B., and T.P. AEs were reported by 111 (3.2%) of 3422 vaccine recipients and 45 (4.0%) of 1139 placebo recipients, and there was no differential temporal clustering among AN7973 vaccine recipients, compared Rabbit Polyclonal to P2RY13 with placebo recipients. One or more medically attended events were reported by 1027 (30%) of 3422 vaccine recipients and 346 (30.4%) of 1139 in the placebo group. No medically attended events were reported by 2.1% of subjects for any preferred term in either group. There were 4 deaths (0.1%) in the vaccine group (myocardial infarction, ovarian carcinoma with metastases to the liver, malignant neoplasm, and diabetes mellitus/liver disease) and 7 deaths (0.6%) in the placebo group (malignant brain neoplasm, cardiomegaly, cardiac disorder prior to motor vehicle accident, gunshot, malignant neoplasm of the tongue, pneumonia, and a report of death without a specified diagnosis in an 89-year-old woman) during the follow-up period. Three deaths (1 vaccinee and 2 placebo recipients) occurred within 3 weeks of vaccine exposure. Twelve participants (0.4%) in the vaccine group and 1 participant (0.1%) in the placebo group reported AESIs/pIMDs. Eight subjects were aged 18C64 years, and 5 were 64 years. In the H5N1 vaccine group, 2 subjects reported psoriasis and 2 reported polymyalgia rheumatica, and there was 1 report each of celiac disease, Crohns disease, autoimmune hepatitis, rheumatoid arthritis, facial palsy, erythema nodosum, radiculitis, and fourth cranial nerve palsy. One subject with polymyalgia rheumatica also was diagnosed with temporal arteritis. These events were not temporally clustered, and none were assessed as vaccine related by the investigators. DISCUSSION In this large, multicenter, phase III study, a 2-dose schedule of 3.75 g HA AS03A-adjuvanted H5N1 A/Indonesia/05/2005 influenza vaccine induced vaccine-homologous HAI antibody titers that fulfilled licensure criteria for seroconversion and seroprotection in adults aged 18C64 and AN7973 65 years (US licensure age strata) [7], and in adults aged 18C60 and 61 years (European licensure age strata) [8], at 42 days after the primary dose. The majority of participants in all age strata retained A/Indonesia/05/2005 HAI titers of 1 1:40 at 6 months. In addition, the immunogenic consistency of 3 consecutive lots of antigen, combined with 3 consecutive lots of adjuvant, was revealed by adjusted GMT ratios at day 42. These observations validate the selection of an AS03A-adjuvanted formulation previously based on phase I/II data [3]. In addition to developing antigen-sparing pandemic vaccines, it has been suggested that national pandemic and prepandemic planning incorporate vaccination strategies whereby a population is primed with stockpiled avian influenza vaccine, then subsequently vaccinated with a pandemic vaccine matched to the emergent influenza strain [15C17]. Such a strategy would require vaccines that induce cross-reactivity against drift variant viruses, since influenza viruses can evolve into phylogenetically and antigenically distinct clades, and stockpiled vaccine might not exactly match the eventual pandemic strain [1]. Protective cross-reactive responses have been demonstrated in preclinical studies in which ferrets that received AS03-adjuvanted A/Vietnam/1194/2004 vaccine subsequently survived a lethal vaccine-heterologous challenge with AN7973 A/Indonesia/05/2005 [18], and clinical studies have shown that a 2-dose series of AS03A-adjuvanted A/Vietnam/1194/2004 vaccine elicits cross-reactive immune responses against clade 2 strains when doses are given 21 days apart, and 6 or 12 months apart [4, 19C22]. This study provides additional evidence of cross-reactive MN immune responses against clade 1 A/Vietnam/1194/2004 following administration of AS03A-adjuvanted A/Indonesia/05/2005 vaccine. None of the 18C64-year-old group and 0.3% of the 65-year-old group had AN7973 HAI antibody titers of 1:10 against the AN7973 vaccine strain at baseline. However, 70% of participants aged 65 years were seropositive for MN antibodies against the vaccine-homologous and/or drift-variant strain before vaccination, including 11 of 12 participants aged 75 years who were seropositive for A/Vietnam/1194/2004. This phenomenon has been observed in previous studies, and it is thought that elderly people with prolonged natural exposure to seasonal influenza viruses and/or multiple lifetime vaccinations may develop antibodies with antigenic cross-reactivity with H5N1 strains [23, 24]. Previous exposure to seasonal influenza vaccination has been reported to reduce immune responses to subsequent pandemic influenza vaccination [25C29]. Recent experience with AS03A-adjuvanted H1N1 pandemic influenza vaccine showed that although licensure criteria for immunogenicity against the vaccine strain were consistently fulfilled, postvaccination antibody titers were lower.