The Impact Of Pre-existing Immunity Against VTT Vector On The Effect Of The Recombinant Vaccine Based On VTT For SARS

Tiantan strain of vaccinia virus (wtVTT) as the smallpox vaccine successfully eliminated the smallpox epidemic in China during the worldwide smallpox eradication campaign. This strain had attracted more attention again recently for its potential to develop recombinant vaccinia virus due to the nature properties of good immunogenicity, moderate reactogenicity, and relatively mild complications in humans. In this study, we generated a Tiantan-based vaccinia vaccine against Severe acute respiratory syndrome (SARS) virus, termed VTT-S, which was introduced the full-length spike protein (S) gene of SARS-associated coronavirus (SARS-CoV) into the promoter of HA gene of Tiantan strain to develop an attenuated virulence Tiantan-based vaccine of SARS. Considering many adult humans have neutralizing antibodies to VTT as a result of vaccination to fight against smallpox before 1980, a investigation was performed to evaluate if VTT-S could work effectively in the setting of pre-immunity against the vector. Either VTT-S or modified vaccinia virus Akara strains that was inserted S gene into deletion III locus (MVA-S) was inoculated BALB/C mice followed a pre-injection of wtVTT virus to test the efficacy of which the anti-S antibodies level induced by these two vaccinia-based vaccines. The result indicated that there was much less impact of the anti-vector pre-immunity on the efficacy of VTT-S in comparison with MVA-S. Meanwhile, VTT-S showed much higher immunogenic in terms of inducing potent neutralization antibodies against S than MVA-S when the both vaccines were given orally or intranasally, suggesting the potential future use of VTT as a vaccine carrier for human trials. In addition, we investigated that the effect of the routes between priming injection of vaccinia vector and the subsequent immunization with the recombinant vaccinia vaccines on the efficacy of the VTT-based vaccines. The result suggested that the routes of immunization were crucial for the foreign gene expression of the recombinant viccinia vaccine. In addition, we tried another attenuated virulence virus, termed TTZC1, which was constructed by inserting foreign GFP gene into the HA gene of the wtVTT, to pre-immunize the mice taking place of wtVTT, then VTT-S or MVA-S was inoculated as above. The aim was to detect if the attenuated wtVTT would have less impact of pre-existing immunity. The result turned out to be true as we speculated first. Taken together, VTT-S could elicit strong humoral response against S protein of SARS-CoV via oral and intranasal routes, and the level of Nab induced by VTT-S was much higher than MVA-S, which was proved capable of high-level gene transfer and activation of B cells to the S protein in previous studies (Chen et al.,2005). Pre-existing anti-VTT Nabs had a minimal effect on the potency of VTT-S vaccine compared with MVA-S. The routes of immunizations were crucial for the efficacy of the recombinant vaccinia vaccine. Pre-existing immunity of TTZC1 had less impact than wtVTT on the VTT-S effect, considering it was also an attenuated strain, which made it a better vaccine of the smallpox prevention.