectiveness of influenza vaccines in elderly persons in the United States, 2012/2013-2017/2018 seasons

npj Vaccines ◽

10.1038/s41541-021-00373-w ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Marina Amaral de Avila Machado ◽

Cristiano S. Moura ◽

Michal Abrahamowicz ◽

Brian J. Ward ◽

Louise Pilote ◽

...

Keyword(s):

Standard Dose ◽

Relative Effectiveness ◽

The Elderly ◽

The United States ◽

The Other ◽

Influenza Vaccines ◽

Quadrivalent Vaccine ◽

High Dose ◽

Elderly Persons ◽

Real World Setting

AbstractInfluenza immunization protects seniors against influenza and its potentially serious complications. It is uncertain whether standard-dose (SD) quadrivalent vaccine offers better protection over other formulations in the elderly. In this study, we compared the effectiveness of SD-trivalent, high-dose (HD) trivalent, SD-quadrivalent, and adjuvanted trivalent vaccines in seniors (≥65 years) in a real-world setting. We selected over 200,000 individuals in each of 6 influenza seasons from 2012 to 2018 using MarketScan® databases. The two outcomes were hospitalization or emergency room (ER) visit due to (1) influenza or (2) pneumonia. Here, SD-quadrivalent was associated with higher risk of influenza-related hospitalization/ER visit (adjusted hazard ratio (aHR) 1.14 and 95% confidence interval (95% CI) 1.05–1.24) and of pneumonia-related hospitalization/ER visit (aHR 1.04 and 95% CI 1.01–1.07) vs. HD-trivalent. SD-trivalent followed similar trends compared to HD-trivalent (aHR 1.16 and 95% CI 1.06–1.27 for hospitalized/ER visit influenza; aHR 1.07 and 95% CI 1.05–1.10 for hospitalized/ER visit pneumonia). We could not demonstrate risk differences between SD vaccine formulations and between adjuvanted trivalent and one of the other three vaccines. Risk estimates slightly varied across seasons. These findings suggest that SD vaccine formulations vs. HD-trivalent were associated with higher risk of hospitalization/ER visit for influenza and pneumonia in seniors.

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Effectiveness of the MF59-adjuvanted trivalent or quadrivalent seasonal influenza vaccine among adults 65 years of age or older, a systematic review and meta-analysis

10.22541/au.161933909.92394260/v1 ◽

2021 ◽

Author(s):

Brenda Coleman ◽

Ruth Sanderson ◽

Mendel Haag ◽

Ian McGovern

Keyword(s):

Influenza Vaccine ◽

Seasonal Influenza ◽

Standard Dose ◽

Meta Analysis ◽

Grey Literature ◽

Influenza Vaccines ◽

High Dose ◽

Case Control Studies ◽

Cluster Randomized ◽

Meta Analyses

Background: Standard dose seasonal influenza vaccines often produce modest immunogenic responses in adults ≥65 years old. MF59 is intended to elicit a greater magnitude and increased breadth of immune response. Objective: To determine the effectiveness of seasonal MF59-adjuvanted trivalent/quadrivalent influenza vaccine (aTIV/aQIV) relative to no vaccination or vaccination with standard or high dose egg-based influenza vaccines among people ≥65 years old. Methods: Cochrane methodological standards and PRISMA-P guidelines were followed. Real-world evidence from non-interventional studies published in peer reviewed journals and grey literature from 1997 through to July 15, 2020, including cluster-randomized trials, were eligible. Two reviewers independently extracted data and risk of bias was assessed using the ROBINS-I tool. Results: Twenty-one studies conducted during the 2006/07-2019/20 influenza seasons were included in the qualitative review; 16 in the meta-analyses. Meta-analysis of test-negative studies found that aTIV reduced medical encounters due to lab-confirmed influenza with pooled estimates of 40.7% (95% CI: 21.9, 54.9; I2=0%) for general practitioner visits and 58.5% (40.7, 70.9; I2=52.9%) for hospitalized patients. The pooled estimate of VE from case-control studies was 51.3% (39.1, 61.1; I2=0%) against influenza- or pneumonia-related hospitalization. The pooled estimates for the relative VE of aTIV for the prevention of influenza related medical encounters were 13.9% (4.2, 23.5; I2=95.9%) compared with TIV, 13.7% (3.1, 24.2; I2=98.8%) compared with QIV, and 2.8% (-2.9, 8.5; I2=94.5%) compared with HD TIV. Conclusions: Among adults ≥65 years aTIV demonstrated significant absolute VE, improved relative VE compared to non-adjuvanted standard-dose TIV/QIV, and comparable relative VE to high-dose TIV.

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Comparative effectiveness of influenza vaccines among U.S. Medicare beneficiaries ages 65 years and older during the 2019-20 season

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1727 ◽

2020 ◽

Author(s):

Hector S Izurieta ◽

Michael Lu ◽

Jeffrey Kelman ◽

Yun Lu ◽

Arnstein Lindaas ◽

...

Keyword(s):

Standard Dose ◽

The Elderly ◽

Influenza Vaccines ◽

Influenza B ◽

High Dose ◽

Medicare Beneficiaries ◽

Health Seeking ◽

Inverse Probability ◽

Seeking Behavior ◽

The U.S

Abstract Background Around 50,000 influenza-associated deaths occur annually in the U.S., overwhelmingly among individuals ages >65 years. Although vaccination is the primary prevention tool, investigations have shown low vaccine effectiveness (VE) in recent years, particularly among the elderly. We analyzed the relative VE (RVE) of all influenza vaccines among Medicare beneficiaries ages >65 years to prevent influenza hospital encounters during the 2019-20 season. Methods Retrospective cohort study using Poisson regression and inverse probability of treatment weighting (IPTW). Exposures included egg-based high-dose trivalent (HD-IIV3), egg-based adjuvanted trivalent (aIIV3), egg-based standard dose (SD) quadrivalent (IIV4), cell-based SD quadrivalent (cIIV4), and recombinant quadrivalent (RIV4) influenza vaccines. Results We studied 12.7 million vaccinated beneficiaries. Following IPTW, cohorts were well balanced for all covariates and health-seeking behavior indicators. In the adjusted analysis, RIV4 (RVE 13.3%, 95% CI 7.4%, 18.9%), aIIV3 (RVE 8.2%, 95% CI 4.2%, 12.0%), and HD-IIV3 (RVE 6.8%, 95% CI 3.3%, 10.1%) were significantly more effective in preventing hospital encounters than the reference egg-based SD IIV4, while cIIV4 was not significantly more effective than IIV4 (RVE 2.8%, 95% CI -2.8%, 8.2%). Our results were consistent across all analyses. Conclusions In this influenza B-Victoria and A(H1N1)-dominated season, RIV4 was moderately more effective than other vaccines, while the HD-IIV3 and aIIV3 were more effective than the IIV4 vaccines, highlighting the contributions of antigen amount and adjuvant use to VE. Egg adaptation likely did not substantially affect our RVE evaluation. Our findings, specific to the 2019-20 season, should be evaluated in other studies using virological case confirmation.

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Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa255 ◽

2020 ◽

Vol 222 (8) ◽

pp. 1383-1391

Author(s):

Benjamin J Cowling ◽

Mark G Thompson ◽

Tiffany W Y Ng ◽

Vicky J Fang ◽

Ranawaka A P M Perera ◽

...

Keyword(s):

Older Adults ◽

Influenza Vaccine ◽

Standard Dose ◽

Controlled Trial ◽

Community Dwelling ◽

Influenza Vaccines ◽

High Dose ◽

Systemic Reactions ◽

Local Reactions ◽

Systemic Symptoms

Abstract Background We analyzed data from a randomized controlled trial on the reactogenicity of 3 enhanced influenza vaccines compared with standard-dose (SD) inactivated influenza vaccine. Methods We enrolled community-dwelling older adults in Hong Kong, and we randomly allocated them to receive 2017–2018 northern hemisphere formulations of SD vaccine (FluQuadri; Sanofi Pasteur), MF59-adjuvanted vaccine (FLUAD; Seqirus), high-dose (HD) vaccine (Fluzone High-Dose; Sanofi Pasteur), or recombinant hemagglutinin vaccine (Flublok; Sanofi Pasteur). Local and systemic reactions were evaluated at days 1, 3, 7, and 14 after vaccination. Results Reported reactions were generally mild and short-lived. Systemic reactions occurred in similar proportions of participants by vaccine. Some local reactions were slightly more frequently reported among recipients of the MF59-adjuvanted and HD vaccines than among SD vaccine recipients. Participants reporting feverishness 1 day after vaccination had mean fold rises in postvaccination hemagglutination inhibition titers that were 1.85-fold higher (95% confidence interval, 1.01–3.38) for A(H1N1) than in those who did not report feverishness. Conclusions Some acute local reactions were more frequent after vaccination with MF59-adjuvanted and HD influenza vaccines, compared with SD inactivated influenza vaccine, whereas systemic symptoms occurred at similar frequencies in all groups. The association between feverishness and immunogenicity should be further investigated in a larger population. Clinical Trials Registration NCT03330132.

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