Developmental Milestones/Developments to Date:
Current Assessment/State of the Field:
Elizabeth K. Leffel, Douglas S. Reed, “Marburg and Ebola Viruses as Aerosol Threats,” Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science, 2004;2(3):186-191.
- “Although transmission during naturally occurring outbreaks is believed to occur from close personal contact with blood or other body fluids, or the failure to practice proper medical hygiene as relates to blood-borne pathogens, in the past 10 years several publications have indicated that filoviruses possess a number of properties that would make them suitable as biological weapons.”
- “While the possibility of aerosol exposure cannot be ruled out in some cases, it is clear that direct contact is the primary means of transmission.”
- “The high mortality rates, coupled with the knowledge that these viruses possess properties considered desirable in biological weapons, explains the considerable concern about their potential use.”
- “Without data there can be little understanding of the level of threat that filoviruses present. For example, it is not clear from the available data whether filoviruses would cause large-scale infections and deaths if disseminated by aerosol over a city without extensive preparation or modification (“weaponization”).”
Singer, Peter, A., Daar, Abdallah, S.,”How biodevelopment can enhance biosecurity: Without global biotech research on disease, agriculture, and the environment, efforts to secure the world from biothreats are bound to falter—and vice versa,” Bulletin of the Atomic Scientists | WWW.THEBULLETIN.ORG M a r c h / A p r i l 2 0 0 9. p. 23.
Jiao, Guan-Sheng, et. al, “Antidotes to anthrax lethal factor intoxication. Part 1: Discovery of potent lethal factor inhibitors with in vivo efficacy,” PanThera Biopharma, LLC, Aiea, HI & Laboratory of Bacterial Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, Bioorganic & Medicinal Chemistry Letters, Accepted 12 August 2010.
- “Three forms of the disease anthrax caused by Bacillus anthracis are characterized by the route of exposure. Infection of an open wound leads to cutaneous anthrax, and ingestion of contaminated food causes gastrointestinal anthrax.”
- “Sub-nanomolar small molecule inhibitors of anthrax lethal factor have been identified using SAR and Merck L915 (4) as a model compound. One of these compounds (16) provided 100% protection in a rat lethal toxin model of anthrax disease.”
- “Given the effec- tiveness of B. anthracis as a weapon of bioterrorism,5 the major role LF plays in the pathogenesis of anthrax, and validation of LF as a target for small molecule drug intervention,6 we began our search for an antidote to LF intoxication.”
- “The resulting SAR led to the identification of the 3,5-di- methyl-4-fluoroaniline analog as the most potent inhibitor pos- sessing sub-micromolar inhibitory activity.”
- “One compound, the aniline 16, was capable of providing 100% protec- tion at this dose. Repeating this experiment with lower doses of 16 indicated that this compound was fully protective at both 5.0 and 2.5 mg/kg, although at the lowest dose the animals became ill approximately 3 h after treatment with LT but appeared fully recovered by 24 h post exposure (data not shown).”
- “In summary, we have identified sub-nanomolar inhibitors of anthrax lethal factor with potent in vivo efficacy.”
Thomas, Richard, et. al., “Influence of particle size on the pathology and efficacy of vaccination in a murine model of inhalational anthrax,” Journal of Medical Microbiology(2010), 59, 1415–1427, August 19, 2010.
- “Deposition of Bacillus anthracis endospores within either the lungs or nasal passages of A/J mice after aerosol exposure was influenced by different particle sized aerosols and resulted in different infection kinetics.”
- “Particle size-related deposition of B. anthracis endospores has previously been shown to increase MLD and mean time-to-death (MTD) in the guinea pig model (Druett et al., 1953). A murine model has not been reported for the investigation of particle size-dependent effects of inhalational anthrax and the subsequent assessment of therapeutics.”
- “Inhalation of greater numbers of endospores within 12 mm particles is required to induce infection.”
- “Immediately after aerosol deposition (0 h), endospores were primarily localized to either the lungs or nasal passages depending on the size of the inhaled particles (Fig. 2).”
- “Deposition in the nasal passages was significantly higher with the 12 mm particle aerosol and bacterial counts remained higher than those associated with the infection caused by the inhalation of 1 mm particle aerosols over the 96 h time-course.”
- “A subunit vaccine based on the rPA constituent of anthrax toxin has been developed. The rPA vaccine is efficacious against anthrax caused by the inhalation of endospores within a small-particle aerosol in murine and non-human primate models (Flick-Smith et al., 2005; Williamson et al., 2005).”
- “This study represents the first investigation of the effect of therapeutic intervention on respiratory anthrax infection caused by deposition of endospores within the URT.”
Brady, Rebecca, et al., “Analysis of Antibody Responses to Protective Antigen-Based Anthrax Vaccines through Use of Competitive Assays,” Clinical and Vaccine Immunology, vol. 17, no. 9, p. 1390-1397, September 2010.
- “In this study, we examined the antibody response in humans as well as nonhuman primates and rabbits, animal species that will be used to generate efficacy data to support the approval of new anthrax vaccines.”
- “We found that PA-based vaccines elicited IgC antibodies to each of the four PA domains in all three species.”
- “These findings provide information that will be useful when linking animal protection data to humans via an antibody bridge to establish efficacy of new anthrax vaccines.”
Greenberg, David, et. al., “Identifying experimental surrogates for Bacillus anthracis spores: a review,” Investigative Genetics 2010, 1:4, September 1, 2010.
- “The risks associated with surrogate use are of critical concern. Surrogates are typically used to replace a pathogen that, if used, would present a poten- tial threat to public health. B. anthracis is classified as a BSL-3 organism and work must be conducted under highly contained conditions not suitable for fate and transport experiments. Ideally, an attenuated strain of B. anthracis would be a good surrogate because it should behave similarly to the pathogenic strains and pose little risk.”
- “The results of these stu- dies indicate that B. anthracis is most closely related to B. cereus, B. thuringiensis and B. mycoides, which are grouped together as the B. cereus group (Figure 1). In contrast, B. subtilis, B. atrophaeus, B. megaterium, and Geobacillus are more distant relatives of B. anthracis. As their chromosomal genomes are very similar, some authors have suggested that B. cereus, B. thuringiensis and B. anthracis are actually a single species separated only by different plasmid composition .”
- “The exosporium can be highly vari- able, both among B. anthracis relatives [155-157] and within B. anthracis, as shown by differences between the Vollum and Sterne strains .”
- “Interestingly, dry spore density is simi- lar among the surrogates listed in Table 1, despite volume differences . Thus, the right choice of sur- rogate appears to depend on the dispersion medium under consideration.”
- “Our goal was to examine the various possible surrogates for B. anthracis, review the criteria for selecting an appropriate surrogate, compare the potential surrogates by these criteria and, ultimately, choose the most appro- priate surrogate for our purposes.”
- “After examination of the first criteria, safety of use, we are left with B. atro- phaeus, B. thuringiensis, B. megaterium and B. subtilis as potential surrogates. However, after further examina- tion of genetic relatedness and the consequential mor- phological differences, B. thuringiensis emerges as the most appropriate candidate for a B. anthracis surrogate.”
- “We recommend B. thuringiensis as the most appro- priate surrogate based upon existing empirical data. As a result of the phenotypic similarity within the B. cereus group it will be important to utilize a B. thurin- giensis strain that has a publically available genome sequence, such as B. thuringiensis serovar israelensis (ATCC 35646; GenBank No. AAJM01000000). This will allow for strain-specific markers to be identified [217,218] which can be used as the basis for assays that can readily detect this strain and distinguish it from con-specifics as well as near neighbour species.”
Pharmaceutical Research and Manufacturers of America, “Medicines in Development for Infectious Diseases,” Report, Biopharmaceutical Research Continues Against Infectious Diseases with 395 Medicines and Vaccines in Testing, www.pharma.org, September 10, 2010.
- “America’s biopharmaceutical research companies are developing 395 medicines and vaccines to combat the many threats posed by infectious diseases. Each of these medicines in development is either in clinical trials or under review by the Food and Drug Administration.”
- “Among the medicines now being tested are 88 antibiotics/antibacterials for treating bacterial infections such as pneumonia and tuberculosis; 96 antivirals for treating such viruses as hepatitis, herpes and influenza; and 145 vaccines to prevent or treat diseases such as staph infections and pneumococcal infections. Not included in this report are medicines in development for HIV infection.”
- “Two combined monoclonal antibodies that bind to, neutralize, and destroy toxins caused by Escherichia coli infections.”
- “A medicine for the most common and difficult-to-treat form of hepatitis C that inhibits the enzyme essential for viral replication.”
- “An anti-malarial drug that has shown activity against Plasmodium falciparum malaria that is resistant to current treatments.”
- “A potential new class of antibiotics to treat methicillin-resistant Staphylococcus aureus (MRSA).”
- “A novel treatment that works by blocking the ability of the smallpox virus to spread to other cells, thus preventing it from causing disease.”
- “‘Included are several developments for anthax vaccines.'”
Julie Steenhuysen, “U.S. Invests in Drug to Protect Against Radiation” 17 September 2010, Reuters/Yahoo!News. http://news.yahoo.com/s/nm/20100917/hl_nm/us_radiation_drug_clevelandbiolabs Last checked 24 September 2010.
- “Tiny Biotech Cleveland BioLabs Inc has won a $45 million contract from the Department of Defense to conduct clinical trials of a drug to prevent cell damage in the event of a nuclear attack.”
- “The drug works by interfering with a process of programmed cell death called apoptosis — basically a form of cell suicide. ‘This helps the body rid itself of damaged cells’, Fonstein said, ‘interfering with this process appears to strengthen the body’s ability to recover from radiation exposure.’”
- “The compound is made from a salmonella protein that naturally makes cells resistant to cell suicide.”
- “’This is the first product that is close to completion of the scientific studies for protecting populations that might be exposed to (radiation fallout),’ Rear Admiral Craig Vanderwagen, a former official at the U.S. Department of Health and Human Services who has advised the company.”
- “The drug is intended to protect the public in the event of a dirty bomb or a Chernobyl-like accident.”
- “Fonstein said the drug, known as CBLB502, could be approved for use in humans by mid-2012.”
Editors, ”U.S. Awards Contract For Radiation Treatment Work’‘. GSN. Sept. 7, 2010. http://gsn.nti.org/gsn/nw_20100907_7386.php
- “Funding from the department’s Biomedical Advanced Research and Development Authority is to be used to develop a medical treatment which uses myeloid progenitor cells, which can develop into any type of blood cell. The medication, CLT-008, is intended to foster the growth of and assist the body’s progenitor cells, according to an agency release.”
- “The Biomedical Advanced Research and Development Authority also approved millions of dollars in new funding for additional work on a treatment for plague and tularemia — two disease agents classified as potential bioterrorism threats, according to a press release.”
- “The antibiotic could be used against tularemia and plague infections as well as more common illnesses such as pneumonia that are growing increasingly resistant to antibiotics.”
- “”This new antibiotic is part of our push against antibiotic resistance for certain bacterial infections, and at the same time could provide a new treatment for plague and tularemia biothreats””
Matishak, Martin, “Biodefense System Overhaul Was Necessary, HHS Secretary Says” Global Security Newswire, 27 September 2010, http://gsn.nti.org/gsn/nw_20100927_8250.php Last Checked 28 September 2010
- “A planned $1.9 billion revamp of the nation’s medical countermeasure enterprise was overdue as government scientists were using decades old technology to confront new and emerging biological threats.”
- “Countermeasures are typically defined as drugs and vaccines that ward against chemical, biological, radiological and nuclear agents and emerging infectious diseases.”
- “Successful countermeasure development also has proven difficult because the private sector saw little financial benefit in producing biodefense medicines and vaccines for the government, according to Sebelius. The development process can be costly and there is little if any market for such products outside the public sector.”
- “Of the initial $1.9 billion investment, $822 million would be spent on initiatives designed to decrease the amount of time the government needed to make pandemic flu vaccines, while the Food and Drug Administration would receive roughly $170 to enhance its regulatory efforts.”
- “Another $678 million would go toward setting up one or more nonprofit organizations that could provide financial support to small firms working on new treatments, as well as provide the companies with new production systems and manufacturing of vaccines for times of high demand.”
- “Sebelius said the ultimate goal of the revamp was a ‘nimble, flexible capacity to produce medical countermeasures rapidly in the face of any attack or threat’ including a naturally occurring, yet previously unrecognized, infectious disease.”
Purlain, Ted, “Experts discover how anthrax toxins disrupt cell mechanisms,” bioprepwatch, http://www.bioprepwatch.com/news/217493-experts-discover-how-anthrax-toxins-disrupt-cell-mechanisms, Last checked October 20, 2010. October 14, 2010.
- “Two groups of anthrax experts at the University of California San Diego recently discovered how two separate toxins from anthrax bacteria function to disrupt critical cell mechanisms during infection.”
- “One group examined anthrax in mice and human cells, while the other looked at how the deadly bioterrorism agent functioned in fruit flies. Together, they showed that the toxins worked in conjunction to stop the final step in a process that allows cells to communicate and adhere to one another through the transportation of certain molecules.”
- “The UCSD researchers’ report, published in the October 14 issue of the journal Nature, concludes that by interfering with the sites of cell to cell communication, anthrax stops the flow of molecular components critical to cell functioning, leading to the failure of critical blood vessels. During the final stages of infection, this is what usually kills victims.”
- “The information the two teams found during their study is becoming increasingly important as scientist try to find better ways to protect large numbers of people from bioterrorist threats.”
Guichard, Annabell, et.al., “Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst,” Nature, Magazine, Volume 467, pg. 854-859, October 14, 2010.
- “Whereas host targets of LF (mitogen-activated protein-kinase kinases) and EF (cAMP-dependent processes)3 have been impli- cated in the initial phase of anthrax1,2, less is understood about toxin action during the final stage of infection. Here we use Drosophila melanogaster to identify the Rab11/Sec15 exocyst, which acts at the last step of endocytic recycling, as a novel target of both EF and LF.”
- “B. anthracis, the aetiological agent of anthrax, secretes three factors that are required for systemic virulence1–3: the toxic enzymatic moieties LF and EF, and protective antigen (PA), which promotes entry of LF and EF into host cells.”
- “It has been speculated that additional host targets may con- tribute to mediating the lethal effects of anthrax toxins7 and inter- actions between the two toxins remain poorly understood.”
- “In summary, LF and EF toxins interact synergistically in Drosophila to block Rab11/Sec15-dependent endocytic recycling, resulting in reduced Notch signalling and cadherin-dependent adhesion at the adherens junction, and these toxins produce very similar effects in mammalian cells.”
- “The reduction in Dl/Notch levels in response to anthrax toxin treatment requires further analysis with respect to potential consequences.”
Wu, Gaobing, et. al., “A Chimeric Protein that Functions as both an Anthrax Dual-Target Antitoxin and a Trivalent Vaccine,” Journal, Antimicrobial Agents and Chemotherapy, Volume 54, No. 1, p. 4750-4757, November 2010, American Society for Microbiology.
- “Effective measures for the prophylaxis and treatment of anthrax are still required for counteracting the threat posed by inhalation anthrax.”
- “In this study, we first demonstrated that the chimeric protein LFn-PA, created by fusing the protective antigen binding domain of lethal factor (LFn) to PA, retained the functions of the respective molecules.”
- “In animal models, LFn-DPA exhibited strong potency in rescuing mice from lethal challenge with LeTx. We also evaluated the immunogenicity and immunoprotective efficacy of LFn-DPA as an anthrax vaccine candidate.”
- “Mice immunized with LFn-DPA tolerated a LeTx challenge that was 5 times its 50% lethal does. Thus, LFn-DPA represents a highly effective trivalent vaccine candidate for both pre-exposure and post-exposure vaccination.”
- “Overall, we have developed a novel and dually functional reagent for the prophylaxis and treatment of anthrax.”
Feals, Jennifer, “NH Air National Guard holds training drill for anthrax exposure,” Seacoastonline.com, NEWS, November 07, 2010.
- “Annual flu shots helped approximately 1,000 Air National Guard members prepare for a large-scale outbreak Saturday. During the four-hour disaster drill simulated to represent the inhalation of anthrax, Guard members practiced disaster response and the role the group would play as a first responder.”
- “A Point of Dispensing (POD) operations unit was set up Saturday on the grounds of the N.H. Air National Guard’s Pease base as members were processed through what would be a mass vaccination dispensing scenario, during which approximately 800 members actually received yearly flu vaccinations.”
- “The exercise, involving the N.H. National Guard and eight of the state’s 15 Public Health Regions, was designed to test the state’s Strategic National Stockpile, Cities Readiness Initiative, Multi-Agency Coordinating Entity and Point of Dispensing plans. A similar response plan could be applied to a national disaster or terrorist attack.”
- “During an actual emergency, medication, supplies and equipment would be shipped from the Strategic National Stockpile to local responders and hospitals. The stockpile was last used during Hurricane Katrina and portions of the nation during the H1N1 outbreak. Three Point of Dispensing Units would be established throughout the state, in the Seacoast as well as northern and central New Hampshire.”