tetano
Editor, Senior Moderator
Vaccine. 2015 Dec 2. pii: S0264-410X(15)01704-1. doi: 10.1016/j.vaccine.2015.11.054. [Epub ahead of print]
[h=1]Evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de-optimization of the 2009 pandemic H1N1 influenza virus, in ferrets.[/h] Broadbent AJ[SUP]1[/SUP], Santos CP[SUP]1[/SUP], Anafu A[SUP]1[/SUP], Wimmer E[SUP]2[/SUP], Mueller S[SUP]2[/SUP], Subbarao K[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Codon-pair bias de-optimization (CPBD) of viruses involves re-writing viral genes using statistically underrepresented codon pairs, without any changes to the amino acid sequence or codon usage. Previously, this technology has been used to attenuate the influenza A/Puerto Rico/8/34 (H1N1) virus. The de-optimized virus was immunogenic and protected inbred mice from challenge. In order to assess whether CPBD could be used to produce a live vaccine against a clinically relevant influenza virus, we generated an influenza A/California/07/2009 pandemic H1N1 (2009 pH1N1) virus with de-optimized HA and NA gene segments (2009 pH1N1-(HA+NA)[SUP]Min[/SUP]), and evaluated viral replication and protein expression in MDCK cells, and attenuation, immunogenicity, and efficacy in outbred ferrets. The 2009 pH1N1-(HA+NA)[SUP]Min[/SUP] virus grew to a similar titer as the 2009 pH1N1 wild type (wt) virus in MDCK cells (∼10[SUP]6[/SUP]TCID[SUB]50[/SUB]/ml), despite reduced HA and NA protein expression on western blot. In ferrets, intranasal inoculation of 2009 pH1N1-(HA+NA)[SUP]Min[/SUP] virus at doses ranging from 10[SUP]3[/SUP] to 10[SUP]5[/SUP] TCID[SUB]50[/SUB] led to seroconversion in all animals and protection from challenge with the 2009 pH1N1 wt virus 28 days later. The 2009 pH1N1-(HA+NA)[SUP]Min[/SUP] virus did not cause clinical illness in ferrets, but replicated to a similar titer as the wt virus in the upper and lower respiratory tract, suggesting that de-optimization of additional gene segments may be warranted for improved attenuation. Taken together, our data demonstrate the potential of using CPBD technology for the development of a live influenza virus vaccine if the level of attenuation is optimized.
Copyright ? 2015. Published by Elsevier Ltd.
[h=4]KEYWORDS:[/h] Codon pair bias de-optimization; Influenza; Vaccine
PMID: 26655630 [PubMed - as supplied by publisher]
[h=1]Evaluation of the attenuation, immunogenicity, and efficacy of a live virus vaccine generated by codon-pair bias de-optimization of the 2009 pandemic H1N1 influenza virus, in ferrets.[/h] Broadbent AJ[SUP]1[/SUP], Santos CP[SUP]1[/SUP], Anafu A[SUP]1[/SUP], Wimmer E[SUP]2[/SUP], Mueller S[SUP]2[/SUP], Subbarao K[SUP]3[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Codon-pair bias de-optimization (CPBD) of viruses involves re-writing viral genes using statistically underrepresented codon pairs, without any changes to the amino acid sequence or codon usage. Previously, this technology has been used to attenuate the influenza A/Puerto Rico/8/34 (H1N1) virus. The de-optimized virus was immunogenic and protected inbred mice from challenge. In order to assess whether CPBD could be used to produce a live vaccine against a clinically relevant influenza virus, we generated an influenza A/California/07/2009 pandemic H1N1 (2009 pH1N1) virus with de-optimized HA and NA gene segments (2009 pH1N1-(HA+NA)[SUP]Min[/SUP]), and evaluated viral replication and protein expression in MDCK cells, and attenuation, immunogenicity, and efficacy in outbred ferrets. The 2009 pH1N1-(HA+NA)[SUP]Min[/SUP] virus grew to a similar titer as the 2009 pH1N1 wild type (wt) virus in MDCK cells (∼10[SUP]6[/SUP]TCID[SUB]50[/SUB]/ml), despite reduced HA and NA protein expression on western blot. In ferrets, intranasal inoculation of 2009 pH1N1-(HA+NA)[SUP]Min[/SUP] virus at doses ranging from 10[SUP]3[/SUP] to 10[SUP]5[/SUP] TCID[SUB]50[/SUB] led to seroconversion in all animals and protection from challenge with the 2009 pH1N1 wt virus 28 days later. The 2009 pH1N1-(HA+NA)[SUP]Min[/SUP] virus did not cause clinical illness in ferrets, but replicated to a similar titer as the wt virus in the upper and lower respiratory tract, suggesting that de-optimization of additional gene segments may be warranted for improved attenuation. Taken together, our data demonstrate the potential of using CPBD technology for the development of a live influenza virus vaccine if the level of attenuation is optimized.
Copyright ? 2015. Published by Elsevier Ltd.
[h=4]KEYWORDS:[/h] Codon pair bias de-optimization; Influenza; Vaccine
PMID: 26655630 [PubMed - as supplied by publisher]