This randomized, controlled, double-blinded, dose-ranging, Phase I/II study in healthy adults, 18 to 49 years old, is designed to investigate the safety, reactogenicity, and dose-related immunogenicity of an investigational inactivated influenza A/H5N1 virus vaccine when given alone or combined with aluminum hydroxide. The primary objectives are to: determine the dose-related safety of subvirion-inactivated H5N1 vaccine adjuvanted with aluminum hydroxide in healthy adults; determine the potential for aluminum hydroxide to enhance the immune response to subvirion-inactivated H5N1 vaccine in healthy adults approximately 1 month following receipt of 2 doses of vaccine; and provide information for the selection of the best dosage level for further studies. The secondary objective is to evaluate dose-related immunogenicity and the percent of subjects responding approximately 1 and 7 months after the first vaccination. This dose optimization will be applied to both younger and older subject populations in subsequent studies. Subjects who meet the entry criteria for the study will be randomized into 8 groups to receive 2 doses of influenza A/H5N1 vaccine containing 3.75, 7.5, 15, or 45 mcg of hemagglutinin (HA) with or without aluminum hydroxide adjuvant by intramuscular (IM) injection (N=60 or 120/vaccine dose group). The first vaccination will occur on Day 0. Symptoms and signs will be assessed in the clinic for at least 15 minutes after inoculation, and the subjects will maintain a memory aid to record oral temperature and systemic and local adverse events (AEs) for 7 days after each immunization. Subjects will be encouraged to take their temperature around the same time each day. All subjects will return to the clinic 2 days and 8 days after each vaccination for assessment of adverse events (AEs) and concomitant medications and targeted physical examination (if indicated). Memory aids will be reviewed at each visit. Approximately Day 28 after the first vaccination, subjects will return to the clinic for blood sample collection and safety follow-up, followed by a second vaccination. Approximately 56 days after first immunization (or about 28 days after the second vaccination), subjects will return to the clinic for immunogenicity blood sample collection, AE and concomitant medication assessment, and targeted physical examination (if indicated). At approximately Day 208 (7 months after the first vaccination), subjects will return to the clinic for a final immunogenicity blood sample collection and for follow-up (which includes a targeted physical examination \[if indicated\]). Blood samples collected prior to each vaccination and on Days 56 and 208 after the first vaccination will be tested in a central laboratory for the levels of neutralizing and HAI antibodies. The primary outcome measures will be the frequencies and severities of AEs in each group and the proportions of subjects who achieve a serum neutralizing antibody titer of greater than or equal to 1:40 against the influenza A/H5N1 virus on Day 56. Serum HAI and neutralizing antibody responses (including frequencies of 4 fold or greater rise in titers; geometric mean titers; and proportions of subjects achieving putative protective titers of neutralizing antibody 1 month after each dose of vaccine and 7 months after first dose) also will be assessed. Although the correlate of protection for infections caused by influenza A/H5N1 viruses in humans is unknown, a serum neutralizing antibody titer of greater than or equal to 1:40 may be considered protective, based on limited data regarding the levels of serum neutralizing antibody present in serum samples collected from humans who survived infections caused by influenza A/H5N1 viruses. This study is linked to DMID protocol 07-0022.
