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 μg of haemagglutinin formulated as whole-virion vaccine, or 3·75 μg of haemagglutinin formulated as split-virion vaccine with AS03A 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 titres 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 AS03A 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: AS03A-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. Funding: Department of Health, National Institute for Health Research Evaluation, Trials and Studies Coordinating Centre.
Bibliographical noteFunding Information:
KGN has been an ad hoc consultant to GlaxoSmithKline, Merck, Sanofi Pasteur, and Novartis. He has received funding to speak at meetings organised by Novartis, Baxter, Berna Biotech, Esteves, and the European Scientific Working Group on Influenza, and H5 vaccines from Novartis to support an MRC-funded research project, and H1N1 vaccines from Baxter AG and GlaxoSmithKline to support this NIHR funded research project. JS N-V-T has received funding to attend influenza related meetings, ad-hoc lecture and consultancy fees and research funding from several influenza antiviral drug and vaccine manufacturers (including both GlaxoSmithKline and Baxter AG), and is a former employee of SmithKline Beecham plc (now GlaxoSmithKline), Roche Products Ltd, and Sanofi Pasteur MSD. MZ and KH have been investigators of clinical trials sponsored by Novartis, Baxter, Sanofi Pasteur, and CSL Australia Ltd. KH has been sponsored by Sanofi Pasteur to take part and speak at one international meeting. RCR has been an investigator of clinical trials sponsored by Novartis Vaccines and Sanofi Pasteur. WSL is in receipt of an unrestricted educational grant towards study of pneumococcal pneumonia from Wyeth, UK. KRA has acted as a paid consultant to the health-care industry generally (for the provision of advice and short courses), but specifically has not advised either Baxter or GSK in relation to either vaccine, or any other body as regards influenza vaccination policy. TC has been an investigator of clinical trials sponsored by Novartis and Roche. The other authors declare that they have no conflicts of interest.
The views and opinions expressed in this report are those of the authors and are not necessarily those of the Health Technology Assessment (HTA) programme, NIHR, National Health Service, or the Department of Health. Our project has been wholly funded by the NIHR HTA Programme , under grant number 09/93/01 . KRA is partly supported as a NIHR senior investigator ( NI-SI-0508-10061 ). We thank colleagues in the UHL Infectious Diseases Unit and Research and Development Department for their support and guidance. We thank GlaxoSmithKline and Baxter AG for the provision of vaccine and the supporting paperwork for regulatory approval; the teams of clinicians, research nurses, administrators, and pharmacy staff at Leicester, Nottingham, and Sheffield for their assistance; and technical staff at the Health Protection Agency, Centre for Infections, for help with the serological analysis; colleagues in the NIHR Centres in Leicester, Nottingham, and Sheffield for their support; the Royal Free Hospital and Medical School Research Ethics Committee for help in expediting ethical approval; staff at the MHRA for accelerating the approval process; and all study participants for their time and support.