Reverse genetics approaches for rational design of inactivated and live attenuated influenza vaccines

Abstract

Influenza viruses are a major cause of respiratory infections in humans. The disease caused by these viruses ranges from nonapparent to deadly infections with multiorgan failure. The severity of the disease is determined by the infecting strain, the immune and health status of the infected individual, and various genetic factors that are currently poorly defined. Inactivated and live attenuated vaccines are available for human use. Inactivated influenza vaccines are safe but their efficacy is suboptimal. Live attenuated influenza vaccines elicit stronger immune responses than inactivated vaccines and are more efficacious in children than inactivated vaccine preparations. In addition, some concerns exist over the biosafety of live attenuated influenza vaccines. Accordingly, the efficacy of current influenza vaccines needs to be improved. Reverse genetics is a technology for the generation of influenza viruses from cloned cDNA, which allows the introduction of mutations at will. This technology has been used extensively to develop novel live attenuated vaccine candidates that possess attenuating mutations in one or several viral proteins, elicit cross-protective antibodies, and replicate efficiently. Reverse genetics has also made possible the development of vaccines to highly pathogenic influenza viruses. These vaccine viruses lack a multi-basic cleavage site in the viral hemagglutinin protein that is recognized by ubiquitous proteases; hence, these viruses can no longer cause systemic infections. The development of such vaccines could not have been achieved without reverse genetics. Here, we review the state of influenza vaccines and the use of reverse genetics to develop improved vaccine viruses.