Potential Bioterrorism Agent Research Articles

Discovery and characterization of an essential Francisella tularensis protein required for tularemia disease development (538.5)

Potential bioterrorism agent Francisella tularensis subspecies tularensis (F. tularensis) causes tularemia; a disease that can cause up to 60% mortality. An essential step to developing tularemia is the ability of F. tularensis to escape the vacuole that it initially occupies to replicate in the cytosol of epithelial cells. We hypothesize F. tularensis possesses virulence factors (VFs) that facilitate this process. In this study, we identified a crucial VF for tularemia development. To identify this VF, we screened a 3,050 Francisella mutant library for microbes deficient in bacterial replication once inside host cells. By using subsequent bioinformatics analysis we identified proteins in a subset of mutated bacteria that fit traits of VFs and we tested their ability to cause tularemia‐induced death in mice. Mice infected with bacteria inactivated in 1 novel gene appeared uninfected whereas wild‐type infected mice died within 2 days. Electron and immunofluorescence micrographs of infected hepatocytes showed that this gene aids the bacteria in exiting lysosome‐associated membrane protein‐1 (LAMP‐1) positive membrane vacuoles leading to bacterial replication in the cytosol. Our findings demonstrate this novel VF enables F. tularensis to escape into the cytosol and ultimately cause disease.

BSL-3 Laboratory Practices in the United States: Comparison of Select Agent and Non–Select Agent Facilities

New construction of biosafety level 3 (BSL-3) laboratories in the United States has increased in the past decade to facilitate research on potential bioterrorism agents. The Centers for Disease Control and Prevention inspect BSL-3 facilities and review commissioning documentation, but no single agency has oversight over all BSL-3 facilities. This article explores the extent to which standard operating procedures in US BSL-3 facilities vary between laboratories with select agent or non-select agent status. Comparisons are made for the following variables: personnel training, decontamination, personal protective equipment (PPE), medical surveillance, security access, laboratory structure and maintenance, funding, and pest management. Facilities working with select agents had more complex training programs and decontamination procedures than non-select agent facilities. Personnel working in select agent laboratories were likely to use powered air purifying respirators, while non-select agent laboratories primarily used N95 respirators. More rigorous medical surveillance was carried out in select agent workers (although not required by the select agent program) and a higher level of restrictive access to laboratories was found. Most select agent and non-select agent laboratories reported adequate structural integrity in facilities; however, differences were observed in personnel perception of funding for repairs. Pest management was carried out by select agent personnel more frequently than non-select agent personnel. Our findings support the need to promote high quality biosafety training and standard operating procedures in both select agent and non-select agent laboratories to improve occupational health and safety.

Teaching Bioterrorism Preparedness with Simulation - The Pneumonic Plague Example

Future bioterrorism acts are an unfortunate possibility for which healthcare providers and medical systems must prepare. Plague, caused by Yersinia pestis, is a potential bioterrorism agent which healthcare providers in the developed world have only a low familiarity. This article provides a teaching strategy using medical simulation to assist healthcare professionals and institutions in preparing for bioterrorism events.

Validation of IMP Dehydrogenase Inhibitors in a Mouse Model of Cryptosporidiosis

Cryptosporidium parasites are a major cause of diarrhea and malnutrition in the developing world, a frequent cause of waterborne disease in the developed world, and a potential bioterrorism agent. Currently, available treatment is limited, and Cryptosporidium drug discovery remains largely unsuccessful. As a result, the pharmacokinetic properties required for in vivo efficacy have not been established. We have been engaged in a Cryptosporidium drug discovery program targeting IMP dehydrogenase (CpIMPDH). Here, we report the activity of eight potent and selective inhibitors of CpIMPDH in the interleukin-12 (IL-12) knockout mouse model, which mimics acute human cryptosporidiosis. Two compounds displayed significant antiparasitic activity, validating CpIMPDH as a drug target. The best compound, P131 (250 mg/kg of body weight/day), performed equivalently to paromomycin (2,000 mg/kg/day) when administered in a single dose and better than paromomycin when administered in three daily doses. One compound, A110, appeared to promote Cryptosporidium infection. The pharmacokinetic, uptake, and permeability properties of the eight compounds were measured. P131 had the lowest systemic distribution but accumulated to high concentrations within intestinal cells. A110 had the highest systemic distribution. These observations suggest that systemic distribution is not required, and may be a liability, for in vivo antiparasitic activity. Intriguingly, A110 caused specific alterations in fecal microbiota that were not observed with P131 or vehicle alone. Such changes may explain how A110 promotes parasitemia. Collectively, these observations suggest a blueprint for the development of anticryptosporidial therapy.

Novel Burkholderia mallei Virulence Factors Linked to Specific Host-Pathogen Protein Interactions

Burkholderia mallei is an infectious intracellular pathogen whose virulence and resistance to antibiotics makes it a potential bioterrorism agent. Given its genetic origin as a commensal soil organism, it is equipped with an extensive and varied set of adapted mechanisms to cope with and modulate host-cell environments. One essential virulence mechanism constitutes the specialized secretion systems that are designed to penetrate host-cell membranes and insert pathogen proteins directly into the host cell's cytosol. However, the secretion systems' proteins and, in particular, their host targets are largely uncharacterized. Here, we used a combined in silico, in vitro, and in vivo approach to identify B. mallei proteins required for pathogenicity. We used bioinformatics tools, including orthology detection and ab initio predictions of secretion system proteins, as well as published experimental Burkholderia data to initially select a small number of proteins as putative virulence factors. We then used yeast two-hybrid assays against normalized whole human and whole murine proteome libraries to detect and identify interactions among each of these bacterial proteins and host proteins. Analysis of such interactions provided both verification of known virulence factors and identification of three new putative virulence proteins. We successfully created insertion mutants for each of these three proteins using the virulent B. mallei ATCC 23344 strain. We exposed BALB/c mice to mutant strains and the wild-type strain in an aerosol challenge model using lethal B. mallei doses. In each set of experiments, mice exposed to mutant strains survived for the 21-day duration of the experiment, whereas mice exposed to the wild-type strain rapidly died. Given their in vivo role in pathogenicity, and based on the yeast two-hybrid interaction data, these results point to the importance of these pathogen proteins in modulating host ubiquitination pathways, phagosomal escape, and actin-cytoskeleton rearrangement processes.

Less Is More: Burkholderia pseudomallei and Chronic Melioidosis

ABSTRACTThe Gram-negative bacterium Burkholderia pseudomallei is the causative agent of melioidosis, a serious infectious disease of humans and animals. Once considered an esoteric tropical disease confined to Southeast Asia and northern Australia, research on B. pseudomallei has recently gained global prominence due to its classification as a potential bioterrorism agent by countries such as the United States and also by increasing numbers of case reports from regions where it is not endemic. An environmental bacterium typically found in soil and water, assessing the true global prevalence of melioidosis is challenged by the fact that clinical symptoms associated with B. pseudomallei infection are extremely varied and may be confused with diverse conditions such as lung cancer, tuberculosis, or Staphyloccocus aureus infection. These diagnostic challenges, coupled with lack of awareness among clinicians, have likely contributed to underdiagnosis and the high mortality rate of melioidosis, as initial treatment is often either inappropriate or delayed. Even after antibiotic treatment, relapses are frequent, and after resolution of acute symptoms, chronic melioidosis can also occur, and the symptoms can persist for months to years. In a recent article, Price et al. [mBio 4(4):e00388-13, 2013, doi:10.1128/mBio.00388-13] demonstrate how comparative genomic sequencing can reveal the repertoire of genetic changes incurred by B. pseudomallei during chronic human infection. Their results have significant clinical ramifications and highlight B. pseudomallei’s ability to survive in a wide range of potential niches within hosts, through the acquisition of genetic adaptations that optimize fitness and resource utilization.

Rodents as Potential Couriers for Bioterrorism Agents

Many pathogens that can cause major public health, economic, and social damage are relatively easily accessible and could be used as biological weapons. Wildlife is a natural reservoir for many potential bioterrorism agents, and, as history has shown, eliminating a pathogen that has dispersed among wild fauna can be extremely challenging. Since a number of wild rodent species live close to humans, rodents constitute a vector for pathogens to circulate among wildlife, domestic animals, and humans. This article reviews the possible consequences of a deliberate spread of rodentborne pathogens. It is relatively easy to infect wild rodents with certain pathogens or to release infected rodents, and the action would be difficult to trace. Rodents can also function as reservoirs for diseases that have been spread during a bioterrorism attack and cause recurring disease outbreaks. As rats and mice are common in both urban and rural settlements, deliberately released rodentborne infections have the capacity to spread very rapidly. The majority of pathogens that are listed as potential agents of bioterrorism by the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases exploit rodents as vectors or reservoirs. In addition to zoonotic diseases, deliberately released rodentborne epizootics can have serious economic consequences for society, for example, in the area of international trade restrictions. The ability to rapidly detect introduced diseases and effectively communicate with the public in crisis situations enables a quick response and is essential for successful and cost-effective disease control.

Evolution toward high-level fluoroquinolone resistance in Francisella species

Francisella tularensis, a CDC class A potential bioterrorism agent, is a Gram-negative bacterium responsible for tularaemia. Understanding the mechanisms of resistance to antibiotics used as first-line treatment is of major security relevance. We propagated the three parental reference strains Francisella tularensis subsp. holarctica live vaccine strain, Francisella novicida and Francisella philomiragia with increasing concentrations of ciprofloxacin, a fluoroquinolone used as curative and prophylactic treatment for tularaemia. This evolution procedure provided us with high-level ciprofloxacin-resistant mutants and all evolutionary intermediates towards high-level resistance. We determined the resistance levels to other fluoroquinolones (levofloxacin and moxifloxacin) and other antibiotic families (aminoglycosides, tetracyclines and macrolides) and characterized the genetic changes in the fluoroquinolone target genes encoding DNA gyrase and topoisomerase IV. All high-level resistant mutants shared cross-resistance to the tested fluoroquinolones, while some also revealed striking levels of cross-resistance to other clinically relevant antibiotic classes. High-level resistant mutants carried one to three mutations, including some not previously reported. We mapped all mutations onto known topoisomerase three-dimensional structures. Along the pathways towards high-level resistance, we identified complex evolutionary trajectories including polymorphic states and additional resistance mechanisms likely to be associated with efflux processes. Our data demonstrated the efficiency and speed of in vitro production of mutants highly resistant to fluoroquinolones in Francisella species. They emphasize the urgent need to identify all antibiotic resistance mechanisms in these species, develop molecular tools for their detection and design new therapeutic alternatives for tularaemia.

The Microbial Rosetta Stone Central Agricultural Database: An Information Resource on High-Consequence Plant Pathogens.

Microbial pathogens of humans, animals, and plants can serve as potential agents of biowarfare, bioterrorism, and biocrime. Previously, the Microbial Rosetta Stone (MRS) Central database, an easily accessible informational resource tool, was developed to assist law enforcement personnel in the event of a disease investigation by providing key information on pathogens of concern. Although the database already contained information on a few high-profile plant pathogens, the coverage was insufficient considering the large number of plant pathogens that pose a threat, not only to agricultural production but also to natural plant resources such as forests and rangelands. In this project, 100 plant pathogens of high consequence were selected for study, existing literature on these agents was reviewed, and both the sources and key pathogen information provided therein were curated in the new Agricultural Database (AgDB), an accessory to the existing MRS Central Database. Chosen for inclusion in the MRS Central AgDB were plant pathogens having significant potential for damage to U.S. agricultural and natural ecosystems. The selection process included review of several previously developed plant-pathogen threat lists and recommendations from experts within the U.S. plant biosecurity community. Pathogen information was collected by searching a number of relevant literature databases, sites on the World Wide Web, and other resources. For inclusion in the MRS, the information was curated into categories: pathogen taxonomy, nomenclature synonyms, disease symptoms and geographic distribution, plant hosts, insect vectors, detection and diagnostic methods, laboratory and field protocols, sample collection, and epidemiology. The resulting AgDB enhances the MRS Central Database by summarizing and linking key information on high-threat plant diseases and their causal agents to relevant scientific literature and internet resources. The AgDB contains critical, key information on high-consequence plant pathogens, curated in a format that is readily accessible and easily searched. The resource enhances the existing MRS Central Database and provides law enforcement, forensic, and investigative personnel with an additional tool with which to respond to microbial emergencies, particularly those affecting the agricultural and environmental sectors.

Crystal structure of Junin virus nucleoprotein

Junin virus (JUNV) has been identified as the aetiological agent of Argentine haemorrhagic fever (AHF), which is a serious public health problem with approximately 5 million people at risk. It is treated as a potential bioterrorism agent because of its rapid transmission by aerosols. JUNV is a negative-sense ssRNA virus that belongs to the genus Arenavirus within the family Arenaviridae, and its genomic RNA contains two segments encoding four proteins. Among these, the nucleoprotein (NP) has essential roles in viral RNA synthesis and immune suppression, but the molecular mechanisms of its actions are only partially understood. Here, we determined a 2.2 Å crystal structure of the C-terminal domain of JUNV NP. This structure showed high similarity to the Lassa fever virus (LASV) NP C-terminal domain. However, both the structure and function of JUNV NP showed differences compared with LASV NP. This study extends our structural insight into the negative-sense ssRNA virus NPs.

The Use of Colorimetric Sensor Arrays to Discriminate between Pathogenic Bacteria

A colorimetric sensor array is a high-dimensional chemical sensor that is cheap, compact, disposable, robust, and easy to operate, making it a good candidate technology to detect pathogenic bacteria, especially potential bioterrorism agents like Yersinia pestis and Bacillus anthracis which feature on the Center for Disease Control and Prevention’s list of potential biothreats. Here, a colorimetric sensor array was used to continuously monitor the volatile metabolites released by bacteria in solid media culture in an Advisory Committee on Dangerous Pathogen Containment Level 3 laboratory. At inoculum concentrations as low as 8 colony-forming units per plate, 4 different bacterial species were identified with 100% accuracy using logistic regression to classify the kinetic profile of sensor responses to culture headspace gas. The sensor array was able to further discriminate between different strains of the same species, including 5 strains of Yersinia pestis and Bacillus anthracis. These preliminary results suggest that disposable colorimetric sensor arrays can be an effective, low-cost tool to identify pathogenic bacteria.

Brucella as a Potential Agent of Bioterrorism

Perception on bioterrorism has changed after the deliberate release of anthrax by the postal system in the United States of America in 2001. Potential bioterrorism agents have been reclassified based on their dissemination, expected rate of mortality, availability, stability, and ability to lead a public panic. Brucella species can be easily cultured from infected animals and human materials. Also, it can be transferred, stored and disseminated easily. An intentional contamination of food with Brucella species could pose a threat with low mortality rate. Brucella spp. is highly infectious through aerosol route, making it an attractive pathogen to be used as a potential agent for biological warfare purposes. Recently, many studies have been concentrated on appropriate sampling of Brucella spp. from environment including finding ways for its early detection and development of new decontamination procedures such as new drugs and vaccines. There are many ongoing vaccine development studies; some of which recently received patents for detection and therapy of Brucella spp. However, there is still no available vaccine for humans. In this paper, recent developments and recent patents on brucellosis are reviewed and discussed. Keywords: Biotechnology, bioterrorism, brucellosis, decontamination, diagnosis, patents, Salmonella typhimurium, polymorphonuclear leukocytes, bioterrorism, bioweapon

Inactivation of Bacterial Bioterrorism Agents in Water: A Summary of Seven USEPA and CDC Research Studies

Past use of weaponized Bacillus anthracis spores has prompted increased interest in studying the inactivation of potential bacterial bioterrorism agents in drinking water. Conditions for chemically inactivating many regulated waterborne disease‐causing species are well known, but there are only limited data available on inactivating microorganisms that could potentially be used as biological weapons. Information on the likelihood of such agents surviving in drinking water containing disinfectants is needed to ensure that end users are sufficiently protected.

Comparing various epithelial cell lines as in vitro models for Francisella tularensis non‐phagocytic infections

The potential bioterrorism agent Francisella tularensis subspecies tularensis (F. tularensis) causes the disease tularemia; if untreated the disease can result in up to 60% mortality. As an intracellular bacterium, F. tularensis invades and occupies non‐phagocytic epithelial cells of its host – a process critical to the development of disease. To study epithelial infections, many cell culture models have been developed; yet choosing a suitable model from the literature is challenging due to varied infection parameters and inaccurate assessments of intracellular bacterial loads. In our lab, we have developed an epithelial cell model using a murine surrogate of F. tularensis Francisella tularensis subspecies novicida (F. novicida) and the cultured hepatocyte cell line BNL CL.2. Since our model emulates the murine model of tularemia, we hypothesize BNL CL.2 cells will be more susceptible to F. novicida infection compared to other models currently present in the literature. We assessed 8 different models with the same parameters using antibiotic survival assays and an immunofluorescence strategy to label intracellular vs extracellular bacteria. We found that while COS‐7, CMT‐93, and HEK‐293 cell lines may be suitable for studying specific aspects of infection such as invasion or replication; overall, BNL CL.2 cells were the most appropriate cell line to study F. tularensis epithelial infections in vitro.Grant Funding Source: NSERC and CIHR

Tempering the risk: Rift Valley fever and bioterrorism

Rift Valley fever virus (RVFV) is an arthropod-borne pathogen that primarily affects ruminants in eastern and sub-Saharan Africa first described following an outbreak on a farm in Kenya in 1931. Periodic outbreaks of RVFV since that time have resulted in significant losses to the African livestock industry as well as large numbers of infections in some of the most impoverished human populations. In one 2006/2007 outbreak across Kenya, Somalia and Tanzania alone, there were an estimated 145 000 human cases, and the ban imposed on imports after the 1997/1998 outbreak in Somalia led to a collapse of the vital livestock industry. Previously ignored, it is only in the past decade that the international community has started to take an increased interest in the disease. This followed the recognition of its potential to spread beyond the confines of the African continent after a large outbreak in Saudi Arabia in 2000. There has also been acknowledgement of the widespread presence of arthropod vectors capable of transmitting RVFV in many nonendemic regions of the world. This has led to a range of increased efforts in better understanding the virus and developing tools to predict outbreaks, combat the disease and limit its spread (Anyamba et al. 2010; Pepin et al. 2010). However, a more longstanding, parallel interest in the disease has also developed internationally; one centred around the biosecurity implications of the virus. The United States for instance, included RVFV as a candidate pathogen in its offensive biological weapons programme; a programme officially closed in 1969 (Borio et al. 2002). In more recent times, the classification of the virus as a potential bioterrorism agent has spurred investment and activity, particularly in the area of vaccine development and diagnostics (Borio et al. 2002; Sidwell & Smee 2003). While biosecurity interest has contributed to this increased funding over the past few decades, most notably from military sources such as the US Army Medical Research Institute of Infectious Diseases (USAMRIID), it may have acted as an impediment to international collaboration, with research being restricted to fewer, more expensive laboratories. After the signing of the US Patriot Act of 2002 and the classification of RVFV as a ‘select agent’, visiting experts and scientific collaborators are, for instance, now required to provide fingerprints, signed affidavits and be registered with intelligence services before working with the pathogen. Such measures are likely to act as a disincentive amongst scientists wanting to study the virus and could ultimately serve to drive experts to dedicate their efforts to other pathogens with fewer working restrictions (Animal & Plant Health Inspection Service, Centre for Disease Control & Prevention 2005, 2011). These restrictions have also been applied in parts of Europe as well, with national legislation such as the Anti-terrorism, Crime and Security Act 2001 of the UK, which also includes RVFV as a potential bioterrorism agent. For comparison and contrast, we include the current lists of biological agents and toxins around which bioterrorism legislation has been passed in the US and UK in Table 1. Focus on US policy internationally stems from its greater leadership role within the global community and the influence and impact its decisions have on people and institutions far beyond its borders. With large numbers of laboratories worldwide affected by US policy either directly through funding or indirectly as a result of political influence, restrictions have also resulted in the transfer between laboratories of RVFV samples for culture also becoming constrained and increasingly expensive. This undermines efforts to lower the industrial production costs of existing vaccines and of commercial kits for virus neutralisation and ELISA diagnostic tests (currently the prescribed tests for international livestock trade) (World Organization for Animal Health 2008). Expertise and experience thus tends to remain confined to a limited number of laboratories and companies by and large located in high income countries where investigation of the disease is neither a significant economic or health priority nor considered sufficiently profitable for drug companies. The resulting monopolies on expert technical knowledge and skills not only delays progress in developing new therapies

Brucella as a Potential Agent of Bioterrorism

Perception on bioterrorism has changed after the deliberate release of anthrax by the postal system in the United States of America in 2001. Potential bioterrorism agents have been reclassified based on their dissemination, expected rate of mortality, availability, stability, and ability to lead a public panic. Brucella species can be easily cultured from infected animals and human materials. Also, it can be transferred, stored and disseminated easily. An intentional contamination of food with Brucella species could pose a threat with low mortality rate. Brucella spp. is highly infectious through aerosol route, making it an attractive pathogen to be used as a potential agent for biological warfare purposes. Recently, many studies have been concentrated on appropriate sampling of Brucella spp. from environment including finding ways for its early detection and development of new decontamination procedures such as new drugs and vaccines. There are many ongoing vaccine development studies; some of which recently received patents for detection and therapy of Brucella spp. However, there is still no available vaccine for humans. In this paper, recent developments and recent patents on brucellosis are reviewed and discussed.

Rift Valley Fever and a New Paradigm of Research and Development for Zoonotic Disease Control

Although Rift Valley fever is a disease that, through its wider societal effects, disproportionately affects vulnerable communities with poor resilience to economic and environmental challenge, Rift Valley fever virus has since its discovery in 1931 been neglected by major global donors and disease control programs. We describe recent outbreaks affecting humans and animals and discuss the serious socioeconomic effects on the communities affected and the slow pace of development of new vaccines. We also discuss the mixed global response, which has largely been fueled by the classification of the virus as a potential bioterrorism agent and its potential to migrate beyond its traditional eastern African boundaries. We argue for a refocus of strategy with increased global collaboration and a greater sense of urgency and investment that focuses on an equity-based approach in which funding and research are prioritized by need, inspired by principles of equity and social justice.

In Vitro Activity of Tigecycline Against Francisella tularensis Subsp. holarctica in Comparison with Doxycycline, Ciprofloxacin and Aminoglycosides

Francisella tularensis is the etiological agent of tularemia which is a zoonosis of the northern hemisphere. For decades, streptomycin was considered the drug of choice, despite possible side effects, and vestibular toxicity in particular. Alternatives are tetracylines and chloramphenicol which are bacteriostatic agents that are associated with a considerable risk of relapse. The aim of the present study was to assess the in vitro susceptibility of F.tularensis subsp. holarctica biovar II strains to tigecycline, a member of a new class of glycylcyclines. Fourteen F.tularensis strains isolated from patients in Central Anatolia region of Turkey were examined. Minimum inhibitory concentration (MIC) values of tigecycline, doxycycline, streptomycin, gentamicin, and ciprofloxacin were determined using the E-test method on glucose-cysteine blood agar plates. Interpretation of results was made according to CLSI clinical breakpoints. All strains were susceptible to the antibiotics traditionally used to treat tularemia. Tigecycline showed good in vitro activity to all the isolates (MIC range: 0.094-0.38 mg/L). In this study, tigecycline was more active than doxycycline against F.tularensis subsp. holarctica strains, according to MIC50 (0.19 mg/L) and MIC90 (0.25 mg/L) values. Doxycycline (MIC90: 0.38 mg/L) showed good in vitro activity against all the isolates and MIC values interpreted according to the CLSI criteria for potential bioterrorism agents, have shown ranges below the breakpoint for sensitivity determination (S ≤ 4 mg/L). Ciprofloxacin had the lowest MIC50 and MIC90 values. In case the other antibiotics can not be used or intravenous therapy is required, tigecycline may be an important therapeutic alternative agent. However, confinement of tigecycline in the treatment of multi-drug resistant bacterial infections, its parenteral way of administration and overall cost were considered as the major limitations of tigecycline in tularemia treatment.

Query Fever Endocarditis

Acute query (Q) fever caused by Coxiella burnetii infection can present with various signs and symptoms such as flulike illness, pneumonia, or hepatitis, creating a diagnostic challenge. Patients with previous valve surgery are at a higher risk of developing chronic Q fever endocarditis, several months or years following initial infection despite treatment. Q fever was primarily seen in patients who have contact with farm animals. It is being seen in military or contracted personnel returning from Middle East deployment or in close proximity to a farm. The incidence has increased nearly seven times because it became a nationally reported disease in 1999. The Centers for Disease Control and Prevention (CDC) lists C. burnetii as a potential bioterrorism agent caused by its inhalation transmission and bacterial resistance to heat and chemicals. Currently, vaccination is not available in the United States. In Australia, vaccination has resulted in a decrease in prevalence.

Current status of vaccine development for tularemia preparedness

Tularemia is a high-risk infectious disease caused by Gram-negative bacterium Francisella tularensis. Due to its high fatality at very low colony-forming units (less than 10), F. tularensis is considered as a powerful potential bioterrorism agent. Vaccine could be the most efficient way to prevent the citizen from infection of F. tularensis when the bioterrorism happens, but officially approved vaccine with both efficacy and safety is not developed yet. Research for the development of tularemia vaccine has been focusing on the live attenuated vaccine strain (LVS) for long history, still there are no LVS confirmed for the safety which should be an essential factor for general vaccination program. Furthermore the LVS did not show protection efficacy against high-risk subspecies tularensis (type A) as high as the level against subspecies holarctica (type B) in human. Though the subunit or recombinant vaccine candidates have been considered for better safety, any results did not show better prevention efficacy than the LVS candidate against F. tularensis infection. Currently there are some more trials to develop vaccine using mutant strains or nonpathogenic F. novicida strain, but it did not reveal effective candidates overwhelming the LVS either. Difference in the protection efficacy of LVS against type A strain in human and the low level protection of many subunit or recombinant vaccine candidates lead the scientists to consider the live vaccine development using type A strain could be ultimate answer for the tularemia vaccine development.