Live attenuated tularemia vaccines: Recent developments and future goals

Abstract

In the aftermath of the 2001 anthrax attacks in the U.S., numerous efforts were made to increase the level of preparedness against a biological attack both in the US and worldwide. As a result, there has been an increase in research interest in the development of vaccines and other countermeasures against a number of agents with the potential to be used as biological weapons. One such agent, Francisella tularensis, has been the subject of a surge in the level of research being performed, leading to a substantial increase in knowledge of the pathogenic mechanisms of the organism and the induced immune responses. This information has facilitated the development of multiple new Francisella vaccine candidates. Herein we review the latest live attenuated F. tularensis vaccine efforts. Historically, live attenuated vaccines have demonstrated the greatest degree of success in protection against tularemia and the greatest promise in recent efforts to develop of a fully protective vaccine. This review summarizes recent live attenuated Francisella vaccine candidates and the lessons learned from those studies, with the goal of collating known characteristics associated with successful attenuation, immunogenicity, and protection.

Live Attenuated Mutants of Francisella tularensis Protect Rabbits against Aerosol Challenge with a Virulent Type A Strain

“…LVS was included in these challenge studies because new vaccine candidates would need to be at least as safe as LVS while providing better protection than LVS to warrant further consideration as a human vaccine. LVS has been shown to be safe and immunogenic in rats, rabbits, nonhuman primates, and humans (3,4,7,14,15,(35)(36)(37)(38). LVS is the only tularemia vaccine that was formally evaluated in human efficacy trials conducted in the 1960s (7,8,10,13,14,39).…”

“…LVS was found to provide at least partial protection against aerosol exposure to SCHU S4, although the level of protection was dependent on the dose and route of vaccination as well as the challenge dose. In addition to concerns about protection against aerosol challenge, the potential for reversion has been a concern raised against LVS as a human vaccine (3). All of the vaccines tested here, including LVS, were attenuated in rabbits, producing at most a mild fever response no more than 1 day in duration and a small eschar at the site of vaccination but no other clinical signs indicative of disease.…”

“…Initial attempts to develop a tularemia vaccine focused on a killed vaccine, which was ineffective (2,3). Subsequently, an attenuated type B strain of F. tularensis obtained from the former Soviet Union was passaged in vitro and evaluated as a vaccine.…”

“…Recent efforts to develop a tularemia vaccine have focused on live attenuated vaccines using site-specific deletion of virulence genes (3,(19)(20)(21)(22)(23)(24)(25)(26)(27). Studies have identified a number of mutations that attenuate F. tularensis to various degrees.…”

Putting the Jigsaw Together - A Brief Insight Into the Tularemia

“…Despite the undisputed protective effect of the live vaccine strain, however, the vaccine was not licensed for human use due to difficulties with its standardization. To eliminate this problem researchers prepared targeted mutants of the LVS, the holarctica strain FSC 200, and the Schu S4 strain that are highly attenuated and are protective against challenge with virulent strains of F. tularensis [227][228][229]. Some of these may constitute a promising basis for the construction of a new live vaccine in the future.…”