Francisella tularensis (Ft) is a Category A biothreat agent for which there currently is no FDA-approved
vaccine. Thus, there is a substantial effort underway to develop an effective
tularemia vaccine. While it is well established that gender can significantly impact susceptibility to primary
infection, the impact of gender on
vaccine efficacy is not well established. Thus, development of a successful
vaccine against
tularemia will require an understanding of the impact gender has on
vaccine-induced protection against this organism. In this study, a role for gender in
vaccine-induced protection following Ft challenge is identified for the first time. In the present study, mucosal vaccination with inactivated Ft (iFt) LVS elicited gender-based protection in C57BL/6Tac mice against respiratory challenge with Ft LVS. Specifically, vaccinated male mice were more susceptible to subsequent Ft LVS challenge. This increased susceptibility in male mice correlated with increased bacterial burden, increased tissue
inflammation, and increased proinflammatory
cytokine production late in post-challenge
infection. In contrast, improved survival of iFt-vaccinated female mice correlated with reduced bacterial burden and enhanced levels of Ft-specific Abs in serum and broncho-alveolar lavage (BAL) fluid post-challenge. Furthermore, vaccination with a live
attenuated vaccine consisting of an Ft LVS
superoxide dismutase (SodB) mutant, which has proven efficacious against the highly virulent Ft SchuS4 strain, demonstrated similar gender bias in protection post-Ft SchuS4 challenge. Of particular significance is the fact that these are the first studies to demonstrate that gender differences impact disease outcome in the case of lethal respiratory
tularemia following mucosal vaccination. In addition, these studies further emphasize the fact that gender differences must be a serious consideration in any future
tularemia vaccine development studies.