The non-structural proteins of RSV: targeting interferon antagonists for vaccine development

Over fifty years have passed since the identification of respiratory syncytial virus (RSV) as an important pediatric pathogen. However, an effective vaccine is still lacking. Immunization with formalin-inactivated RSV resulted in vaccine-enhanced disease; thus, a greater focus has been placed more recently on developing live attenuated RSV vaccines. The difficulty in identifying a live attenuated vaccine candidate has been balancing appropriate attenuation with sufficient immunogenicity. With the advent of reverse genetics systems for RSV, researchers have been able to generate recombinint vaccine candidates by introducing specific mutations into the genome wild-type RSV. These systems provide a means to determine the effects of known attenuating mutations and identifying novel methods of attenuating the virus without decreasing immunogenicity. In addition, different mutations can be combined in a single genome to fine-tune the level of attenuation and immunogenicity to achieve the proper balance in a viable vaccine candidate. Among the targets for attenuation are the small RSV nonstructural (NS) proteins. The NS proteins have multiple functions during the virus life cycle, including antagonizing the antiviral effects of interferon and directly augmenting virus replication. This review will outline the progress in understanding the functions of the NS proteins and how altering these functions by reverse genetic manipulation can be a useful path toward rationally designing a safe and effective live-attenuated RSV vaccine.