Application of cleavage activation mutants of influenza virus as live vaccines

Abstract

Influenza viruses are major human and animal pathogens. In man, they are responsible for annual epidemics and less frequent but more severe pandemics. Avian influenza viruses cause devastating outbreaks in poultry, and influenza virus infections in pigs and horses also lead to high economic losses. Vaccination is an effective instrument to control the disease burden of human and, to some extent, also of animal influenza. Inactivated human vaccines have been used for more than 60 years. Furthermore, cold-adapted, live attenuated vaccines have been licensed in some countries. Attenuated viruses with reduced pathogenicity can also be obtained when the cleavage site of the hemagglutinin is mutated. Such protease activation mutants have not only been generated for the production of inactivated vaccines against highly pathogenic avian influenza viruses, but they have also the potential to be used as live vaccines. Two types of protease activation mutants have been investigated for use as live vaccines. In the first group, the polybasic cleavage site of the hemagglutinin, a prime determinant of pathogenicity, was cut short to a single arginine. These viruses require additional mutations in other genes for full attenuation. In the second group, polybasic ormonobasic cleavage sites are replaced by an elastase cleavage site. These viruses are fully attenuated, yet have retained their immunogenicity.