FLUAD vs. FLUZONE HD Influenza Vaccine in Residents of Long Term Care

Flu Clinical Trial

Official title:

Non-inferiority Study of Adjuvanted vs. High Dose Flu Vaccine in Residents of Long Term Care

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03694808
• Other study ID #: 10-27-29
• Secondary ID: 1R01AI129709-01A
• Status: Completed
• Phase: Phase 4
• Start date: September 23, 2018
• Est. completion date: January 31, 2023

Study information

• Verified date: April 2024
• Source: University Hospitals Cleveland Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Adjuvanted flu vaccine, Fluad, is not immunologically inferior to HD influenza vaccine in older persons living in long-term care.

Description:

As the primary endpoint, this trial is be using pre- to post-vaccine changes in HAI titers to compare seroconversion rates and post-vaccination HAI titers to calculate the ratio of the geometric mean titers in the two treatment groups. HAI is an in vitro bioassay that determines a subject's serum levels of anti-influenza antibodies. The FDA uses this as a standard immunogenicity assay for licensure. The trial will follow guidelines set out in the FDA guidance document discussing non-inferiority immunogenicity studies. As additional methods to assess immunogenicity, an assessment of anti-NA by performing NA inhibition assays (NAI) and SVN assays will be added. A recent trial supported the use of NAI and SVN assays as a correlate for protection in a trial of geriatric subjects. A healthy human challenge model showed that NAI is more predictive of protection and reduced disease than HAI In the large HD vaccine clinical efficacy trial (n=31,989) one third of subjects also had immunogenicity data that allowed looking for correlations of immune assays with protection. Their conclusions were that HAI and other immune assays are potential correlates of influenza vaccine protection in older adults, and that the protective thresholds for the HAI assay in the elderly appear consistent with those previously described for younger adults, provided the assay virus matches the circulating virus. Significance Data compiled by CDC in 2011-2012 showed that there were 1,383,700 residents in NHs. Also about 4,742,500 patients received services from home health agencies, and 1,244,500 patients received services from hospices, collectively accounting for much of the frailest in the US. Overall, these provider sectors served over 8 million people annually (2013). This study will focus on residents in NHs but the findings of this study are highly relevant to persons frail enough to require such services in all of settings where the vast majority are at least 65 years old and thus appropriate for Fluad or HD, influenza vaccines licensed for this age group. The SD influenza vaccine has diminished efficacy in the older population with the more debilitated LTC residents being among the worst responders yet with the highest mortality. Deaths due to pneumonia and influenza and chronic lung disease were 20 times higher among NH residents compared to community residents. The current availability of two vaccines specifically for the elderly that both appear to work better than SD vaccine begs the question: is the newer and less-costly Fluad vaccine non-inferior or even superior to HD vaccine? The proposed study aims to initially address non-inferiority using immunologic endpoints as this is feasible in the clinical trial R01 grant structure and a critical first step to obtain head-to-head data from the same trial, cohort and vaccine years. This proposed study itself may provide direct guidance on vaccine usage or inform a future trial assessing actual superiority should that be appropriate based on the results of this study. HD vaccine is increasingly used by older Americans despite its greater cost over the SD vaccine and no preferential recommendation by the Advisory Committee on Immunization Practices (ACIP), the CDC committee responsible for making the vaccine recommendations for the U.S. A finding of non-inferiority in the primary endpoint would provide a strong rationale to consider using Fluad over HD that could result in some cost avoidance across large long-term care system in the U.S. The trial is not powered for a superiority analysis but in a non-inferiority trial if the findings are substantial enough they may show superiority. In the normal seasonal setting, influenza strains drift antigenically and therefore vary from year to year. The CDC's prediction many months before the vaccination season sets the composition for the next season's vaccine, but does not always correctly anticipate the exact strain match that eventually actually circulates. There are Medicare claims data and modeling in the NH population that there is a significant increase in death and hospitalization in bad match over good match years particularly when A/H3N2 predominates. In those mismatched years in particular, heterologous immunity or immunity to other non-exact match strains becomes much more important if the vaccine is going to provide any benefit that season. Fluad is an adjuvanted vaccine that has been shown to have a more broad-based or heterologous immunity than SD vaccine that is not adjuvanted. HD is also not adjuvanted. Broad based immunity is especially desirable for A/H3N2 immunity as that has had 4 different circulating strains in the last 5 years while circulating A/H1N1 has been the same for 5 years; i.e., vaccine mismatch is more likely with the A/H3N2 circulating strain. A/H3N2 is associated with the majority of influenza hospitalizations and death among the elderly.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 478
• Est. completion date: January 31, 2023
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years and older

Eligibility

Inclusion Criteria:

• > 65 years old
• Able to obtain consent from subject or legally authorized representative (subject to provide assent if cognitively/physically able to do so)
• Able to participate throughout the study period

Exclusion Criteria:

• Recent illness (within 30 days) severe enough to require hospitalization or physician-directed outpatient pharmacotherapy
• Administration of immunomodulatory agents (e.g. oral corticosteroids except prednisone < 10 mg daily, cyclosporine, and biologics (DMARDS) for Rheumatologic/Dermatologic conditions) in the last 3 months
• Cancer requiring treatment in the past three years, except for non- melanoma skin cancers or cancers that have clearly been cured or carry an excellent prognosis including prostate cancer.
• Myocardial infarction, major heart surgery (i.e. valve replacement or bypass surgery), stroke, deep vein thrombosis or pulmonary embolus in the past 4 months
• Allergies or history of significant adverse reactions to any component of influenza vaccine including egg protein and latex or after a previous dose of any influenza vaccine.
• History of Guillian-Barré Syndrome within 6 weeks of a prior influenza vaccine.

Related Conditions & MeSH terms

• Flu

Intervention

Drug:
• Fluad Vaccine
single adjuvanted dose (AD) intramuscular injection
• Fluzone HD Vaccine
single high dose (HD) intramuscular injection

Locations

Country	Name	City	State
United States	Louis Stokes Cleveland VA Medical Center	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio

Sponsors (6)

Lead Sponsor	Collaborator
David H. Canaday	Brown University, Case Western Reserve University, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), US Department of Veterans Affairs

Country where clinical trial is conducted

United States, 

References & Publications (18)

2013. Long-Term Care Services in the United States: 2013 Overview. In CDC, editor HHS, Disease Control and Prevention, National Center for Health Statistics, Hyattsville, Maryland.

Ansaldi F, Bacilieri S, Durando P, Sticchi L, Valle L, Montomoli E, Icardi G, Gasparini R, Crovari P. Cross-protection by MF59-adjuvanted influenza vaccine: neutralizing and haemagglutination-inhibiting antibody activity against A(H3N2) drifted influenza viruses. Vaccine. 2008 Mar 17;26(12):1525-9. doi: 10.1016/j.vaccine.2008.01.019. Epub 2008 Feb 1. — View Citation

Centers for Disease Control and Prevention (CDC). Estimates of deaths associated with seasonal influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010 Aug 27;59(33):1057-62. — View Citation

DiazGranados CA, Dunning AJ, Kimmel M, Kirby D, Treanor J, Collins A, Pollak R, Christoff J, Earl J, Landolfi V, Martin E, Gurunathan S, Nathan R, Greenberg DP, Tornieporth NG, Decker MD, Talbot HK. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014 Aug 14;371(7):635-45. doi: 10.1056/NEJMoa1315727. — View Citation

Dunning AJ, DiazGranados CA, Voloshen T, Hu B, Landolfi VA, Talbot HK. Correlates of Protection against Influenza in the Elderly: Results from an Influenza Vaccine Efficacy Trial. Clin Vaccine Immunol. 2016 Jan 13;23(3):228-35. doi: 10.1128/CVI.00604-15. — View Citation

Falsey AR, Treanor JJ, Tornieporth N, Capellan J, Gorse GJ. Randomized, double-blind controlled phase 3 trial comparing the immunogenicity of high-dose and standard-dose influenza vaccine in adults 65 years of age and older. J Infect Dis. 2009 Jul 15;200(2):172-80. doi: 10.1086/599790. — View Citation

FDA. 2007. Guidance for Industry Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines. In Center for Biologics Evaluation and Research.

Frey SE, Reyes MR, Reynales H, Bermal NN, Nicolay U, Narasimhan V, Forleo-Neto E, Arora AK. Comparison of the safety and immunogenicity of an MF59(R)-adjuvanted with a non-adjuvanted seasonal influenza vaccine in elderly subjects. Vaccine. 2014 Sep 3;32(39):5027-34. doi: 10.1016/j.vaccine.2014.07.013. Epub 2014 Jul 18. — View Citation

Hancock K, Veguilla V, Lu X, Zhong W, Butler EN, Sun H, Liu F, Dong L, DeVos JR, Gargiullo PM, Brammer TL, Cox NJ, Tumpey TM, Katz JM. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. N Engl J Med. 2009 Nov 12;361(20):1945-52. doi: 10.1056/NEJMoa0906453. Epub 2009 Sep 10. — View Citation

Iob A, Brianti G, Zamparo E, Gallo T. Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy. Epidemiol Infect. 2005 Aug;133(4):687-93. doi: 10.1017/s0950268805003936. — View Citation

Izurieta HS, Thadani N, Shay DK, Lu Y, Maurer A, Foppa IM, Franks R, Pratt D, Forshee RA, MaCurdy T, Worrall C, Howery AE, Kelman J. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet Infect Dis. 2015 Mar;15(3):293-300. doi: 10.1016/S1473-3099(14)71087-4. Epub 2015 Feb 9. Erratum In: Lancet Infect Dis. 2015 Apr;15(4):373. Lancet Infect Dis. 2015 Mar;15(3):263. — View Citation

Izurieta HS, Thadani N, Shay DK. Corrections. Comparative effectiveness of high-dose versus standard-dose influenza vaccines in US residents aged 65 years and older from 2012 to 2013 using Medicare data: a retrospective cohort analysis. Lancet Infect Dis. 2015 Mar;15(3):263. doi: 10.1016/S1473-3099(15)70070-8. No abstract available. — View Citation

Mannino S, Villa M, Apolone G, Weiss NS, Groth N, Aquino I, Boldori L, Caramaschi F, Gattinoni A, Malchiodi G, Rothman KJ. Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy. Am J Epidemiol. 2012 Sep 15;176(6):527-33. doi: 10.1093/aje/kws313. Epub 2012 Aug 31. — View Citation

Memoli MJ, Shaw PA, Han A, Czajkowski L, Reed S, Athota R, Bristol T, Fargis S, Risos K, Powers JH, Davey RT Jr, Taubenberger JK. Evaluation of Antihemagglutinin and Antineuraminidase Antibodies as Correlates of Protection in an Influenza A/H1N1 Virus Healthy Human Challenge Model. mBio. 2016 Apr 19;7(2):e00417-16. doi: 10.1128/mBio.00417-16. — View Citation

Menec VH, MacWilliam L, Aoki FY. Hospitalizations and deaths due to respiratory illnesses during influenza seasons: a comparison of community residents, senior housing residents, and nursing home residents. J Gerontol A Biol Sci Med Sci. 2002 Oct;57(10):M629-35. doi: 10.1093/gerona/57.10.m629. — View Citation

Pop-Vicas A, Rahman M, Gozalo PL, Gravenstein S, Mor V. Estimating the Effect of Influenza Vaccination on Nursing Home Residents' Morbidity and Mortality. J Am Geriatr Soc. 2015 Sep;63(9):1798-804. doi: 10.1111/jgs.13617. Epub 2015 Aug 17. — View Citation

Richardson DM, Medvedeva EL, Roberts CB, Linkin DR; Centers for Disease Control and Prevention Epicenter Program. Comparative effectiveness of high-dose versus standard-dose influenza vaccination in community-dwelling veterans. Clin Infect Dis. 2015 Jul 15;61(2):171-6. doi: 10.1093/cid/civ261. Epub 2015 Mar 31. — View Citation

Van Buynder PG, Konrad S, Van Buynder JL, Brodkin E, Krajden M, Ramler G, Bigham M. The comparative effectiveness of adjuvanted and unadjuvanted trivalent inactivated influenza vaccine (TIV) in the elderly. Vaccine. 2013 Dec 9;31(51):6122-8. doi: 10.1016/j.vaccine.2013.07.059. Epub 2013 Aug 6. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	To Pilot Clinical Objective: Efficacy of FLUAD Will be Compared to FLUZONE HD.	A record review and a blood 2 weeks after the influenza season is over will be done. From a record review the dates and diagnoses of hospitalizations and/or "influenza like illness" (ILI) will be recorded. Serologic evidence of influenza infection ( >=4-fold titer rise beyond the post-vaccine titers) will be determined from the remote blood draw. An exploratory analysis will be performed comparing the efficacy of the two vaccines.	6-8 months post vaccine administration
Primary	Overall Hemagglutinin Inhibition (HAI) H1N1 Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.	1 month post vaccine administration
Primary	Overall Hemagglutinin Inhibition (HAI) H3N2 Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.	1 month post vaccine administration
Primary	Overall Hemagglutinin Inhibition (HAI) B Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.	1 month post vaccine administration
Primary	Overall HAI H1N1 Seroconversion Rate Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.	1 month post vaccine administration
Primary	Overall HAI H3N2 Seroconversion Rate Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.	1 month post vaccine administration
Primary	Overall HAI B Seroconversion Rate Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	HAI is an in vitro bioassay testing subjects' sera for specific anti-influenza antibodies to each strain in the vaccine. Seroconversion is 4-fold rise in antibody titer. The FDA uses this as the standard immunogenicity assay for licensure. The investigators will follow the guidelines set out in the FDA guidance document on non-inferiority immunogenicity studies for the analysis plan.	1 month post vaccine administration
Secondary	Overall Neuraminidase Inhibition (NAI) H1N1 Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Neuraminidase inhibition (NAI) assays will be performed to measure anti-neuraminidase titers. Seroconversion is 4-fold rise in antibody titer.	1 month post vaccine administration
Secondary	Overall Neuraminidase Inhibition (NAI) H3N2 Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Neuraminidase inhibition (NAI) assays will be performed to measure anti-neuraminidase titers. Seroconversion is 4-fold rise in antibody titer.	1 month post vaccine administration
Secondary	Overall H1N1 NAI Seroconversion Rate Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Neuraminidase inhibition (NAI) assays will be performed to measure anti-neuraminidase titers. Seroconversion is 4-fold rise in antibody titer.	1 month post vaccine administration
Secondary	Overall NAI H3N2 Seroconversion Rate Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Neuraminidase inhibition (NAI) assays will be performed to measure anti-neuraminidase titers. Seroconversion is 4-fold rise in antibody titer.	1 month post vaccine administration
Secondary	Overall Serum Virus Neutralization (SVN) H1N1 Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Serum virus neutralization (SVN) assays will be performed to measure the ability of serum to inhibit influenza infection.	1 month post vaccine administration
Secondary	Heterologous Immunity at 1 Month Post-vaccination Will be Compared Between FLUAD and FLUZONE HD.	Hemagglutinin inhibition (HAI), neuraminidase inhibition (NAI) assays and serum virus neutralization (SVN) assays will be performed with heterologous A/H3N2 strains to determine if Fluad has an increased breadth of both B and T cell responses as would be predicted from an adjuvanted vaccine.	1 month post vaccine administration
Secondary	Overall Serum Virus Neutralization (SVN) H3N2 Titer Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Serum virus neutralization (SVN) assays will be performed to measure the ability of serum to inhibit influenza infection.	1 month post vaccine administration
Secondary	Overall Serum Virus Neutralization (SVN) H1N1 Seroconversion Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Serum virus neutralization (SVN) assays will be performed to measure the ability of serum to inhibit influenza infection.	1 month post vaccine administration
Secondary	Overall Serum Virus Neutralization (SVN) H3N2 Seroconversion Between FLUAD and FLUZONE HD at 1 Month Post-vaccination.	Serum virus neutralization (SVN) assays will be performed to measure the ability of serum to inhibit influenza infection.	1 month post vaccine administration