Phase 3 Randomized, Multicenter, Placebo-Controlled Study to Evaluate Safety, Immunogenicity, and Lot-to-Lot Consistency of an Adjuvanted Cell Culture-Derived, H5N1 Subunit Influenza Virus Vaccine in Healthy Adult Subjects

Abstract

A cell-based process may be better suited for vaccine production during a highly pathogenic avian influenza (HPAI) pandemic. This was a phase 3, randomized, controlled, observer-blind, multicenter study evaluated safety, immunogenicity, and lot-to-lot consistency of two doses of a MF59-adjuvanted, H5N1 influenza pandemic vaccine manufactured on a cell culture platform (aH5N1c) in 3196 healthy adult subjects, stratified into two age groups: 18 to <65 and ≥65 years. Immunogenicity was measured using hemagglutination inhibition (HI) titers. HI antibody responses increased after the first aH5N1c vaccine dose, and 3 weeks after the second vaccination (Day 43), age-appropriate US Center for Biologics Evaluation and Research (CBER) and former European Medicines Authority Committee for Medicinal Products for Human Use (EMA CHMP) immunogenicity criteria were met. Six months after the first vaccination, HI titers were above baseline but no longer met CBER and CHMP criteria. No relevant changes over time were seen in placebo subjects. Solicited AEs were more frequent in the active treatment than the placebo group, primarily due to injection site pain. No serious adverse events (SAEs) related to aH5N1c- were reported. aH5N1c influenza vaccine elicited high levels of antibodies following two vaccinations administered 21 days apart and met both CBER and former CHMP immunogenicity criteria at Day 43 among both younger and older adults with a clinically acceptable safety profile. Consistency of the three consecutive aH5N1c vaccine lots was demonstrated (NCT02839330).

Keywords: H5N1; adult; cell culture-derived; elderly; influenza; pandemic; vaccine.

Figure 1

Disposition of subjects. ^a Includes subjects for whom blood was drawn but not on Day 1. ^b Includes subjects for whom blood was drawn out of the time window specified in the protocol.

Figure 2

(a) Pairwise comparisons of the geometric mean titer (GMT) ratios of hemagglutination inhibition (HI) titers from Groups A (Lot 1, No.181053), B (Lot 2, No.181054), and C (Lot 3, No.181675). Protocol-defined equivalence range of the 95% confidence intervals (CI) was 0.667 to 1.5. (b) Proportion of subjects with HI ≥1:40 on Day 43 in the pooled aH5N1c and placebo groups. Center for Biologics Evaluation Research (CBER) criteria were met if the lower bound of the 95% CI was ≥70% in subjects aged 18 to <65 years and ≥60% in subjects aged ≥65 years.

Figure 3

Percentages of subjects with at least one solicited adverse event (AE) within 7 days after the first, second, or any vaccination.

Figure 4

Percentages of subjects with unsolicited adverse events (AE), serious adverse events (SAE), AE leading to study withdrawal, medically attended AEs, new onset chronic disease (NOCD), AE of special interest (AESI), or death from Day 1 through study termination.