605. Long-Term Protection Afforded by a Single Administration of an Ad-Based Anti-Y. pestis Vaccine Against a Lethal Respiratory Challenge with Y. pestis (2006)

The aerosol form of the bacterium Yersinia pestis causes the pneumonic plague, a virulent and rapidly fatal disease that develops within days post-infection. In the context of a bioterror threat, an ideal anti-plague vaccine should elicit rapid, robust and long-acting protective immunity after a single dose. At present, no plague vaccines are available for use in the USA. One candidate for developing a subunit vaccine is the Yersinia pestis V antigen, a protein that influences the function of the Yersinia outer membrane proteins (Yops) virulence factors and has local anti-inflammatory effects in the host. Although protective immunity against Y. pestis challenge can be induced with recombinant V antigen, this immunization regimen requires multiple administrations and recent evidence suggests that long-term protection against Y. pestis requires strong cellular immune responses that are not stimulated by protein-based vaccines. Based on the knowledge that adenovirus (Ad)-based vaccine platforms rapidly induce humoral and cellular immune responses against expressed transgenes, we tested the hypothesis that a single administration of a replication-defective Ad gene transfer vector encoding the Y. pestis V antigen (AdsecV) could stimulate long-lasting protective immune responses, including cellular immune responses, without a requirement for repeat vaccine administration. To test the efficacy of the vaccine, mice immunized with a single administration of 1011 pu AdsecV were challenged intranasally 4 wk or 6 months after vaccination with doses of Y. pestis CO92 up to 106 cfu. At four wk post-administration, control mice that received saline (naive) or 1011 pu AdNull, a control vector, died within 3 to 5 days after challenge. In contrast, 100% of AdsecV-immunized mice (10/ 10) survived the intranasal challenge with 104 cfu and 8/10 and 9/10 of mice survived after infection with 105 and 106 cfu Y. pestis CO92, respectively (p<0.0001 for all doses). When mice immunized with a single dose of AdsecV were challenged 6 months post-administration, 100% of animals (10/10) survived intranasal infection with 104 cfu and 9/10 survived intranasal infection with 106 cfu Y. pestis CO92 (p<0.0001 for each dose). None of the control animals (naive or immunized with 1011 pu AdNull) survived the challenge. Protection was correlated with high anti-V antibody titers and, importantly, V- specific T cell responses (measured by ELISPOT). Consistent with the concept that cellular immune responses were relevant to protection, immunization of CD8+ T cell deficient mice (Cd8atm1Mak) with AdsecV did not protect any mice (0/10) from an intranasal infection with Y. pestis CO92 4 wk after immunization. These data suggest that AdsecV is a promising candidate as an effective single dose vaccine against the plague and that the cellular immune responses evoked by the vaccine play an important role in protection against respiratory infection with Y. pestis. The aerosol form of the bacterium Yersinia pestis causes the pneumonic plague, a virulent and rapidly fatal disease that develops within days post-infection. In the context of a bioterror threat, an ideal anti-plague vaccine should elicit rapid, robust and long-acting protective immunity after a single dose. At present, no plague vaccines are available for use in the USA. One candidate for developing a subunit vaccine is the Yersinia pestis V antigen, a protein that influences the function of the Yersinia outer membrane proteins (Yops) virulence factors and has local anti-inflammatory effects in the host. Although protective immunity against Y. pestis challenge can be induced with recombinant V antigen, this immunization regimen requires multiple administrations and recent evidence suggests that long-term protection against Y. pestis requires strong cellular immune responses that are not stimulated by protein-based vaccines. Based on the knowledge that adenovirus (Ad)-based vaccine platforms rapidly induce humoral and cellular immune responses against expressed transgenes, we tested the hypothesis that a single administration of a replication-defective Ad gene transfer vector encoding the Y. pestis V antigen (AdsecV) could stimulate long-lasting protective immune responses, including cellular immune responses, without a requirement for repeat vaccine administration. To test the efficacy of the vaccine, mice immunized with a single administration of 1011 pu AdsecV were challenged intranasally 4 wk or 6 months after vaccination with doses of Y. pestis CO92 up to 106 cfu. At four wk post-administration, control mice that received saline (naive) or 1011 pu AdNull, a control vector, died within 3 to 5 days after challenge. In contrast, 100% of AdsecV-immunized mice (10/ 10) survived the intranasal challenge with 104 cfu and 8/10 and 9/10 of mice survived after infection with 105 and 106 cfu Y. pestis CO92, respectively (p<0.0001 for all doses). When mice immunized with a single dose of AdsecV were challenged 6 months post-administration, 100% of animals (10/10) survived intranasal infection with 104 cfu and 9/10 survived intranasal infection with 106 cfu Y. pestis CO92 (p<0.0001 for each dose). None of the control animals (naive or immunized with 1011 pu AdNull) survived the challenge. Protection was correlated with high anti-V antibody titers and, importantly, V- specific T cell responses (measured by ELISPOT). Consistent with the concept that cellular immune responses were relevant to protection, immunization of CD8+ T cell deficient mice (Cd8atm1Mak) with AdsecV did not protect any mice (0/10) from an intranasal infection with Y. pestis CO92 4 wk after immunization. These data suggest that AdsecV is a promising candidate as an effective single dose vaccine against the plague and that the cellular immune responses evoked by the vaccine play an important role in protection against respiratory infection with Y. pestis.