Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial

Background Effective antigen-sparing vaccines are needed to confront pandemic influenza. Whole-virion and oil-in-water adjuvanted vaccines are the most effective formulations against H5N1 avian influenza. We assessed the safety and immunogenicity in adults in the UK of pandemic H1N1 whole-virion vaccine and oil-in-water adjuvanted vaccine purchased by the UK government in 2009. Methods In our randomised, observer-blind, parallel-group, controlled trial, healthy adults aged 18-44 years, 45-64 years, and 65 years and older (from Oct 19, to Nov 12,2009) received two doses of vaccine given 21 days apart: either 7.5 mu g of haemagglutinin formulated as whole-virion vaccine, or 3.75 mu g of haemagglutinin formulated as split-virion vaccine with AS03(A), oil-in-water adjuvant. Assignment was by a computer-generated code, with random permuted blocks of two, four, and six. All participants and investigators were unaware of vaccine assignments. The trial was done at three hospitals in the UK. We measured antibody litres with a haemagglutination-inhibition assay at baseline; 7,14, and 21 days after each vaccination; and at 6 months after the first dose. Primary outcome was vaccine immunogenicity of the full analysis set by the EU Committee of Human Medicinal Products licensing criteria. This study is registered with ISRCTN, number ISRCTN92328241. Findings At day 0, baseline antibody (titre >= 1/8) was detected in 44 (13%) of 347 participants. Sera from 95% to 98% of participants were assessed for immunogenicity on days 7,14,21,28,35, and 42, and at 6 months. On day 21 after one dose of adjuvanted AS03(A) or whole-virion vaccine, 63 (94%, 95 CI 85.4-98.4) of 67 and 50 (71%, 59.4-81.6) of 70 participants aged 18-44 years, 51 (77%, 65.3-86.7) of 66 and 26 (39%, 27.1-51.5) of 67 aged 45-64 years, and 19 (51%, 34.4-68.1) of 37 and 11 (32%, 17.4-50.5) of 34 aged 65 years or older had titres of 1:40 or greater. On day 42 (21 days after the second dose), 64(100%, 94.4-100) of 64 and 49 (73%, 60.9-83.2) of 67 participants aged 18-44 years, 59 (91%, 81.0-96.5) of 65 and 29 (43.9%, 31.7-56.7) of 66 aged 45-64 years, and 28 (76%, 58.8-88-2) of 37 and 12 (36%, 20.4-54-9) of 33 aged 65 years or older had titres of 1/40 or greater. At 6 months, 62 (98%, 91.5-100) of 63 and 54 (78%, 66.7-87-3) of 69 participants aged 18-44 years, 54 (82%, 70.4-90-2) of 66 and 37 (55%, 42.6-67.4) of 67 aged 45-64 years, and 21 (57%, 39.5-72.9) of 37 and 10 (29%, 15.1-47-5) of 34 aged 65 years or older had titres of 1/40 or greater. There were no vaccine-related serious adverse events. Whole-virion vaccine was associated with fewer local and systemic reactions than adjuvanted vaccine. Interpretation AS03(A)-adjuvanted vaccine was more immunogenic against pandemic influenza A H1N1 virus than whole-virion vaccine and offers greater antigen-sparing capacity. A two-dose strategy should be considered for older people.