Protective effects of the Francisella tularensis ΔpdpC mutant against its virulent parental strain SCHU P9 in Cynomolgus macaques

Abstract

Tularemia is a severe infectious zoonotic disease caused by Francisella tularensis . Although F. tularensis is considered to be a potential biological weapon due to its high infectivity and mortality rate, no vaccine has been currently licensed. Recently, we reported that F. tularensis SCHU P9 derived Δ pdpC strain lacking the pathogenicity determinant protein C gene conferred stable and good protection in a mouse lethal model. In this study, the protective effect of Δ pdpC was evaluated using a monkey lethal model. Two cynomolgus macaques ( Macaca fascicularis ) intratracheally challenged with the virulent strain SCHU P9 were euthanized on 7 and 11 days post-challenge after the development of severe clinical signs. The bacterial replication in alveolar macrophages and type II epithelial cells in the lungs would cause severe pneumonia accompanied by necrosis. Conversely, two animals subcutaneously immunized with Δ pdpC survived 3 weeks after SCHU P9 challenge. Though one of the two animals developed mild symptoms of tularemia, bacterial replication was limited in the respiratory organs, which may be due to a high level of humoral and cellular immune responses against F. tularensis . These results suggest that the Δ pdpC mutant would be a safe and promising candidate as a live attenuated tularemia vaccine.

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“…No vaccine is yet available for the prevention of this disease. However, clinical assays have been developed in order to find a vaccine against tularemia, and a mutant strain (∆pdpC) tested in animals (mice and monkeys) was demonstrated to be a good candidate for a live attenuated vaccine against F. tularensis [42].…”

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“…Attenuated deletion mutant vaccines are therefore quite reliant and several studies have come forward proving its applicability. Pathogenicity Determinant Protein C gene deletion mutants imparted high cellular and humoral immune response in Cynomolgus macaques [ 34 ]. Similarly, Francisella phagosomal transporter ( fpt ) mutants of fptA and fptF genes provide defence against lethal doses of Francisella and displayed reduced pathology in mouse model [ 35 ].…”