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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

Protection against lethal challenge of control and vaccinated ferrets after challenge with A/Vietnam/1203/04 (H5N1) virus.Ferrets were immunized twice with the H5 VLP vaccine (A/Indonesia/5/05) or placebo (alum) and were challenged with 10 FLD50 of the A/Vietnam/1203/04 H5N1 strain 45 days after the booster injection. A. Mean temperature (5 ferrets per group) B. Percent weight loss (at day 6, 3 ferrets were found dead and the 2 remaining were euthanized due to ≥20% body weight loss C. Survival D. Activity score.
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pone-0015559-g002: Protection against lethal challenge of control and vaccinated ferrets after challenge with A/Vietnam/1203/04 (H5N1) virus.Ferrets were immunized twice with the H5 VLP vaccine (A/Indonesia/5/05) or placebo (alum) and were challenged with 10 FLD50 of the A/Vietnam/1203/04 H5N1 strain 45 days after the booster injection. A. Mean temperature (5 ferrets per group) B. Percent weight loss (at day 6, 3 ferrets were found dead and the 2 remaining were euthanized due to ≥20% body weight loss C. Survival D. Activity score.

Mentions: The challenge with A/Vietnam/1203/04 in the 1.8 and 3.7 µg and placebo groups revealed complete protection from clinical illness in the vaccinated animals only. In the first days after challenge, ferrets in the placebo group had a marked increase in fever followed by a decrease in body temperature while vaccinated animals had no important body temperature fluctuations (Figure 2A). Activity scores in the placebo animals also fell sharply, starting 3 days after challenge. At day 6, 3 of placebo recipients were found dead and the other two were euthanized because they had lost >20% of their body weight. All of the vaccinated ferrets survived the lethal challenge (Figure 2B and 2C) and suffered little observable morbidity (Figure 2D). There was no clear difference in fever, body weight loss or activity scores in the ferrets vaccinated with either the 1.8 or 3.7 µg dose. Upper respiratory tract (URT) and lung tissues harvested in each of the challenge groups 3 days after challenge revealed detectable virus in the URT all placebo recipients (3/3) but only 1/3 and 2/3 in the 1.8 µg and 3.7 µg groups respectively (Table 2).


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)

Protection against lethal challenge of control and vaccinated ferrets after challenge with A/Vietnam/1203/04 (H5N1) virus.Ferrets were immunized twice with the H5 VLP vaccine (A/Indonesia/5/05) or placebo (alum) and were challenged with 10 FLD50 of the A/Vietnam/1203/04 H5N1 strain 45 days after the booster injection. A. Mean temperature (5 ferrets per group) B. Percent weight loss (at day 6, 3 ferrets were found dead and the 2 remaining were euthanized due to ≥20% body weight loss C. Survival D. Activity score.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0015559-g002: Protection against lethal challenge of control and vaccinated ferrets after challenge with A/Vietnam/1203/04 (H5N1) virus.Ferrets were immunized twice with the H5 VLP vaccine (A/Indonesia/5/05) or placebo (alum) and were challenged with 10 FLD50 of the A/Vietnam/1203/04 H5N1 strain 45 days after the booster injection. A. Mean temperature (5 ferrets per group) B. Percent weight loss (at day 6, 3 ferrets were found dead and the 2 remaining were euthanized due to ≥20% body weight loss C. Survival D. Activity score.
Mentions: The challenge with A/Vietnam/1203/04 in the 1.8 and 3.7 µg and placebo groups revealed complete protection from clinical illness in the vaccinated animals only. In the first days after challenge, ferrets in the placebo group had a marked increase in fever followed by a decrease in body temperature while vaccinated animals had no important body temperature fluctuations (Figure 2A). Activity scores in the placebo animals also fell sharply, starting 3 days after challenge. At day 6, 3 of placebo recipients were found dead and the other two were euthanized because they had lost >20% of their body weight. All of the vaccinated ferrets survived the lethal challenge (Figure 2B and 2C) and suffered little observable morbidity (Figure 2D). There was no clear difference in fever, body weight loss or activity scores in the ferrets vaccinated with either the 1.8 or 3.7 µg dose. Upper respiratory tract (URT) and lung tissues harvested in each of the challenge groups 3 days after challenge revealed detectable virus in the URT all placebo recipients (3/3) but only 1/3 and 2/3 in the 1.8 µg and 3.7 µg groups respectively (Table 2).

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