Abstract
Francisella tularensis causes the disease tularemia. Human pulmonary exposure to the most virulent form, F. tularensis subsp. tularensis (Ftt), leads to high morbidity and mortality, resulting in this bacterium being classified as a potential biothreat agent. However, a closely-related species, F. novicida, is avirulent in healthy humans. No tularemia vaccine is currently approved for human use. We demonstrate that a single dose vaccine of a live attenuated F. novicida strain (Fn iglD) protects against subsequent pulmonary challenge with Ftt using two different animal models, Fischer 344 rats and cynomolgus macaques (NHP). The Fn iglD vaccine showed protective efficacy in rats, as did a Ftt iglD vaccine, suggesting no disadvantage to utilizing the low human virulent Francisella species to induce protective immunity. Comparison of specific antibody profiles in vaccinated rat and NHP sera by proteome array identified a core set of immunodominant antigens in vaccinated animals. This is the first report of a defined live attenuated vaccine that demonstrates efficacy against pulmonary tularemia in a NHP, and indicates that the low human virulence F. novicida functions as an effective tularemia vaccine platform.
Highlights
F. tularensis is a highly infectious bacterium that causes tularemia in humans, a disease that has a high mortality rate when acquired through the pulmonary route
The Francisella Pathogenicity Island (FPI) protein IglD is required for Francisella phagosomal escape and intramacrophage replication within macrophages [17,18,19] and Francisella iglD mutant strains are highly attenuated for virulence in mice [20,21]
We constructed F. novicida (Fn) and F. tularensis subsp. tularensis (Ftt) iglD mutant strains and confirmed that both were defective for intramacrophage replication and virulence in mice, in contrast to the respective wildtype strains (Fig. S1; Ftt has 2 identical copies of iglD, and is a iglD1 iglD2 mutant)
Summary
F. tularensis is a highly infectious bacterium that causes tularemia in humans, a disease that has a high mortality rate when acquired through the pulmonary route. F. tularensis is able to survive and replicate within host macrophages, and this ability is essential for its virulence. F. tularensis escapes from the phagosomal compartment and replicates within the cytosol [1]. F. tularensis acquired through the pulmonary route disseminate to tissues outside the lung, where they replicate to high levels within internal organs such as the liver. Tularensis (Ftt) exhibits the highest level of virulence in all mammalian hosts, including humans, and because of the morbidity and mortality associated with disease as well as the potential for aerosol dissemination, it has been designated a category A biothreat agent. A closely-related species, F. novicida (Fn), is considered essentially avirulent for healthy humans and for this reason is exempt from select agent status
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