Attenuated influenza virus vaccines with modified NS1 proteins

The development of reverse genetics techniques allowing the rescue of influenza virus from plasmid DNA has opened up the possibility of inserting mutations into the genome of this virus for the generation of novel live attenuated influenza virus vaccines. Modifications introduced into the viral NS1 gene via reverse genetics have resulted in attenuated influenza viruses with promising vaccine potential. One of the main functions of the NS1 protein of influenza virus is the inhibition of the innate host type I interferon-mediated antiviral response. Upon viral infection, influenza viruses with modified NS1 genes induce a robust local type I interferon response that limits their replication, resulting in disease attenuation in different animal models. Nevertheless, these viruses can be grown to high titers in cell- and egg-based substrates with deficiencies in the type I IFN system. Intranasal inoculation of mice, pigs, horses, and macaques with NS1-modified influenza virus strains induced robust humoral and cellular immune responses, and generated immune protection against challenge with wild-type virus. This protective response was not limited to homologous strains of influenza viruses, as reduced replication of heterologous strains was also demonstrated in animals vaccinated with NS1-modified viruses, indicating the induction of a broad cross-neutralizing response by these vaccine candidates. The immunogenicity of NS1-modified viruses correlated with enhanced activation of antigen-presenting cells. While further studies on their safety and efficacy are still needed, the results obtained so far indicate that NS1-modified viruses could represent a new generation of improved influenza virus vaccines, and they suggest that modifying viral interferon antagonists in other virus families is a promising strategy for the generation of live attenuated virus vaccines.