This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Background: Influenza, a highly communicable acute respiratory disease, is one of the major infectious disease threats to the human population. Influenza virus affects individuals of all ages, causes repeated infections throughout life, and is responsible for annual worldwide epidemics of varying severity. In average years there are an estimated 3 to 5 million cases of severe illness and 0.5 million deaths per year worldwide. There are an estimated 36,000 deaths and more than 200,000 hospitalization caused by influenza every year in the US. Pandemic influenza viruses spread rapidly and cause high levels of disease and death globally. Some of the challenges in developing an effective vaccine for influenza occur because influenza viruses exhibit change in genetic structure each season. None of the current vaccines offer protection in a way that accounts for this genetic change. Other challenges to the development of influenza vaccine occur because of the current technique available for manufacturing this vaccine. Currently the vaccines that are available are made in eggs, which limit the number of doses and also cause lengthy delays in vaccine production. VaxInnate has developed a cross-protective influenza A vaccine, VAX102, which is based on a recombinant protein expressed in E. coli. Unlike the HA and NA viral proteins, the 24 amino acid sequence of M2e has remained remarkably stable in all human influenza A virus isolates since the influenza pandemic of 1918. Thus an influenza vaccine based on the M2e antigen could elicit broad, cross-protective immunity against most human influenza A virus strains. Because the VAX102 vaccine relies on a single cross-reactive influenza A virus antigen manufactured by a recombinant protein fermentation-production process that does not involve eggs, stock-piling of this vaccine is possible to alleviate concerns of vaccine shortages or a need to quickly respond to an emergency.Hypothesis: The hypothesis is that the VAX102 vaccine will be generally well-tolerated and will cause the development of antibodies to influenza virus in at least one dose level tested.
Specific Aims and Procedures (summary): The main purpose of the study is to assess the safety, reactogenicity and tolerability of the VAX102 vaccine given as an injection into the muscle at 3 doses, 10 g, 33 g and 100 g. The vaccine will be given at Day 0 and a booster at Day 28 to healthy adults, 18-49 years of age. Additional purposes of the study are to assess the immune response to the VAX102 vaccine. Volunteers will be consented, screened, and enrolled in a double-blind, randomized, placebo-controlled vaccine study, with a prime-boost design. There are 3 dose groups, with 20 members to each group, to be enrolled starting with the lowest dose and increasing to the highest. The first 8 members of each group will be evaluated with 7 day follow up data after receiving the first dose of vaccine. Lab results and the type of reactions reported by individuals will be reviewed prior to enrolling the remaining 12 members of a group. Before increasing to the next highest dose, each group of 20 will have their 7 day follow up data reviewed. Lab results and the type of reactions reported by individuals for the entire group will be included in the review. This information will be reviewed by a Safety Monitoring Committee. Within each group of 20, the randomization will occur 3:1 for vaccine:placebo. Following the booster dose of vaccine to each group, the safety data for the next 7 day period will be reviewed, before recommending that the next group receive booster dosing. Laboratory studies will be performed to evaluate safety and immune response. Subjects will be asked to keep a diary of local reactions (i.e., redness or swelling) and systemic symptoms such as pain and fatigue. Subjects will be followed frequently during the one month post each dose of study agent, and at other intervals during the 6 months following the first vaccine dose.Experimental Design (summary): All data collected will be reported using descriptive statistics, such as frequencies and percentages in each category. Continuous variables will be summarized by dose group as numbers of subjects, means, standard deviations, medians, and minimum/maximum values. Two-sided, 95% confidence intervals will be calculated for immunogenicity endpoints and differences between each dose and placebo, and among dose groups. Placebo subjects from all dose groups will be grouped together and used for summaries and analyses. Since this is a Phase I study to assess safety and preliminary immunogenicity, no adjustments for multiple statistical testing will be required. Significance (summary): Development of an alternative influenza vaccine that will be protective across multiple influenza seasons and will be produced in a method that will allow for rapid production is critical to global health. New approaches to influenza protection are a national priority.
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