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A Randomized Controlled Trial

John J. Treanor, MD; Gilbert M. Schiff, MD; Frederick G. Hayden, MD; Rebecca C. Brady, MD; C. Mhorag Hay, MD; Anthony L. Meyer, BS; Jeanne Holden-Wiltse, MPH; Hua Liang, PhD; Adam Gilbert, PhD; Manon Cox, PhD

JAMA. 2007;297:1577-1582.

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 µg of an rHA0 vaccine containing 15 µg of hemagglutinin from influenza A/New Caledonia/20/99(H1N1) and influenza B/Jiangsu/10/03 virus and 45 µg of hemagglutinin from influenza A/Wyoming/3/03(H3N2) virus (n = 153); or 135 µg of rHA0 containing 45 µg 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-µg vaccine, and 67% of 135-µg vaccine recipients, while responses to B were seen in 4% of placebo, 65% of 75-µg vaccine, and 92% of 135-µg vaccine recipients. Responses to the H3 component occurred in 11% of placebo, 81% of 75-µg vaccine, and 77% of 135-µg 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 µg of vaccine, and 0 cases in recipients of 135 µg 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

Author Affiliations: University of Rochester, Rochester, NY (Drs Treanor, Hay, and Liang and Ms Holden-Wiltse); Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (Drs Schiff and Brady and Mr Meyer); University of Virginia, Charlottesville (Dr Hayden); Ockham Development Group, Cary, NC (Dr Gilbert); and Protein Sciences Corp, Meriden, Conn (Dr Cox).

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