rLVS Δ<i>capB</i>/Yp F1-V single vector platform vaccine expressing <i>Yersinia pestis</i> 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.