Live attenuated vaccines alone or in combination with an adenovirus-based vaccine protect mice lacking IFN-γ against pneumonic plague.

Two live-attenuated vaccines, LMA and LMP, were evaluated alone or in combination with a trivalent adenoviral vector-based vaccine (Ad5-YFV) for their protective efficacy against pneumonic plague in wild-type (WT) and interferon-γ (IFN-γ) knockout (KO) mice. LMA and LMP comprise triple deletion mutants of Yersinia pestis CO92, which causes pneumonic plague, and Ad5-YFV incorporates three protective plague immunogens. Protection of 80 to 100% was observed in vaccinated mice when challenged with highly lethal intranasal doses of parental Y. pestis CO92. All vaccinated mice generated robust humoral and cellular immune responses. Immunized WT mice generated overall greater antibody responses in both serum and bronchoalveolar lavage fluid with higher percentages of polyfunctional T cell populations. Vaccinated IFN-γ KO mice displayed better B cell activity in germinal centers with higher percentages of activated antigen-specific and memory T cells. Superior lung immunity and recall immune responses were observed in both WT and IFN-γ KO mice immunized using a prime-pull vaccine strategy, which also provided full protection against pneumonic plague to mice lacking IFN-α, IFN-β, and IFN-γ receptors. Depletion of IFN-γ or tumor necrosis factor-α from immunized WT mice before and during infection did not reduce protection against pulmonary Y. pestis CO92 challenge. These data suggest that IFN-γ may not be required for protection against pneumonic plague by these vaccines. Combining live-attenuated and adenovirus-based vaccines resulted in augmentation of systemic and local immune responses, which could be beneficial in providing long-lasting immunity against pneumonic plague.