Randomized Controlled Trial of High Dose Influenza Vaccine among Frail Long-Term Care Residents

Background:  In the US, influenza results in an estimated 226,000 hospitalizations annually.  It is estimated that about 3,000-49,000 influenza-associated deaths occur, with over 90% reported among the elderly over 65 years old. The estimated average total cost per case of influenza in long term care (LTC) facilities in 2013 US$ is $1,886 ± $2,899, with more than 80% due to the cost of hospitalization. The elderly living in LTC facilities have higher influenza exposure risks and lower immune defenses, thus, more effective vaccination options are needed.  Fluzone High-Dose (HD) influenza vaccine is designed specifically for adults 65 years and older.  The HD vaccine contains four times the antigen than the standard-dose (SD) influenza vaccines; it is twice as expensive.  Given the rapid growth of the senior population in the US, it is critical to examine whether HD vaccines can produce an enhanced immunologic response among frail LTC residents thereby providing valuable data for future effectiveness trials and eventually cost-effectiveness analyses.  This clinical trial conducted during the 2011-12 and 2012-13 influenza seasons, assessed the non-inferiority and superiority of HD versus SD influenza vaccine among LTC residents.

Methods:  At baseline in both years combined, 205 eligible consented subjects provided a venous blood sample for hemagglutination inhibition (HI) titers and randomly received SD or HD vaccine.  One month later, blood sampling was repeated. Geometric mean titers (GMTs) and 2-sided 95% confidence intervals (CIs) were calculated.  An upper bound of the 2-sided 95% CI on the ratio of post-vaccination GMT_SD to GMT_HD <1.5 indicated non-inferiority.  A lower bound of the 2-sided 95% CI on the ratio of GMT_HD to GMT_SD ≥1.0 indicated superiority.  Tests were performed separately for the 2011-12 and 2012-13 vaccine formulations which contained different A/H3N2 and B strains.

Results: The completion rate was 82.4% (169/205), including 56 participants in 2011-12 and 113 participants in 2012-13; 34 subjects participated both years.  Mean age of participants was 86.7 years; 71% were ≥85 years.  Most participants were white (99%) and female (68%).  Demographic profiles of both groups were similar.  HD vaccine produced GMT responses to the A/H1N1, A/H3N2, and B strains that were non-inferior to those induced by SD vaccine during both influenza seasons; moreover, HD vaccine induced superior antibody responses to all three strains in 2011-12, and to the A/H3N2 and B strains in 2012-13.  Lack of superiority of HD influenza vaccine to A/H1N1 in 2012-13, may be because 30% of subjects (34/113) participated in both seasons when the A/H1N1 strains were identical. 

Conclusion:  This is the first randomized controlled trial of HD immune response among LTC residents. Results demonstrate that HD influenza vaccine induces superior HI titer responses against most strains compared with SD among frail elderly LTC residents. Although HD vaccine costs more than SD vaccine, Medicare covers both. Future studies should determine the effectiveness of HD compared to SD in preventing influenza in LTC residents and assess cost-effectiveness of the vaccine.

Funding Source: Sanofi Pasteur. ClinicalTrial.gov #NCT01654224.