Abstract
The recent swine H1N1 influenza outbreak demonstrated that egg-based vaccine manufacturing has an Achille's heel: its inability to provide a large number of doses quickly. Using a novel manufacturing platform based on transient expression of influenza surface glycoproteins in Nicotiana benthamiana, we have recently demonstrated that a candidate Virus-Like Particle (VLP) vaccine can be generated within 3 weeks of release of sequence information. Herein we report that alum-adjuvanted plant-made VLPs containing the hemagglutinin (HA) protein of H5N1 influenza (A/Indonesia/5/05) can induce cross-reactive antibodies in ferrets. Even low doses of this vaccine prevented pathology and reduced viral loads following heterotypic lethal challenge. We further report on safety and immunogenicity from a Phase I clinical study of the plant-made H5 VLP vaccine in healthy adults 18–60 years of age who received 2 doses 21 days apart of 5, 10 or 20 µg of alum-adjuvanted H5 VLP vaccine or placebo (alum). The vaccine was well tolerated at all doses. Adverse events (AE) were mild-to-moderate and self-limited. Pain at the injection site was the most frequent AE, reported in 70% of vaccinated subjects versus 50% of the placebo recipients. No allergic reactions were reported and the plant-made vaccine did not significantly increase the level of naturally occurring serum antibodies to plant-specific sugar moieties. The immunogenicity of the H5 VLP vaccine was evaluated by Hemagglutination-Inhibition (HI), Single Radial Hemolysis (SRH) and MicroNeutralisation (MN). Results from these three assays were highly correlated and showed similar trends across doses. There was a clear dose-response in all measures of immunogenicity and almost 96% of those in the higher dose groups (2×10 or 20 µg) mounted detectable MN responses. Evidence of striking cross-protection in ferrets combined with a good safety profile and promising immunogenicity in humans suggest that plant-based VLP vaccines should be further evaluated for use in pre-pandemic or pandemic situations.Trial RegistrationClinicalTrials.gov NCT00984945
Highlights
The recent swine H1N1 influenza pandemic revealed the limitations of the current influenza vaccine manufacturing technologies
We describe the first use of any plant-made Virus-Like Particle (VLP) vaccine in humans: in this case, safety and early immunogenicity following two intramuscular (IM) doses of an H5-VLP candidate vaccine
The principal HI endpoints were the geometric mean titer (GMT) and geometric mean increase (GMI); seroconversion was defined as the proportion of subjects with a fourfold increase in HI titers or a HI titer $32 when pre-vaccination titer was,8, seroprotection was defined as the proportion of subjects with HI titers $40
Summary
The recent swine H1N1 influenza pandemic (pH1N1) revealed the limitations of the current influenza vaccine manufacturing technologies. Regardless of the origin, mechanism of emergence or precise genetic makeup of the ‘’ pandemic strain, our recent experience with pH1N1 demonstrate clearly that the current, egg-based manufacturing system would not be able to respond quickly enough in the face of a highly pathogenic influenza virus adapted for rapid human-tohuman spread. We have recently described a plant-based manufacturing technology that can produce vaccine doses within one month of the sequencing of a pandemic strain [5]. This is accomplished by the cloning the novel hemagglutinin gene into a well-characterized vector followed by transient expression in Nicotiana benthamiana plants. In addition to routine safety monitoring, we determined whether or not IgG and IgE antibodies specific for plant glycans were induced by this novel vaccine candidate
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