Immunologic non-inferiority of a newly licensed inactivated trivalent influenza vaccine versus an established vaccine: a randomized study in US adults

Abstract

A trivalent inactivated influenza vaccine (Fluarix (™) , GlaxoSmithKline Biologicals) was licensed under US accelerated approval regulations. We performed a randomized, observer-blind, post-approval study to demonstrate its immunological non-inferiority versus an established US-licensed vaccine (primary endpoint). Adult (including elderly) subjects received a single injection of newly-licensed vaccine (n = 923) or established vaccine (n = 922). Serum hemagglutination-inhibition titers were determined pre-vaccination and 21-28 days after vaccination. Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 0.1) for all three vaccine strains. Safety was monitored for 6 months. The newly-licensed vaccine was non-inferior to the established vaccine in all subjects (≥ 18 years) and in elderly subjects (≥ 65 years). Adjusted GMT ratios (established/newly-licensed) against the H1N1, H3N2 and B strains were 0.65 (95% CI: 0.58, 0.73), 0.93 (0.83, 1.04) and 1.13 (1.03, 1.25) for all subjects and 0.75 (0.67, 0.85), 0.95 (0.82, 1.09) and 1.13 (1.00, 1.27) for elderly subjects. Corresponding values for the differences in seroconversion rate (established minus newly-licensed) were -0.12 (-0.16, -0.07), -0.02 (-0.06, 0.03) and 0.01 (-0.04, 0.06) for all subjects and -0.11 (-0.16, -0.05), -0.02 (-0.07, 0.04) and 0.02 (-0.04, 0.08) for elderly subjects. The most common adverse events with both vaccines were injection site pain, fatigue and headache, and no serious adverse events or deaths were considered related; there were no clinically relevant differences between the vaccines. In conclusion, the newly-licensed vaccine was well tolerated and immunologically non-inferior to the established vaccine for all three vaccine strains in the whole population and the elderly.

Trial registration: ClinicalTrials.gov NCT00197288.

Figures

Figure 1

Disposition of subjects. ATP: according to protocol; AE: adverse event; SAE: serious adverse event.

Figure 2

Non-inferiority analysis of the newly-licensed vaccine versus the established vaccine for adjusted geometric mean titer ratio. All subjects (≥18 years), according to protocol cohort. H1N1: A/New Caledonia/20/99; H3N2: A/New York/55/2004; B: B/Jiangsu/10/2003. Adjusted GMT: geometric mean antibody titer adjusted for baseline titer; 95% CI: 95% confidence interval; GMT ratio: established vaccine/newlylicensed vaccine Solid square indicates the point estimate of the GMT and hash marks the limits of the 95% confidence intervals. Dashed line indicates non-inferiority limit. Non-inferiority was defined as: the upper limit of the 2-sided 95% CI of the GMT ratio (established vaccine/newly-licensed vaccine) for all three vaccine strains should not exceed 1.5.

Figure 3

Geometric mean titers measured at the second study visit (days 21–28). Data presented separately for all subjects (≥18 years) and for the elderly (≥65 years), according to protocol cohort. Values were calculated in subjects who had a serum sample available at the second study visit: Newly-licensed vaccine, all subjects (≥18 years), n = 866. Established vaccine, all subjects (≥18 years), n = 854. Newly-licensed vaccine, elderly subjects (≥65 years), n = 567. Established vaccine, elderly subjects (≥65 years), n = 550. H1N1: A/New Caledonia/20/99; H3N2: A/New York/55/2004; B: B/Jiangsu/10/2003. Error bars: 95% confidence interval.

Figure 4

Seroconversion rates measured at the second study visit (days 21–28). Data presented separately for all subjects (≥18 years) and for the elderly (≥65 years), according to protocol cohort. Values were calculated in subjects who had serum samples available at baseline and at the second study visit. Newly-licensed vaccine, all subjects (≥18 years), n = 858. Established vaccine, all subjects (≥18 years), n = 846. Newly-licensed vaccine, elderly subjects (≥65 years), n = 562. Established vaccine, elderly subjects (≥65 years), n = 544. H1N1: A/New Caledonia/20/99; H3N2: A/New York/55/2004; B: B/Jiangsu/10/2003. Seroconversion: 4-fold rise in titer and ≥1:40. Error bars: 95% confidence interval.