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Context: A high priority in vaccine research is the development of influenza vaccines that do not use embryonated eggs as the substrate for vaccine production.Objective: To determine the dose-related safety, immunogenicity, and protective efficacy of an experimental trivalent influenza virus hemagglutinin (rHA0) vaccine produced in insect cells using recombinant baculoviruses.Design, Setting, and Participants: Randomized, double-blind, placebo-controlled clinical trial at 3 US academic medical centers during the 2004-2005 influenza season among 460 healthy adults without high-risk indications for influenza vaccine.Interventions: Participants were randomly assigned to receive a single injection of saline placebo (n = 154); 75 microg of an rHA0 vaccine containing 15 microg of hemagglutinin from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus and 45 microg of hemagglutinin from influenza A/Wyoming/3/03(H3N2) virus (n = 153); or 135 microg of rHA0 containing 45 microg of hemagglutinin each from all 3 components (n = 153). Serum samples were taken before and 30 days following immunization.Main Outcome Measures: Primary safety end points were the rates and severity of solicited and unsolicited adverse events. Primary immunogenicity end points were the rates of 4-fold or greater increases in serum hemagglutinin inhibition antibody to each of the 3 vaccine strains before and 28 days after inoculation. The prespecified primary efficacy end point was culture-documented influenza illness, defined as development of influenza-like illness associated with influenza virus on a nasopharyngeal swab.Results: Rates of local and systemic adverse effects were low, and the rates of systemic adverse effects were not different in either vaccine group than in the placebo group. Hemagglutinin inhibition antibody responses to the H1 component were seen in 3% of placebo, 51% of 75-microg vaccine, and 67% of 135-microg vaccine recipients, while responses to B were seen in 4% of placebo, 65% of 75-microg vaccine, and 92% of 135-microg vaccine recipients. Responses to the H3 component occurred in 11% of placebo, 81% of 75-microg vaccine, and 77% of 135-microg vaccine recipients. Influenza infections in the study population were due to influenza B and A(H3N2), and influenza A infections were A/California/7/2004-like viruses, an antigenically drifted strain. Seven cases of culture-confirmed CDC-defined influenza-like illness occurred in 153 placebo recipients (4.6%) compared with 2 cases (1.3%) in 150 recipients of 75 microg of vaccine, and 0 cases in recipients of 135 microg of vaccine.Conclusions: In this study, a trivalent rHA0 vaccine was safe and immunogenic in a healthy adult population. Preliminary evidence of protection against a drifted influenza A(H3N2) virus was obtained, but the sample size was small. Inclusion of a neuraminidase component did not appear to be required for protection.Trial Registration: clinicaltrials.gov Identifier: NCT00328107. [ABSTRACT FROM AUTHOR]