Abstract
Bacillus anthracis, Yersinia pestis, and Francisella tularensis are the causative agents of Tier 1 Select Agents anthrax, plague, and tularemia, respectively. Currently, there are no licensed vaccines against plague and tularemia and the licensed anthrax vaccine is suboptimal. Here we report F. tularensis LVS ΔcapB (Live Vaccine Strain with a deletion in capB)- and attenuated multi-deletional Listeria monocytogenes (Lm)-vectored vaccines against all three aforementioned pathogens. We show that LVS ΔcapB- and Lm-vectored vaccines express recombinant B. anthracis, Y. pestis, and F. tularensis immunoprotective antigens in broth and in macrophage-like cells and are non-toxic in mice. Homologous priming-boosting with the LVS ΔcapB-vectored vaccines induces potent antigen-specific humoral and T-cell-mediated immune responses and potent protective immunity against lethal respiratory challenge with all three pathogens. Protection against anthrax was far superior to that obtained with the licensed AVA vaccine and protection against tularemia was comparable to or greater than that obtained with the toxic and unlicensed LVS vaccine. Heterologous priming-boosting with LVS ΔcapB- and Lm-vectored B. anthracis and Y. pestis vaccines also induced potent protective immunity against lethal respiratory challenge with B. anthracis and Y. pestis. The single vaccine platform, especially the LVS ΔcapB-vectored vaccine platform, can be extended readily to other pathogens.
Highlights
Bacillus anthracis, Yersinia pestis, and Francisella tularensis, the causative agents of anthrax, plague, and tularemia, respectively, are classified as Tier 1 Select Agents of bioterrorism
While >10,000-fold less virulent than the toxic Live Vaccine Strain (LVS) strain in mice, LVS ΔcapB is highly protective - ~100% protection against aerosolized F. tularensis SchuS4 after intranasal (i.n.) immunization, and strong protection after intradermal (i.d.) immunization17. rLVS ΔcapB expressing F. tularensis proteins induces strong cellular and humoral immune responses and protection comparable to immunization with LVS after single i.n. and i.d. immunization either as a standalone vaccine or as a prime vaccine to animals heterologously boosted with recombinant Listeria monocytogenes (Lm) expressing IglC18,19
We report single platform vaccines including homologous LVS ΔcapB-vectored vaccines and heterologous LVS ΔcapB and Lm-vectored vaccines against three Tier I pathogens, the causative agents for anthrax, plague and tularemia
Summary
Yersinia pestis, and Francisella tularensis, the causative agents of anthrax, plague, and tularemia, respectively, are classified as Tier 1 Select Agents of bioterrorism. When B. anthracis, Y. pestis, and F. tularensis infect humans by the respiratory route, the route of greatest concern in an intentional bioterrorist attack, they cause highly fatal diseases - pulmonary anthrax, pneumonic plague, and pneumonic tularemia, respectively. In view of the potential catastrophic consequences of the intentional airborne spread of these pathogens and the increasing development of antibiotic-resistant strains, vaccines are needed to protect against inhaled B. anthracis, Y. pestis, and F. tularensis and other Tier 1 Select Agents. In the case of F. tularensis, subunit vaccines or vaccines comprising live attenuated heterologous vectors expressing F. tularensis proteins show relatively poor efficacy against high dose F. tularensis aerosol challenge in comparison with LVS, which itself is suboptimal[15,16]. Attenuated Lm vectors, including Lm ΔactA, Lm ΔactA ΔinlB, and Lm ΔactA ΔinlB ΔuvrAB prfA(G155S) (abbreviated as Lm ΔactA ΔinlB prfA hereafter), have been developed as vaccine vectors for delivery of cancer and infectious diseases antigens and have major advantages over other vectors as described by us and others[15,18,22,23,24]
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