tetano
Editor, Senior Moderator
Vaccine
Available online 18 September 2012
In Press, Uncorrected Proof ? Note to users
Cover image
Flagellin-HA vaccines protect ferrets and mice against H5N1 highly pathogenic avian influenza virus (HPAIV) infections
Ge Liua, Corresponding author contact information, E-mail the corresponding author, E-mail the corresponding author,
Langzhou Songa,
Lucia Reiserovaa,
Umang Trivedib,
Hong Lia,
Xiangyu Liua,
Diana Noahc,
Fuxiang Houa,
Bruce Weavera,
Lynda Tusseya
a VaxInnate Corporation, 3 Cedar Brook Drive, Cranbury, NJ 08512, USA
b Merck & Co. 126 E. Lincoln Ave, Rahway, NJ 07065, USA
c Southern Research Institute, 2000 9th Avenue South, Birmingham, AL 35205, USA
http://dx.doi.org/10.1016/j.vaccine.2012.09.013, How to Cite or Link Using DOI
Abstract
In order to meet the global demand for rapid production of pandemic influenza vaccines, we have developed a recombinant fusion vaccine platform in which the globular head of hemagglutinin (HA) antigen is genetically fused to bacterial flagellin (a TLR5 ligand). These flagellin-HA fusion vaccine candidates elicit highly protective immunity against a lethal challenge with 2009 pandemic H1N1 (Liu, et al. PLoS ONE 2011; 6:e20928) or H5N1 influenza A/Vietnam/1203/04 (A/VN) infections in mice (Song, et al. Vaccine 2009;27:5875?88). Here we provide the first evidence showing that two A/VN vaccine candidates elicited HA-specific IgG, reduced nasal virus shedding, and conferred full protection against a lethal A/VN infection in ferrets. Furthermore, we show that similar flagellin-HA vaccine candidates of two other H5N1 HPAIV are immunogenic and/or efficacious in mice. Vaccines of A/Indonesia/5/05 (A/IN) induced significant HAI titers to homologous and heterologous A/Anhui/1/05 (A/AN) H5N1 viruses. Two subcutaneous immunizations with doses of either 0.3 μg or 3 μg of A/IN candidates resulted in ≥2.5 log10 unit reduction in day 5 lung virus titer and 90?100% protection against a lethal A/IN challenge in mice. Both R3.HA5 IN and R3.2xHA5 IN vaccines elicited robust neutralizing antibody responses that last for at least 9 months and demonstrated a significant anamnestic antibody response upon further booster immunization. Finally, we found that two vaccine candidates of A/AN induced significant HAI titers in mice. Taken together, our recombinant flagellin-HA platform has been successfully used to generate potent H5N1 HPAIV vaccine candidates. These promising preclinical results justify the advancement of these candidates into the clinic.
Highlights
► Generated two formats of recombinant flagellin-HA vaccines targeting 3 H5N1 HPAIV. ► The vaccines protect ferrets against a lethal A/Vietnam/1203/04 challenge. ► The vaccines protect mice against a lethal A/Indonesia/5/05 challenge. ► Both R3.HA5 and R3.2xHA5 elicit robust long-lasting HAI antibody responses to HPAIV. ► The R3.2xHA5 format vaccines are more immunogenic than the R3.HA5 in mice.
http://www.sciencedirect.com/science/article/pii/S0264410X12013230
Available online 18 September 2012
In Press, Uncorrected Proof ? Note to users
Cover image
Flagellin-HA vaccines protect ferrets and mice against H5N1 highly pathogenic avian influenza virus (HPAIV) infections
Ge Liua, Corresponding author contact information, E-mail the corresponding author, E-mail the corresponding author,
Langzhou Songa,
Lucia Reiserovaa,
Umang Trivedib,
Hong Lia,
Xiangyu Liua,
Diana Noahc,
Fuxiang Houa,
Bruce Weavera,
Lynda Tusseya
a VaxInnate Corporation, 3 Cedar Brook Drive, Cranbury, NJ 08512, USA
b Merck & Co. 126 E. Lincoln Ave, Rahway, NJ 07065, USA
c Southern Research Institute, 2000 9th Avenue South, Birmingham, AL 35205, USA
http://dx.doi.org/10.1016/j.vaccine.2012.09.013, How to Cite or Link Using DOI
Abstract
In order to meet the global demand for rapid production of pandemic influenza vaccines, we have developed a recombinant fusion vaccine platform in which the globular head of hemagglutinin (HA) antigen is genetically fused to bacterial flagellin (a TLR5 ligand). These flagellin-HA fusion vaccine candidates elicit highly protective immunity against a lethal challenge with 2009 pandemic H1N1 (Liu, et al. PLoS ONE 2011; 6:e20928) or H5N1 influenza A/Vietnam/1203/04 (A/VN) infections in mice (Song, et al. Vaccine 2009;27:5875?88). Here we provide the first evidence showing that two A/VN vaccine candidates elicited HA-specific IgG, reduced nasal virus shedding, and conferred full protection against a lethal A/VN infection in ferrets. Furthermore, we show that similar flagellin-HA vaccine candidates of two other H5N1 HPAIV are immunogenic and/or efficacious in mice. Vaccines of A/Indonesia/5/05 (A/IN) induced significant HAI titers to homologous and heterologous A/Anhui/1/05 (A/AN) H5N1 viruses. Two subcutaneous immunizations with doses of either 0.3 μg or 3 μg of A/IN candidates resulted in ≥2.5 log10 unit reduction in day 5 lung virus titer and 90?100% protection against a lethal A/IN challenge in mice. Both R3.HA5 IN and R3.2xHA5 IN vaccines elicited robust neutralizing antibody responses that last for at least 9 months and demonstrated a significant anamnestic antibody response upon further booster immunization. Finally, we found that two vaccine candidates of A/AN induced significant HAI titers in mice. Taken together, our recombinant flagellin-HA platform has been successfully used to generate potent H5N1 HPAIV vaccine candidates. These promising preclinical results justify the advancement of these candidates into the clinic.
Highlights
► Generated two formats of recombinant flagellin-HA vaccines targeting 3 H5N1 HPAIV. ► The vaccines protect ferrets against a lethal A/Vietnam/1203/04 challenge. ► The vaccines protect mice against a lethal A/Indonesia/5/05 challenge. ► Both R3.HA5 and R3.2xHA5 elicit robust long-lasting HAI antibody responses to HPAIV. ► The R3.2xHA5 format vaccines are more immunogenic than the R3.HA5 in mice.
http://www.sciencedirect.com/science/article/pii/S0264410X12013230