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Preclinical and clinical development of plant-made virus-like particle vaccine against avian H5N1 influenza.

Landry N, Ward BJ, Trépanier S, Montomoli E, Dargis M, Lapini G, Vézina LP - PLoS ONE (2010)

Bottom Line: Even low doses of this vaccine prevented pathology and reduced viral loads following heterotypic lethal challenge.The vaccine was well tolerated at all doses.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.

View Article: PubMed Central - PubMed

Affiliation: Medicago Inc, Québec, Canada.

ABSTRACT

Unlabelled: 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 registration: ClinicalTrials.gov NCT00984945.

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Related in: MedlinePlus

Rates and severity of local and systemic adverse events (AEs) during the first 7 days after the first and second doses.Symptoms are graded on the following scale: mild  =  subject is aware of the AE but it causes no limitation of usual activities, moderate  =  subject is aware of the AE and the event causes some limitation of usual activities and severe  =  AE is of such severity that the subject is unable to carry out usual activities.
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Related In: Results  -  Collection


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pone-0015559-g003: Rates and severity of local and systemic adverse events (AEs) during the first 7 days after the first and second doses.Symptoms are graded on the following scale: mild  =  subject is aware of the AE but it causes no limitation of usual activities, moderate  =  subject is aware of the AE and the event causes some limitation of usual activities and severe  =  AE is of such severity that the subject is unable to carry out usual activities.

Mentions: The H5 VLP vaccine was well tolerated. Although the sample size was limited for this first-in-human study, 12 subjects per treatment group should permit the capture of AEs having 10% or 5% incidences with probabilities of ∼72% and ∼46% respectively. There were no Serious AEs reported up to Day 42 (21 days after second dose). The 6-month follow-up period is still ongoing at time of writing. Pain at injection site, redness and headache were the most commonly reported local and systemic reactions (Table 3). Fever >38°C was not reported in any subject. There were no significant differences in the incidence of either local or systemic reactions between any vaccine group and the placebo group except for redness in the 20 µg group after the first dose only (p = 0.04). Local and systemic reactions were mostly mild (Figure 3) and of short duration. The only reactions reported as ‘severe’ were transient headaches in 1/12 (8.3%) in the 20 µg group after first dose and in the 10 µg group after the second dose. However, there was no statistical difference in the overall incidence of headache between the vaccine and placebo recipients.


Preclinical and clinical development of plant-made virus-like particle vaccine against avian H5N1 influenza.

Landry N, Ward BJ, Trépanier S, Montomoli E, Dargis M, Lapini G, Vézina LP - PLoS ONE (2010)

Rates and severity of local and systemic adverse events (AEs) during the first 7 days after the first and second doses.Symptoms are graded on the following scale: mild  =  subject is aware of the AE but it causes no limitation of usual activities, moderate  =  subject is aware of the AE and the event causes some limitation of usual activities and severe  =  AE is of such severity that the subject is unable to carry out usual activities.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3008737&req=5

pone-0015559-g003: Rates and severity of local and systemic adverse events (AEs) during the first 7 days after the first and second doses.Symptoms are graded on the following scale: mild  =  subject is aware of the AE but it causes no limitation of usual activities, moderate  =  subject is aware of the AE and the event causes some limitation of usual activities and severe  =  AE is of such severity that the subject is unable to carry out usual activities.
Mentions: The H5 VLP vaccine was well tolerated. Although the sample size was limited for this first-in-human study, 12 subjects per treatment group should permit the capture of AEs having 10% or 5% incidences with probabilities of ∼72% and ∼46% respectively. There were no Serious AEs reported up to Day 42 (21 days after second dose). The 6-month follow-up period is still ongoing at time of writing. Pain at injection site, redness and headache were the most commonly reported local and systemic reactions (Table 3). Fever >38°C was not reported in any subject. There were no significant differences in the incidence of either local or systemic reactions between any vaccine group and the placebo group except for redness in the 20 µg group after the first dose only (p = 0.04). Local and systemic reactions were mostly mild (Figure 3) and of short duration. The only reactions reported as ‘severe’ were transient headaches in 1/12 (8.3%) in the 20 µg group after first dose and in the 10 µg group after the second dose. However, there was no statistical difference in the overall incidence of headache between the vaccine and placebo recipients.

Bottom Line: Even low doses of this vaccine prevented pathology and reduced viral loads following heterotypic lethal challenge.The vaccine was well tolerated at all doses.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.

View Article: PubMed Central - PubMed

Affiliation: Medicago Inc, Québec, Canada.

ABSTRACT

Unlabelled: 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 registration: ClinicalTrials.gov NCT00984945.

Show MeSH
Related in: MedlinePlus