Respiratory syncytial virus (RSV) live-attenuated vaccines: Development of temperature -sensitive properties and characterization of its stability, airway hyperreactivity, and immune response.

Respiratory syncytial virus (RSV) is a ubiquitous human pathogen that produces a wide spectrum of human respiratory diseases that afflict all age groups, but can take on more serious forms of illness in infants and the elderly. Control of RSV is significant from epidemiological standards since one sees higher morbidity of infants and young children due to RSV-induced bronchiolitis. Thus, control of RSV infection is an important public health problem. Many of the more serious effects of RSV could be mitigated if an appropriate vaccine were to be developed. We developed a live-attenuated vaccine candidate, RSV la64, that proved to be temperature-sensitive and met the challenges of safety (attenuation) and efficacy (sufficient replication to be immunogenic). We were successfully able to pass RSV 1a64 within the ferret model using both nasal swabs and nasal washes, proving that the ferret was an appropriate model to test genetic stability and immunogenicity of potential RSV vaccine candidates. Importantly, RSV Ia64 was able to retain its temperature-sensitive properties without reversion throughout the three ferret passages. RSV Ia64 also elicited a good neutralization antibody titer throughout the study and did not grow to detectable levels within the lung. In addition, RSV Ia64 protected against airway hyperreactivity after challenge with wildtype RSV. Furthermore, this vaccine candidate elicited higher levels of IgA in contrast to the wildtype and evoked higher levels of the important antiviral cytokines, IFNgamma and IL-12, compared to the wildtype. Therefore, we conclude that RSV Ia64 may be a successful five-attenuated vaccine for RSV since it meets many of the requirements at this stage of vaccine development.Ph.D.Health and Environmental SciencesImmunologyPathologyPublic healthUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/132758/2/9990866.pd