Extended Safety and Efficacy Studies of the Attenuated Brucella Vaccine Candidates 16MΔ vjbR and S19Δ vjbR in the Immunocompromised IRF-1 −/− Mouse Model

Abstract

ABSTRACT The global distribution of brucellosis and high incidence in certain areas of the world warrant the development of a safer and efficacious vaccine. For the past 10 years, we have focused our attention on the development of a safer, but still highly protective, live attenuated vaccine for human and animal use. We have demonstrated the safety and protective efficacy of the vaccine candidates 16MΔ vjbR and S19Δ vjbR against homologous and heterologous challenge in multiple immunocompetent animal models, including mice and deer. In the present study, we conducted a series of experiments to determine the safety of the vaccine candidates in interferon regulatory factor-1-knockout (IRF-1 −/− ) mice. IRF-1 −/− mice infected with either wild-type Brucella melitensis 16M or the vaccine strain Brucella abortus S19 succumb to the disease within the first 3 weeks of infection, which is characterized by a marked granulomatous and neutrophilic inflammatory response that principally targets the spleen and liver. In contrast, IRF-1 −/− mice inoculated with either the 16MΔ vjbR or S19Δ vjbR vaccine do not show any clinical or major pathological changes associated with vaccination. Additionally, when 16MΔ vjbR - or S19Δ vjbR -vaccinated mice are challenged with wild-type Brucella melitensis 16M, the degree of colonization in multiple organs, along with associated pathological changes, is significantly reduced. These findings not only demonstrate the safety and protective efficacy of the vjbR mutant in an immunocompromised mouse model but also suggest the participation of lesser-known mechanisms in protective immunity against brucellosis.