Longitudinal phase 2 clinical trials of live, attenuated tularemia vaccine in otherwise healthy research laboratory workers operating in containment laboratories

Background: Tularemia is a bacterial disease caused by the intracellular bacterium Francisella tularensis ( F. tularensis or Ft ). It has been weaponized historically by multiple state actors due to its low infectious aerosol dose, high morbidity and high mortality rate of the pneumonic form. The US Army developed the attenuated Live Vaccine Strain (LVS) from stocks provided by the former Soviet Union in the 1950s. The vaccine has proven to be safe and immunogenic over the ensuing decades in numerous clinical trials and animal as well as human challenge studies. Despite the threat, there are no FDA-approved vaccines nor clinical stage candidates against tularemia. LVS remains unlicensed due to instability in culture and the potential for reversion to the wild-type pathogen. We report here two sequential LVS trials in at-risk laboratory personnel working on tularemia in bio-containment. Methods: Volunteers received a single dose of the Live Vaccine Strain (LVS) live, attenuated tularemia vaccine by scarification under 2 FDA-regulated non-randomized, single-arm protocols (IND 157). Positive immunization was based on local scarification site take reaction, and either a > 1:20 tularemia antigen microagglutination (MA) titer (protocol FY03-24; 2004-8) or greater than 4-fold rise in MA titer (protocol FY07-15; 2009-2017). Those still negative by week 4 were offered a second dose. Results: The LVS vaccine was safe, well tolerated and highly immunogenic. Between the two studies, all recipients (100%) had positive take reactions, with 95.5% of those in study FY03-24 having a positive response following initial vaccination. All but 3 subjects (98%) in protocol FY03-24 had positive MA titer results defined as > 1:20, most within 28-35 days. In protocol FY07-15, 95% of subjects had a 4-fold or greater rise in MA titer, the primary immunogenicity endpoint for that study. Conclusions: LVS vaccine administered to laboratory workers at risk for tularemia exposure over a 12 year period was safe and highly immunogenic. Findings were in line with more than 4 decades of prior similar results. Response rates remained robust despite the vaccine lots employed having been manufactured 2-3 decades prior to the present studies. In the absence of a commercial development effort, or another tularemia vaccine in clinical development, a vaccine protocol under investigational new drug (IND) application could be considered based on the large body of favorable data for this vaccine. The results as well as historical comparator data presented here should serve as a benchmark for future studies.