Combination of live-attenuated and adenovirus-based vaccines provides immediate and durable protection against Yersinia pestis in mice.

Yersinia pestis is the etiological agent of pandemic-causing plague with no Food and Drug Administration (FDA)-approved vaccines. The natural emergence or intentional release of antimicrobial-resistant strains are alarming, necessitating development of new-generation vaccines and immunization strategies that produce rapid and durable immunity. Herein, we evaluated immediate (within 7 days) or long-term (6 months) protection and immune responses by combining patented live-attenuated vaccines (LAVs) with a trivalent adenovirus-type 5-based vaccine (Ad5-YFV) in C57BL/6 mice. Animals were immunized with either a two-dose prime-pull strategy (intramuscular [i.m.] injection of LAVs followed by intranasal [i.n.] instillation of Ad5-YFV, 21 days apart) or a 1-dose strategy by simultaneous administration of LAVs (i.m.) and Ad5-YFV (i.n.). Animals immunized with both strategies were either challenged after 6 months or, with the simultaneous strategy, 7 days post-vaccination in lethal pneumonic or bubonic Y. pestis CO92 infection models. Mice immunized with both strategies were completely protected and elicited robust and durable humoral and cellular immune responses through 6 months. Simultaneous vaccination also protected animals against bubonic (100%) and pneumonic (80%) challenges 7 days post-vaccination with rapid induction of immunoglobulin M (IgM), IgG3, and total IgG humoral responses. Thus, these vaccines and strategies are suitable for reactive (emergency) and preventive (in endemic regions) use.