Dose-Escalating Trial Using Vero Cell-culture Derived H5N1 +/- Aluminum in Adults

This is a phase I, randomized, double-blind, placebo-controlled, dose-ranging clinical trial of the safety, reactogenicity, and immunogenicity of intramuscular immunization with inactivated, Vero cell-culture derived influenza A/H5N1 vaccine given alone or with aluminum hydroxide to healthy young adults. The primary objectives are to determine the dose-related safety of an inactivated, cell-culture grown whole virus influenza A/H5N1 vaccine with or without aluminum hydroxide adjuvant in healthy adults; to determine the potential for aluminum hydroxide to enhance the immune response to inactivated whole virus H5N1 vaccine in healthy adults approximately 1 month following receipt of 2 doses of vaccine; and to 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. The primary endpoints are adverse event (AE) or serious adverse event (SAE) information (solicited in the clinic and via memory aids, concomitant medications, periodic targeted physical assessment, and laboratory safety evaluations in a subset of subjects); proportion of subjects in each dose group achieving a serum neutralizing antibody titer of greater than or equal to 40 against the influenza A/H5N1 virus 28 days after receipt of the second dose of vaccine (approximately Day 56); proportion of subjects in each dose group achieving a serum hemagglutination inhibition (HAI) antibody titer of greater than or equal to 40 against the influenza A/H5N1 virus 28 days after receipt of the second dose of vaccine (approximately Day 56); geometric mean titer (GMT) and frequency of 4-fold or greater increases in neutralizing antibody titers in each group 28 days after receipt of the second dose of vaccine; and GMT and frequency of 4-fold or greater increases in serum HAI antibody titers in each group 28 days after receipt of the second dose of vaccine (approximately Day 56). The secondary endpoints are GMT and frequency of 4-fold or greater increases in neutralizing antibody titers in each group 1 month and 7 months after receipt of the first dose of vaccine; and GMT and frequency of 4-fold or greater increases in serum HAI antibody titers in each group 1 month and 7 months after receipt of the first dose of vaccine. Approximately 300 healthy adults, 18-40 years old inclusive, will be enrolled at up to 5 sites in the United States for up to 9 months, including the screening period. Two doses of vaccine or placebo will be injected into the deltoid muscle approximately 28 days apart. The study will be conducted in 2 stages. During Stage 1, 90 subjects will be randomized to receive saline placebo or 7.5 micrograms (with or without aluminum hydroxide), 15 micrograms (with or without aluminum hydroxide), or 45 micrograms (without aluminum hydroxide) (6 groups; N=15 per group). Blood for safety evaluations will be obtained from all subjects in the Stage 1 cohort at screening, and before and 1 week after each vaccination. Subjects in Stage 1 will receive their second vaccinations following review of available clinical and laboratory safety data by the Safety Monitoring Committee (SMC). If no dose-limiting toxicity or safety-related issues are noted during the week after administration of the first dose of vaccine during Stage 1 (based on review of clinical and laboratory safety data by the SMC), then Stage 1 subjects will receive a second vaccination. A complete Stage 1 safety report will be reviewed by the SMC prior to the enrollment of the 210 additional subjects in Stage 2 (N=50 per formulation group total). Sera for immune assessment of antigen-specific immune responses will be collected from all subjects at baseline (Day 0), 1 month after each vaccine dose, and 6 months after the second vaccine dose. This study is linked to DMID protocol 07-0022.