A/H5N1 VACCINE PHASE I/II STUDY IN HEALTHY ADULTS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza is a serious illness which occurs in epidemic fashion every year. During the 1918 pandemic, up to 40 million deaths occurred worldwide. Significant numbers of deaths, illness and social disruption were also noted during the 1957 and 1968 pandemics. The recent emergence of novel influenza virus strains in human populations (so-called "bird flu" influenza A/H5N1 and H9N2 viruses) has bolstered ongoing global efforts to develop pandemic preparedness plans. According to the World Health Organization, at least 52 human cases of H5 bird flu have been identified in the last year in Thailand and Vietnam and 39 (75%) have died. Global spread of this disease would be catastrophic. Development and testing of an influenza vaccine against potential H5N1 pandemic strains is an international public health priority - please see the attached letter from the Deputy Director of DMID/NIAID/NIH. The primary goals of this study are to determine, among healthy adults, 1) the lowest dose level of A/H5N1 influenza vaccine that will result in an acceptable antibody response; and 2) the safety profile of this H5 vaccine. This proposal describes a randomized, double-blinded, placebo-controlled, dose-ranging, Phase I/II study of A/H5N1 influenza vaccine in approximately 450-470 healthy adults, 18 to 64 years old, inclusive. Participants will be randomly assigned to receive 2 doses of saline placebo (N=50), or 7.5, 15, 45, or 90 g of the influenza A/H5N1 virus vaccine (N=100/dose group) by intramuscular injection in the upper arm. The study will proceed in 2 stages. The first stage (Stage I) consists of an initial vaccination of 25 subjects in each vaccine dose group and 13 subjects in the placebo group (113 subjects total), followed by a 7-day safety assessment period. The 7 day safety data following the vaccination of Stage I subjects will be reviewed by a Data and Safety Monitoring Board (DSMB). Following this review, the DSMB will make a recommendation as to whether enrollment and vaccination of the Stage II subjects should proceed. If there are no safety issues among Stage I participants, then Stage II of the study will be initiated. There will be another DMSB review of Stage I participants' safety data after the second dose of vaccine is given. If there are no safety issues in the Stage I subjects following the second vaccination, then the Stage II subjects will receive their second vaccination. Stage I participants will also have extra blood taken for a blood count and chemistry panel prior to and after each vaccine dose; these lab tests will help to monitor any effect of the vaccine on the liver, kidneys or blood cells. All participants will receive two doses of vaccine. The first vaccination will occur on Day 0. Symptoms and signs will be assessed in the clinic for 30 minutes after inoculation, and the subjects will maintain a memory aid to record oral temperature and systemic and local adverse events (AE) for 7 days after each immunization. All subjects will receive a safety follow-up telephone call at 2 to 3 days after each vaccination to elicit any AE information. Subjects will return to the clinic 7 days after each vaccination for review of the memory aid, assessment of AEs and concomitant medications, and a targeted physical examination (if indicated). At 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. Safety follow-up will be identical to that performed after the first vaccination. Approximately 28 days after the second vaccination, subjects will return to the clinic for blood sample collection, AE and concomitant medication assessment, and a targeted physical examination if indicated. Approximately 7 months after the first vaccination, subjects will return to the clinic for a final blood sample and follow-up. All blood samples will be tested in a central laboratory for antibody levels. The primary outcome measures will be the frequency and severity of AEs in each dose group and the proportions of subjects who achieve a predefined level of protective antibody against A/H5N1 flu.