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Cross-clade protective immune responses to influenza viruses with H5N1 HA and NA elicited by an influenza virus-like particle.

Bright RA, Carter DM, Crevar CJ, Toapanta FR, Steckbeck JD, Cole KS, Kumar NM, Pushko P, Smith G, Tumpey TM, Ross TM - PLoS ONE (2008)

Bottom Line: However, an apparent association rate of antibody binding to HA correlated with protection and was enhanced using VLPs, particularly when delivered intranasally, compared to rHA vaccines.This is the first report describing the use of an H5N1 VLP vaccine created from a clade 2 isolate.The results show that a non-replicating virus-like particle is effective at eliciting a broadened, cross-clade protective immune response to proteins from emerging H5N1 influenza isolates giving rise to a potential pandemic influenza vaccine candidate for humans that can be stockpiled for use in the event of an outbreak of H5N1 influenza.

View Article: PubMed Central - PubMed

Affiliation: Novavax, Inc., Rockville, Maryland, USA. rbright@novavax.com

ABSTRACT

Background: Vaccination is a cost-effective counter-measure to the threat of seasonal or pandemic outbreaks of influenza. To address the need for improved influenza vaccines and alternatives to egg-based manufacturing, we have engineered an influenza virus-like particle (VLP) as a new generation of non-egg or non-mammalian cell culture-based candidate vaccine.

Methodology/principal findings: We generated from a baculovirus expression system using insect cells, a non-infectious recombinant VLP vaccine from both influenza A H5N1 clade 1 and clade 2 isolates with pandemic potential. VLPs were administered to mice in either a one-dose or two-dose regimen and the immune responses were compared to those induced by recombinant hemagglutinin (rHA). Both humoral and cellular responses were analyzed. Mice vaccinated with VLPs were protected against challenge with lethal reassortant viruses expressing the H5N1 HA and NA, regardless if the H5N1 clade was homologous or heterologous to the vaccine. However, rHA-vaccinated mice showed considerable weight loss and death following challenge with the heterovariant clade virus. Protection against death induced by VLPs was independent of the pre-challenge HAI titer or cell-mediated responses to HA or M1 since vaccinated mice, with low to undetectable cross-clade HAI antibodies or cellular responses to influenza antigens, were still protected from a lethal viral challenge. However, an apparent association rate of antibody binding to HA correlated with protection and was enhanced using VLPs, particularly when delivered intranasally, compared to rHA vaccines.

Conclusion/significance: This is the first report describing the use of an H5N1 VLP vaccine created from a clade 2 isolate. The results show that a non-replicating virus-like particle is effective at eliciting a broadened, cross-clade protective immune response to proteins from emerging H5N1 influenza isolates giving rise to a potential pandemic influenza vaccine candidate for humans that can be stockpiled for use in the event of an outbreak of H5N1 influenza.

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Protection from influenza virus challenge.At week 5, mice vaccinated with H5N1 clade 2-dervied vaccines were challenged intranasally with a lethal dose of reassortant influenza virus (A/Viet Nam/1203/2004 (clade 1) or A/Indonesia/05/2005 (clade 2)) and monitored daily for weight loss and mortality. The data are plotted as percentage of the average initial weight. Percentage of (A) original weight or (B) survival following challenge with clade 2 AIndonesia/05/2005 reassortant virus. Percentage of (C) original weight or (D) survival following challenge with clade 1 A/Viet Nam/1203/2004 reassortant virus. Mice that lost greater than 75% body weight were euthanized. Naïve mice were unvaccinated.
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pone-0001501-g006: Protection from influenza virus challenge.At week 5, mice vaccinated with H5N1 clade 2-dervied vaccines were challenged intranasally with a lethal dose of reassortant influenza virus (A/Viet Nam/1203/2004 (clade 1) or A/Indonesia/05/2005 (clade 2)) and monitored daily for weight loss and mortality. The data are plotted as percentage of the average initial weight. Percentage of (A) original weight or (B) survival following challenge with clade 2 AIndonesia/05/2005 reassortant virus. Percentage of (C) original weight or (D) survival following challenge with clade 1 A/Viet Nam/1203/2004 reassortant virus. Mice that lost greater than 75% body weight were euthanized. Naïve mice were unvaccinated.

Mentions: Mice that received either H5N1 clade 1 or clade 2 vaccines or unvaccinated control mice were challenged intranasally with a predetermined lethal dose of either a reassortant homologous or heterologous virus to evaluate the protective efficacy of each vaccine candidate. All mice vaccinated intramuscularly or intranasally with either VLP vaccine or intranasally only with rHA vaccines were protected from death following the lethal challenge of homologous virus whereas, all non-vaccinated, naïve mice lost greater than 25% of their original body weight and died from complications associated with infection by day 6 post-challenge (Fig. 6). Mice vaccinated with either VLP vaccine lost less than 5% of their original weight by day 6 following homologous viral challenge, regardless of the route of inoculation. In addtion, all VLP-vaccinated mice survived challenge, with little weight loss, following heterologous challenge (i.e. Indonesia clade 2 VLP vaccinated mice were protected against Viet Nam clade 1 challenge). However, there was more pronounced weight loss in mice vaccinated intramuscularly with either of the H5N1 rHA antigens following heterologous challenge, even though all mice survived. By day 21 post-challenge, all mice recovered to their original body weight, despite little or no detectable serum HAI antibodies against heterologous H5N1 virus prior to challenge (Table 3). In contrast, all mice vaccinated intranasally with rHA showed considerable weight loss and mortality similar tonaïve unvaccinated animals. Despite lower HAI titers compared to mice vaccinated with clade 2 vaccines, similar results were observed with mice vaccinated with Viet Nam VLPs and rHA vaccines (data not shown).


Cross-clade protective immune responses to influenza viruses with H5N1 HA and NA elicited by an influenza virus-like particle.

Bright RA, Carter DM, Crevar CJ, Toapanta FR, Steckbeck JD, Cole KS, Kumar NM, Pushko P, Smith G, Tumpey TM, Ross TM - PLoS ONE (2008)

Protection from influenza virus challenge.At week 5, mice vaccinated with H5N1 clade 2-dervied vaccines were challenged intranasally with a lethal dose of reassortant influenza virus (A/Viet Nam/1203/2004 (clade 1) or A/Indonesia/05/2005 (clade 2)) and monitored daily for weight loss and mortality. The data are plotted as percentage of the average initial weight. Percentage of (A) original weight or (B) survival following challenge with clade 2 AIndonesia/05/2005 reassortant virus. Percentage of (C) original weight or (D) survival following challenge with clade 1 A/Viet Nam/1203/2004 reassortant virus. Mice that lost greater than 75% body weight were euthanized. Naïve mice were unvaccinated.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2200794&req=5

pone-0001501-g006: Protection from influenza virus challenge.At week 5, mice vaccinated with H5N1 clade 2-dervied vaccines were challenged intranasally with a lethal dose of reassortant influenza virus (A/Viet Nam/1203/2004 (clade 1) or A/Indonesia/05/2005 (clade 2)) and monitored daily for weight loss and mortality. The data are plotted as percentage of the average initial weight. Percentage of (A) original weight or (B) survival following challenge with clade 2 AIndonesia/05/2005 reassortant virus. Percentage of (C) original weight or (D) survival following challenge with clade 1 A/Viet Nam/1203/2004 reassortant virus. Mice that lost greater than 75% body weight were euthanized. Naïve mice were unvaccinated.
Mentions: Mice that received either H5N1 clade 1 or clade 2 vaccines or unvaccinated control mice were challenged intranasally with a predetermined lethal dose of either a reassortant homologous or heterologous virus to evaluate the protective efficacy of each vaccine candidate. All mice vaccinated intramuscularly or intranasally with either VLP vaccine or intranasally only with rHA vaccines were protected from death following the lethal challenge of homologous virus whereas, all non-vaccinated, naïve mice lost greater than 25% of their original body weight and died from complications associated with infection by day 6 post-challenge (Fig. 6). Mice vaccinated with either VLP vaccine lost less than 5% of their original weight by day 6 following homologous viral challenge, regardless of the route of inoculation. In addtion, all VLP-vaccinated mice survived challenge, with little weight loss, following heterologous challenge (i.e. Indonesia clade 2 VLP vaccinated mice were protected against Viet Nam clade 1 challenge). However, there was more pronounced weight loss in mice vaccinated intramuscularly with either of the H5N1 rHA antigens following heterologous challenge, even though all mice survived. By day 21 post-challenge, all mice recovered to their original body weight, despite little or no detectable serum HAI antibodies against heterologous H5N1 virus prior to challenge (Table 3). In contrast, all mice vaccinated intranasally with rHA showed considerable weight loss and mortality similar tonaïve unvaccinated animals. Despite lower HAI titers compared to mice vaccinated with clade 2 vaccines, similar results were observed with mice vaccinated with Viet Nam VLPs and rHA vaccines (data not shown).

Bottom Line: However, an apparent association rate of antibody binding to HA correlated with protection and was enhanced using VLPs, particularly when delivered intranasally, compared to rHA vaccines.This is the first report describing the use of an H5N1 VLP vaccine created from a clade 2 isolate.The results show that a non-replicating virus-like particle is effective at eliciting a broadened, cross-clade protective immune response to proteins from emerging H5N1 influenza isolates giving rise to a potential pandemic influenza vaccine candidate for humans that can be stockpiled for use in the event of an outbreak of H5N1 influenza.

View Article: PubMed Central - PubMed

Affiliation: Novavax, Inc., Rockville, Maryland, USA. rbright@novavax.com

ABSTRACT

Background: Vaccination is a cost-effective counter-measure to the threat of seasonal or pandemic outbreaks of influenza. To address the need for improved influenza vaccines and alternatives to egg-based manufacturing, we have engineered an influenza virus-like particle (VLP) as a new generation of non-egg or non-mammalian cell culture-based candidate vaccine.

Methodology/principal findings: We generated from a baculovirus expression system using insect cells, a non-infectious recombinant VLP vaccine from both influenza A H5N1 clade 1 and clade 2 isolates with pandemic potential. VLPs were administered to mice in either a one-dose or two-dose regimen and the immune responses were compared to those induced by recombinant hemagglutinin (rHA). Both humoral and cellular responses were analyzed. Mice vaccinated with VLPs were protected against challenge with lethal reassortant viruses expressing the H5N1 HA and NA, regardless if the H5N1 clade was homologous or heterologous to the vaccine. However, rHA-vaccinated mice showed considerable weight loss and death following challenge with the heterovariant clade virus. Protection against death induced by VLPs was independent of the pre-challenge HAI titer or cell-mediated responses to HA or M1 since vaccinated mice, with low to undetectable cross-clade HAI antibodies or cellular responses to influenza antigens, were still protected from a lethal viral challenge. However, an apparent association rate of antibody binding to HA correlated with protection and was enhanced using VLPs, particularly when delivered intranasally, compared to rHA vaccines.

Conclusion/significance: This is the first report describing the use of an H5N1 VLP vaccine created from a clade 2 isolate. The results show that a non-replicating virus-like particle is effective at eliciting a broadened, cross-clade protective immune response to proteins from emerging H5N1 influenza isolates giving rise to a potential pandemic influenza vaccine candidate for humans that can be stockpiled for use in the event of an outbreak of H5N1 influenza.

Show MeSH
Related in: MedlinePlus