Safety and Cross-Reactive Immunogenicity of Candidate AS03-Adjuvanted Prepandemic H5N1 Influenza Vaccines: A Randomized Controlled Phase 1/2 Trial in Adults

Background. The tocopherol-based oil-in-water emulsion adjuvant system family (AS03) improves antigen sparing with split-virion H5N1 influenza vaccines, representing an important development for pandemic preparedness. In this phase 1/2 randomized, controlled, observer-blinded study in 680 adults, we assessed the immunogenicity and safety of A/Indonesia/5/05 H5N1 (IBCDC-RG2, clade 2.1) prepandemic candidate vaccines produced at 2 separate manufacturing sites. Methods. Two doses, each of which contained 3.75 mg of hemagglutinin antigen, were given 21 days apart either without adjuvant or with an adjuvant system containing 11.86 mg or 5.93 mg of tocopherol (AS03). Results. The AS03-adjuvanted A/Indonesia/05/2005 (NIBRG-14) vaccines were significantly more immunogenic than nonadjuvanted vaccine in homologous assays. Neutralizing cross-clade immunogenicity against clades 1, 2.2, and 2.3 was demonstrated at day 42 with all vaccines; at 6 months, seroconversion rates were highest for clade 2.2 (60.7%) and for clade 1 (38.3%). Adjuvantation was associated with increased short-term injection-site reactions (pain) in 80% of participants, with such reactions assessed as being of grade 3 severity for <= 4.0% of doses. No other safety or reactogenicity concerns were identified over 6 months of follow-up. Conclusions. Humoral responses against the adjuvanted 3.75-mg hemagglutinin antigen vaccines from both manufacturing sites fulfilled European and US licensure criteria for immunogenicity for influenza vaccines.