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. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial The studies were registered at ClinicalTrials.gov as [NCT00584844][1] (trial FY03-24) and [NCT00787826][2] (trial FY07-15). An additional protocol FY15-14 was registered as [NCT03867162][3] but never enrolled subjects. ### Funding Statement The study was funded by the US Department of Defense. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All human subjects research studies described were approved by the Institutional Review Board of the U.S. Army Medical Research and Development Command (formerly Medical Research and Materiel Command) prior to commencement. Protocol FY03-24 was conducted from 1 October 2004 to 6 October 2009, while protocol FY07-15 ran from 28 August 2009 to 4 December 2017. The studies were registered at ClinicalTrials.gov as [NCT00584844][1] (trial FY03-24) and [NCT00787826][2] (trial FY07-15). An additional protocol FY15-14 was registered as [NCT03867162][3] but never enrolled subjects. Informed consent was obtained from all subjects prior to enrollment. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00584844&atom=%2Fmedrxiv%2Fearly%2F2023%2F01%2F11%2F2023.01.09.23284371.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00787826&atom=%2Fmedrxiv%2Fearly%2F2023%2F01%2F11%2F2023.01.09.23284371.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT03867162&atom=%2Fmedrxiv%2Fearly%2F2023%2F01%2F11%2F2023.01.09.23284371.atom