Combination of live attenuated and adenovirus-based vaccines completely protects interferon gamma (IFNγ) knockout mice against pneumonic plague

Two live attenuated vaccines (LAVs), LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their efficacy and immune responses in wild type (WT) and interferon gamma (IFN{gamma}) knockout (KO) mice in a C57BL/6 background. While LMA and LMP are triple deletion mutants of Yersinia pestis CO92 strain, Ad5-YFV incorporates three protective plague immunogens. An impressive 80-100% protection was observed in all vaccinated animals against highly lethal intranasal challenge doses of parental Y. pestis CO92. All vaccinated mice generated robust humoral and cellular immune responses. The immunized WT mice showed overall better antibody responses in both serum and bronchoalveolar lavage fluid with much higher percentages of polyfunctional T cell populations. On the other hand, vaccinated IFN{gamma} KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen specific T cells and memory T cells. In addition, depletion of IFN{gamma} and tumor necrosis factor alpha (TNF) from immunized WT mice prior to and during infection did not reduce protection against pulmonary Y. pestis CO92 challenge. These data demonstrated a dispensable nature of IFN{gamma} in mediating protection by the aforementioned vaccines. This is the first detailed immunogenicity study of two plague LAVs administered either alone or in combination with an Ad5-YFV vaccine in a prime-boost immunization strategy in IFN{gamma} KO mice. Further, by combining advantages of live-attenuated and adenovirus-based vaccines, augmentation of generalized immune responses were observed which could be beneficial in providing long-lasting immunity in the host.