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

<i>Yersinia pestis</i>, 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 Δ<i>capB</i>/Yp F1-V, that utilizes a highly attenuated <i>capB</i> mutant of <i>Francisella tularensis</i> Live Vaccine Strain as a vector to express a fusion protein of <i>Y. pestis</i> 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 <i>Y. pestis</i>. Here, we report on the immunogenicity and efficacy of rLVS Δ<i>capB</i>/Yp F1-V and additional LVS Δ<i>capB</i>-vectored vaccine candidates in mice. We demonstrate that three homologous prime-boost immunizations with an optimized dose of rLVS Δ<i>capB</i>/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 <i>Y. pestis</i> EV76 strain vaccine; moreover, mice immunized with the rLVS Δ<i>capB</i>/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 Δ<i>capB</i>/Yp F1-V correlates with F1 and LcrV-specific serum antibody levels. Our results highlight the potential of rLVS Δ<i>capB</i>/Yp F1-V to address the unmet need for a plague vaccine.