Three great plague pandemics, resulting in nearly 200 million deaths in human history and usage as a biowarfare agent, have made Yersinia pestis as one of the most virulent human pathogens. In late 2017, a large plague outbreak raged in Madagascar attracted extensive attention and caused regional panics. The evolution of local outbreaks into a pandemic is a concern of the Centers for Disease Control and Prevention (CDC) in plague endemic regions. Until now, no licensed plague vaccine is available. Prophylactic vaccination counteracting this disease is certainly a primary choice for its long-term prevention. In this review, we summarize the latest advances in research and development of plague vaccines.

Two mutant strains ofYersinia pestisKIM5+, a Δcrpmutant and a mutant with arabinose-dependent regulated delayed-shutoffcrpexpression (araCP_BADcrp), were constructed, characterizedin vitro, and evaluated for virulence, immunogenicity, and protective efficacy in mice. Both strains were highly attenuated by the subcutaneous (s.c.) route. The 50% lethal doses (LD₅₀s) of the ΔcrpandaraCP_BADcrpmutants were approximately 1,000,000-fold and 10,000-fold higher than those ofY. pestisKIM5+, respectively, indicating that both strains were highly attenuated. Mice vaccinated s.c. with 3.8 × 10⁷CFU of the Δcrpmutant developed high anti-Y. pestisand anti-LcrV serum IgG titers, both with a strong Th2 bias, and induced protective immunity against subcutaneous challenge with virulentY. pestis(80% survival) but no protection against pulmonary challenge. Mice vaccinated with 3.0 × 10⁴CFU of thearaCP_BADcrpmutant also developed high anti-Y. pestisand anti-LcrV serum IgG titers but with a more balanced Th1/Th2 response. This strain induced complete protection against s.c. challenge and partial protection (70% survival) against pulmonary challenge. Our results demonstrate that arabinose-dependent regulatedcrpexpression is an effective strategy to attenuateY. pestiswhile retaining strong immunogenicity, leading to protection against the pneumonic and bubonic forms of plague.

Hospital- and community-acquired infections with Pseudomonas aeruginosa cause a high rate of morbidity and mortality in patients who have underlying medical conditions. The spread of multidrug-resistant P. aeruginosa strains is becoming a great challenge for treatment using antibiotics. Thus, a vaccine as one of the alternative strategies is urgently required to prevent P. aeruginosa infection.

A Yersinia pestis mutant synthesizing an adjuvant form of lipid A (monophosphoryl lipid A, MPLA) displayed increased biogenesis of bacterial outer membrane vesicles (OMVs). To enhance the immunogenicity of the OMVs, we constructed an Asd-based balanced-lethal host-vector system that oversynthesized the LcrV antigen of Y. pestis , raised the amounts of LcrV enclosed in OMVs by the type II secretion system, and eliminated harmful factors like plasminogen activator (Pla) and murine toxin from the OMVs.

To develop an effective Pseudomonas aeruginosa outer-membrane-vesicle (OMV) vaccine, we eliminated multiple virulence factors from a wild-type (WT) P. aeruginosa strain, PA103, to generate a recombinant strain, PA-m14. Strain PA-m14 was tailored with a pSMV83 plasmid carrying the pcrV-hitA _T fusion gene to produce OMVs.

In this study, a novel recombinant attenuated Yersinia pseudotuberculosis PB1+ strain (χ10069) engineered with Δ yopK Δ yopJ Δ asd triple mutations was used to deliver a Y. pestis fusion protein, YopE amino acid 1 to 138-LcrV (YopE _Nt138 -LcrV), to Swiss Webster mice as a protective antigen against infections by yersiniae.