Immunogenicity Profile of a 3.75-μg Hemagglutinin Pandemic rH5N1 Split Virion AS03A-Adjuvanted Vaccine in Elderly Persons: A Randomized Trial

The past decade has seen unprecedented preparation for a human influenza pandemic. Until the 2009 outbreak of human cases of (swine) influenza A (H1N1), the avian influenza H5N1 viruswas considered a potential cause of a human influenza pandemic. The H5N1 virusremains a considerable threat to human health, and it is important that pandemicpreparedness planning for an outbreak continues. Moreover, vaccine development strategies for a potential H5N1 pandemiccan guide development of vaccines to combat the 2009/10 H1N1 pandemicand other future potential influenza pandemics. Development of an influenza vaccine that induces a cross-reactive immune response is a key component of a pandemicpreparedness strategy. Such a vaccine is likely to prime the immune system to mount a rapid response to vaccination with a drifted strain and/or to infection and may be used before the onset of a pandemicor in its early stages. Even partial cross-protection may have a considerable impact on infection rates during early pandemicstages [1, 2]. The vaccine must provide a high and long-lasting immune response at a relatively low antigen dose, because the need for a high dose would exhaust the limited global production capacity for influenza antigen. Formulation of pandemicvaccines using adjuvants to stimulate a robust immune response is an important approach to reducing the antigen dose and eliciting a cross-reactive response [3]. An H5N1 pandemicvaccine based on the A/Vietnam/1194/2004 clade 1 strain is licensed to be used in the event of an imminent H5N1 pandemic. The vaccine is adjuvanted with AS03A, a novel tocopherol oil-in-water emulsion-based adjuvant system (11.86 mg of tocopherol). It is licensed to be delivered via a schedule of 2 injections administered 3 weeks apart [4]. In a study in adults aged 18-60 years, the lowest dose investigated (3.75 μg hemagglutinin [HA]) elicited immune responses against the vaccine strain that met all US Center for Biologics Evaluation and Research and European Committee for Human Medicinal Products (CHMP) immunologic licensurecriteria [5]. Much higher doses were needed to induce a moderate immune response with a nonadjuvanted H5N1 split-virus vaccine [6], indicating that adjuvantation with AS03A allows successful dose sparing. In addition, the vaccine has been shown to induce a cross-reactive immune response (hemagglutination inhibition [HI]) and neutralizing antibodies and CD4 T cell–mediated immune response) against drifted clade 2 H5N1 strains [5, 7–10] An acceptable safety and reactogenicityprofile has been demonstrated [5, 8, 11]. Studies with seasonal influenza vaccines suggest that the reduced immune response to vaccination in elderly populations is due – at least in part – to immunosenescence[12]. It is possible that elderly people may therefore need additional or higher doses. This study aimed to assess the immune response in an elderly population to 2 single or 2 double doses of the AS03A-adjuvanted H5N1 pandemicvaccine, administered 21 days apart, compared with the same dosage and schedule without the adjuvant system.