Immunogenicity and Safety of an AS03-Adjuvanted H7N9 Pandemic Influenza Vaccine in a Randomized Trial in Healthy Adults

Abstract

Background: Almost 700 cases of human infection with avian influenza A/H7N9 have been reported since 2013. Pandemic preparedness strategies include H7N9 vaccine development.

Methods: We evaluated an inactivated H7N9 vaccine in an observer-blind study in healthy adults aged 18-64 years. Participants (420) were randomized to receive 1 of 4 AS03-adjuvanted vaccines (low or medium dose of hemagglutinin with AS03_A or AS03_B), one nonadjuvanted vaccine, or placebo. The coprimary immunogenicity objective determined whether adjuvanted vaccines elicited an immune response against the vaccine-homologous virus, 21 days after the second vaccine dose per US and European licensure criteria in the per-protocol cohort (n = 389).

Results: All adjuvanted vaccines met regulatory acceptance criteria. In groups receiving adjuvanted formulations, seroconversion rates were ≥85.7%, seroprotection rates ≥91.1%, and geometric mean titers ≥92.9% versus 23.2%, 28.6%, and 17.2 for the nonadjuvanted vaccine. The AS03 adjuvant enhanced immune response at antigen-sparing doses. Injection site pain occurred more frequently with adjuvanted vaccines (in ≤98.3% of vaccinees) than with the nonadjuvanted vaccine (40.7%) or placebo (20.0%). None of the 20 serious adverse events reported were related to vaccination.

Conclusions: Two doses of AS03-adjuvanted H7N9 vaccine were well tolerated and induced a robust antibody response at antigen-sparing doses in healthy adults.

Clinical trials registration: NCT01999842.

Keywords: AS03; H7N9; adjuvant system; antigen sparing; influenza; pandemic; vaccine.

Figure 1.

Participant flow chart. Values represent numbers of participants. Abbreviations: HA/AS03_A, hemagglutinin (HA) adjuvanted with AS03_A; HA/AS03_B, hemagglutinin (HA) adjuvanted with AS03_B.

Figure 2.

Seropositivity rate and geometric mean titer (GMT) for vaccine-homologous (A) and vaccine-heterologous (B) microneutralization antibodies (adapted per-protocol cohort). The vaccine homologous strain used for testing was a H7N9 virus developed by reverse genetics with hemagglutinin (HA) and neuraminidase genes derived from A/Anhui/1/2013 (H7N9) and 6 genes from A/PR/8/34. The vaccine heterologous strain was a H7N1 virus developed by reverse genetics with the HA gene derived from A/mallard/Netherlands/12/2000 (H7N3) and 7 genes from A/PR/8/34. Bars represent GMT values; error bars, 95% confidence intervals (CI); percentages above the bars, seropositivity rate; and horizontal gridline, cutoff value for the assay. The adapted per-protocol cohort includes data for days 0, 21, and 42 from the day 42 per-protocol cohort; day 182 data from the day 182 per-protocol cohort; and day 385 data from the day 385 per-protocol cohort. Day 21 was 21 days after the first vaccination, day 42 was 21 days after the second vaccination, and day 182 was 182 days after the first vaccination. Abbreviations: d, day; HD, high-dose; LD, low-dose; MD, medium-dose; Pre, prevaccination measurement.