• K G Nicholson, K R Abrams, S Batham, T W Clark, K Hoschler, W S Lim, M Medina, J S Nguyen-Van-Tam, R C Read, F C Warren, and M Zambon.
• Vaccine Evaluation Centre, University Hospitals of Leicester NHS Trust, Department of Inflammation, Infection and Immunity, University of Leicester, UK. kgn2@le.ac.uk
• Health Technol Assess. 2010 Dec 1;14(55):193-334.

ObjectivesTo evaluate the immunogenicity of a two-dose schedule of Baxter cell-cultured, non-adjuvanted, whole-virion H1N1 vaccine, and GlaxoSmithKline AS03(A)-adjuvanted split-virion H1N1 vaccine with respect to the EU Committee for Medicinal Products for Human Use (CHMP) and the US Food and Drug Administration (FDA) licensing criteria.DesignAn age-stratified, randomised, observer-blind, parallel-group, multicentre controlled trial was carried out in volunteers aged ≥ 18-44, ≥ 45-64 and ≥ 65 years.SettingThree teaching hospitals in the UK (Leicester Royal Infirmary, Leicester; Nottingham City Hospital, Nottingham; and Royal Hallamshire Hospital, Sheffield).ParticipantsThree hundred and forty-seven subjects were identified and randomised to AS03(A)-adjuvanted split-virion H1N1 vaccine or whole-virion (WV) vaccine in age groups [≥ 18-44 years (n = 140), ≥ 45-64 years (n = 136) and ≥ 65 years (n = 71)].InterventionsVaccine was administered by intramuscular injection into the deltoid muscle of the non-dominant arm. One hundred and seventy-five randomised subjects were allocated AS03(A)-adjuvanted split H1N1 vaccine; one hundred and sixty-nine subjects had a second dose of the same vaccine 21 days later. One hundred and seventy-two subjects were allocated WV vaccine; one hundred and seventy-one subjects had a second dose of the same vaccine 21 days later. Serum samples for antibody measurements were collected on days 0 (before the first vaccination), 7, 14, 21 (before the second vaccination), 28, 35, 42 and 180. Subjects were observed for local and systemic reactions for 30 minutes after each injection, and for the next 7 days they recorded, in self-completed diaries, the severity of solicited local (pain, bruising, erythema and swelling) and systemic symptoms (chills, malaise, muscle aches, nausea and headache), oral temperature and use of analgesic medications.Main Outcome MeasuresVaccine immunogenicity using the CHMP and the FDA licensing criteria. Antibody titres were measured using haemagglutination inhibition (HI) and microneutralisation (MN) assays at baseline and 7, 14 and 21 days after each vaccination and at day 180. The three immunogenicity criteria end points were the seroprotection rate, the seroconversion rate and the mean-fold titre elevation.ResultsBoth vaccine doses were given in 340 subjects (98%). Data from 680 (99%) of 687 issued diary cards were returned. Sera were obtained from 340 (98.0%), 333 (96.0%), 341 (98.3%), 331 (95.4%), 329 (94.8%) and 332 (95.7%) subjects on days 7, 14, 21, 28, 35 and 42, respectively. Three hundred and forty-six and 345 subjects were included in the safety and immunogenicity analyses, respectively. Prevaccination antibody was detected by HI (titre ≥ 1 : 8) and MN (titre ≥ 1 : 10) in 14% and 31% of subjects, respectively. Among the 298 (85.9%) subjects without baseline antibody on HI assay, a titre of ≥ 1 : 40 (seroprotection) was achieved after a single dose of AS03(A)-adjuvanted vaccine and WV vaccine by day 21 in 93.0% and 65.5%, respectively, of subjects between 18 and 44 years, 76.4% and 36.1% of subjects between 45 and 64 years, and 53.1% and 30.0% of subjects ≥ 65 years. Among all 347 subjects, a titre of ≥ 1 : 40 was achieved after a single dose of AS03(A)-adjuvanted vaccine and WV vaccine by day 21 in 94.0% and 71.4%, respectively, of subjects between 18 and 44 years, 77.3% and 38.8% of subjects between 45 and 64 years, and 51.4% and 32.4% of subjects ≥ 65 years. The age-adjusted odds ratio (OR) for adjuvanted compared with WV vaccine, in terms of seroprotection, was 4.42 [95% confidence interval (CI) 2.63 to 7.44, p < 0.001]. On day 42, among subjects without baseline antibody on HI assay, a titre of ≥ 1 : 40 was achieved after the second dose of AS03(A)-adjuvanted vaccine and WV vaccine by 100% and 67.9%, respectively, of subjects between 18 and 44 years, 89.3% and 41% of subjects between 45 and 64 years, and 76.5% and 34.5% of subjects ≥ 65 years. Among all 347 subjects, a titre of ≥ 1 : 40 was achieved on day 42 after the second dose of AS03(A)-adjuvanted vaccine and WV vaccine in 100% and 73.1%, respectively, of subjects between 18 and 44 years, 90.8% and 43.9% of subjects between 45 and 64 years, and 75.7% and 36.4% of subjects ≥ 65 years. The age-adjusted OR for adjuvanted vaccine compared with WV vaccine, in terms of seroprotection, was 11.21 (95% CI 5.80 to 21.64, p < 0.001). Age-related decline in antibody response occurred after both doses of both vaccines. WV vaccine was associated with fewer local and systemic reactions and lower immune responses than was AS03(A)-adjuvanted vaccine. The most frequent solicited local event was pain, reported by 28% and 76% of subjects after either dose of WV or adjuvanted vaccine, respectively (OR 7.71, 95% CI 4.48 to 13.24, p < 0.0001). The most common systemic event was myalgia, reported by 24% and 49% of subjects after either dose of WV or adjuvanted vaccine (OR 2.99, 95% CI 1.86 to 4.80, p < 0.0001).ConclusionsAS03(A)-adjuvanted 2009 H1N1 vaccine is more immunogenic and provides greater antigen-sparing capacity than WV 2009 H1N1 vaccine.Trial RegistrationCurrent Controlled Trials ISRCTN92328241.FundingThis project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 14, No. 55. See the HTA programme website for further project information.

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