rLVS ΔcapB/Yp F1-V single vector platform vaccine expressing Yersinia pestis F1 and LcrV antigens provides complete protection against lethal respiratory challenge with virulent plague bacilli

Yersinia pestis, the causative agent of plague, is classified as a Tier I Select Agent of bioterrorism and is among a few pathogens of high concern as a potential cause of a future pandemic. Currently, there is no licensed vaccine against plague. Previously, we developed a live attenuated vaccine candidate, rLVS ΔcapB/Yp F1-V, that utilizes a highly attenuated capB mutant of Francisella tularensis Live Vaccine Strain as a vector to express a fusion protein of Y. pestis F1 and LcrV antigens. We showed that homologous prime-boost vaccination with this vaccine provided potent protection in mice against lethal respiratory challenge with virulent Y. pestis. Here, we report on the immunogenicity and efficacy of rLVS ΔcapB/Yp F1-V and additional LVS ΔcapB-vectored vaccine candidates in mice. We demonstrate that three homologous prime-boost immunizations with an optimized dose of rLVS ΔcapB/Yp F1-V provided complete protection against pneumonic plague in a stringent mouse model, outperforming other candidates and matching the survival efficacy of the toxic and unlicensed live attenuated Y. pestis EV76 strain vaccine; moreover, mice immunized with the rLVS ΔcapB/Yp F1-V vaccine had minimal weight loss post-challenge that was significantly less than mice immunized with the EV76 vaccine. Protection induced by rLVS ΔcapB/Yp F1-V correlates with F1 and LcrV-specific serum antibody levels. Our results highlight the potential of rLVS ΔcapB/Yp F1-V to address the unmet need for a plague vaccine.