A rhesus monkey model of respiratory syncytial virus (RSV) to evaluate the immunogenicity and protective efficacy of a DNA vaccine.

摘要

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and children worldwide. To date, there is no single animal model that reproduces all human disease states, making it difficult to adequately characterize all aspects of disease progression and resolution. Moreover, after nearly fifty years of research, investigators have yet to develop a safe and effective vaccine against RSV. While numerous vaccine strategies have been tested with varying degrees of success, none have been found to possess the appropriate balance between immunogenicity and safety. The object of this work was to first establish a model of experimental infection in infant Rhesus macaques using human RSV. A gene-based vaccine was then developed to evaluate its safety, immunogenicity and protective efficacy. DNA vaccines are capable of inducing strong and persistent cell-mediated and humoral immune responses, and have been shown to be safe and immunogenic in neonatal models. A vaccine encoding the fusion protein (F) and nucleoprotein (NP) of bovine RSV was designed and initially tested in mice. Vaccinated mice produced RSV-specific antibodies as soon as two weeks following inoculation and their levels continued to increase until the time of sacrifice (week 10). Virus-specific CTL activity was also demonstrated in immunized mice. Preliminary evaluation of the lung following experimental infection indicated decreased levels of viral RNA in vaccinated, but not unvaccinated mice. Infant rhesus macaques were then vaccinated at 1.5 months of age, and received a boost four weeks later. Eight weeks post-immunization, vaccinated and unvaccinated infants were challenged with a clinical isolate of human RSV. Immunological results indicated that the vaccine was well tolerated and immunogenic. Vaccinated animals developed both humoral and cellular immune responses and these were higher when compared to controls. No virus replication was detected the lungs of vaccinated animals, but was present in unvaccinated controls. Histopathological evaluation of the lungs of both groups suggested that the infection in vaccinated animals was less severe. These preliminary data are encouraging and suggest the feasibility of a DNA vaccine for use against human RSV.