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Anthrax vaccines

 
Intelligence Encyclopedia: Anthrax Vaccine
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Anthrax is an infection that is caused by the bacterium Bacillus anthracis.

Several different types of anthrax infection can be caused by the bacterium. Entry of bacteria through a skin wound can produce a skin infection known as cutaneous anthrax. Microorganisms can also contaminate food or water. Ingestion of the contaminated food or water produces gastrointestinal anthrax. The most serious type of anthrax results from the inhalation of the spore form of the bacterium. Inhalation anthrax has a high mortality rate.

In the 1990s, United States military personnel in the Persian Gulf region faced the possibility of retaliatory strikes using biological weapons, in particular anthrax. Domestically, the use of Bacillus anthracis spores by terrorists is a reality. Although not directly related by evidence to the September 11, 2001, terrorist attacks on the World Trade Center and Pentagon in the United States, letters containing powdered anthrax bacteria and spores were sent to a number of politicians, media personalities, and U.S. citizens. Even more ominously, the terrorists responsible for the September 11 attacks had attempted to procure a small crop dusting aircraft. Such an aircraft could potentially disperse several hundred kilograms of anthrax spores upwind of a major urban center in only a few hours. One scenario developed by scientists for Washington, D.C. indicated that up to three million people could be sickened or killed by such an attack.

For some years, military personnel and others at risk for anthrax exposure (i.e., researchers and those handling animals) have received an anthrax vaccine. For example, U.S. military personnel were vaccinated in 1990, during the Gulf War, and again prior to another response in that region in 1998.

The increasing risk and incidence of anthrax exposure, however, have made the development of different and safer anthrax vaccines a priority. The use of anthrax against civilians, and the ominous scenarios of anthrax spores released in the ventilation systems of office buildings and over large urban centers, have created the possibility that millions of people would potentially require vaccination. As well, large stockpiles of anthrax vaccine (as well as antibiotics) would be required, in anticipation of future outbreaks.

Current anthrax vaccine. The anthrax vaccine now in use dates back to the time of Louis Pasteur, in the mid-nineteenth century. Pasteur noted that the injection of animals with an attenuated type of Bacillus anthracis protected the animals from contracting anthrax. An attenuated strain of bacteria is one that can be capable of growth, but which does not cause disease. The body's immune system will react to the bacteria, and produce antibodies that will protect the animal or person from future exposure to the disease-causing bacteria. A modification of this attenuated vaccine developed in the late 1930s still serves as the anthrax vaccine given to animals.

In the late nineteenth century, the use of live bacteria as vaccines was still too dangerous for humans. In the early years of the twentieth century, researchers began exploring the use of components of the anthrax bacterium as a protective measure. In 1954, a product was developed that consisted of soluble material called protective antigen, which is released by Bacillus anthracis, and which can be precipitated out of solution—along with two other cell components called the lethal factor and the edema factor—by the use of aluminum potassium sulfate (alum). Filtering the suspension captures the antigenic compounds.

By 1960, the selection of a strain of Bacillus anthracis that produced more of the protective antigen, the use of growth media that was free of protein (that could also stimulate an immune reaction), and the use of aluminum hydroxide instead of alum had produced a superior vaccine. The improved product, anthrax vaccine adsorbed (AVA), was approved for use in the United States in 1965. AVA remains the only licensed vaccine in the United States as of early 2003.

Protective antigen, lethal factor, and edema factor. The protective antigen is a protein that can insert into the membrane of a host cell to create a hole, or pore, through the membrane. The pore then functions as a portal to allow the other two components to get inside of the host cell.

The lethal factor is a type of enzyme classified as a zinc protease. The enzyme attacks and breaks host proteins into smaller and nonfunctional pieces. Destroying host cell proteins is lethal to the host cell, hence the factor's name.

Edema factor is a toxin. The destruction of the host cells allows this toxin to enter the bloodstream, where it can kill cells of the immune system. Disabling the host's immune response allows the bacteria and the toxin to spread throughout the body.

Side effects of the anthrax vaccine. Like some other vaccines, AVA can cause side effects, which can, in rare instances, be life threatening or fatal. Data regarding adverse events are available from the Vaccine Event Reporting System (a U.S. vaccine safety surveillance program that is under the direction of the Food and Drug Administration and the Centers for Disease Control and Prevention). From January 1, 1990 through August 31, 2000, 1,859,000 doses of anthrax vaccine were administered in the United States. The number of adverse events was 1,544 (e.g. sensitivity at injection site, headache, muscle ache) with 76 of these being serious (e.g., heart failure, blood infection). Other than reaction at the site of injection, it is still not clear whether the other maladies were directly due to the vaccine. Nonetheless, the number of adverse reactions were small.

Echoing this data, a report released in March 2002 by the U.S. National Academy of Sciences Institute of Medicine concluded that AVA is "acceptably safe." However, the report noted the lack of data on the long-term effects of the vaccine.

Studies conducted by the Department of Defense on vaccinated military personnel found that most adverse events were minor, were localized to the site of injection, and cleared up within a few days.

The involvement of anthrax vaccine to the development of a multi-symptom debilitating syndrome reported in military personnel deployed in the Persian Gulf conflicts ("Gulf War Syndrome") was investigated by the Centers for Disease Control and Prevention. No scientific evidence of an association was found. However, studies conducted on Canadian and British soldiers stationed in the Gulf and in Bosnia (where anthrax deployment was also a threat) were not as conclusive.

Limitations of the anthrax vaccine. While the risks posed by AVA may not be pronounced, the vaccine is problematic from the standpoints of supply and quality of the product.

In addition to aluminum, the vaccine contains benzethonium chloride as a preservative and formaldehyde to keep the vaccine mixture stable upon storage. Despite regulatory examinations that have confirmed the safety of the vaccine, there continues to be debate as to the possible long-term harm from the presence of these chemicals.

Another problem concerns the frequency of vaccination that is required to establish immunity. Primary vaccination requires three injections at 0, 2, and 4 weeks, followed by three booster injections at 6, 12, and 18 months. To maintain the immunity, annual injections are recommended.

Such a frequent regimen of injections is inconvenient and requires almost two years to establish peak protection. The vaccine is not designed to confer rapid immunity.

The nature of the vaccine's preparation—collection of material extruded by the bacteria—makes the vaccine crude in terms of its exact composition and proportion of the various components. This unpredictability, and the scarcity of the vaccine have limited the wide-spread availability of AVA.

The vaccine is currently manufactured at a single facility in the U.S., and only in sufficient quantity for use by those at risk of infection, such as combat personnel and researchers.

Further Reading

Periodicals

Advisory Committee on Immunization Practices. "Recommendations of the Advisory Committee on Immunization Practices: Use of Anthrax Vaccine in the United States." Morbidity and Mortality Weekly Report no. 49(2000): 1–20.

Bradley, K. A., J. Mogridge, M. Mourey, et al. "Identification of the Cellular Receptor for Anthrax Toxin." Nature no. 414 (2001): 225–229.

Friedlander, A. M. "Tackling Anthrax." Nature no. 414 (2001): 160–161.

Joellenbeck, L. M., L. L. Zwanziger, J. S. Durch, et al. The Anthrax Vaccine: Is It Safe? Does It Work? Washington, DC: National Academies Press, 2002.

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Wikipedia: Anthrax vaccines
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Home > Library > Miscellaneous > Wikipedia
Anthrax vaccines
Vaccine description
Target disease Anthrax
Type Protein subunit
Identifiers
CAS number  ?
ATC code J07AC01
PubChem  ?
Therapeutic considerations
Pregnancy cat.

?
Legal status
Routes  ?

Anthrax vaccines are vaccines against the infectious disease anthrax. Anthrax is caused by the spore-forming bacterium Bacillus anthracis, that most commonly occurs in wild and domestic mammals.[1][2] Anthrax also occurs in humans when they are exposed to infected animals, hides, or tissue from infected animals, or when they are directly exposed to B. anthracis. Depending on the route of infection, anthrax disease can occur in three forms: cutaneous, inhalational, and rarely, gastrointestinal.

Contents

History

Louis Pasteur, Jean Joseph Henri Toussaint an William S. Greenfield independently demonstrated the first anthrax vaccines in 1881, only a few years after Robert Koch had proven Bacillus anthracis the cause of the disease (1877). The Pasteur and Greenfield vaccines were based on live-attenuated cultures of Bacillus anthracis and effectively protected livestock from the disease. Since then, human or animal vaccines have been based on live-attenuated strains, anthrax spores, or cell-free vaccines prepared from bacterial supernatants or protein subunits, usually adsorbed onto aluminum salts, such as aluminum hydroxide. Recently, novel plasmid DNA (pDNA) approaches have been proposed.[3][4]

Licensing and product in the USA

The only FDA-licensed human anthrax vaccine' in the United States, Anthrax Vaccine Adsorbed (AVA, trade name BioThrax), is produced by Emergent BioDefense Corporation, formerly known as BioPort Corporation in Lansing, Michigan. The parent company of Emergent BioDefense is Emergent BioSolutions of Rockville, Maryland. Both Emergent BioSolutions and Porton International Group, Ltd., Porton Down, UK, are controlled by Fuad El-Hibri.

The anthrax vaccine is produced from culture filtrates of an avirulent, nonencapsulated strain known as V770-NP1-R.[5] No living organisms are present in the vaccine.[5] In the U.S., the principal purchasers of the vaccine are the Department of Defense and Department of Health and Human Services. Ten million doses of the vaccine have been purchased for the U.S. Strategic National Stockpile.

The anthrax vaccine was originally licensed in 1970 by the U.S. National Institutes of Health (NIH) and in 1972 the U.S. Food and Drug Administration (FDA) took over responsibility for vaccine licensure and oversight. In 1997, the Clinton administration initiated the Anthrax Vaccine Immunization Program, under which active U.S. service personnel were to be immunized with the vaccine. Much controversy has surrounded the program since its inception. Since vaccination was mandatory, a perception developed that the anthrax vaccine was unsafe, causing sometimes serious side effects. Mandatory vaccinations were halted due to an injunction which was put into place on October 27, 2004. The injunction cast questions about numerous substantive challenges regarding the anthrax vaccine in footnote #10,[6] yet the procedural findings centered on FDA procedural issues, stating that additional public comment should have been sought before the FDA issued its Final Rule declaring the vaccine safe and effective in December 2003. The FDA's incomplete rulemaking from 1985 effectively rendered the anthrax vaccine program illegal. The basis was the never finalized FDA Proposed Rule. In that rulemaking the FDA published, but never finalized, a licensing rule for the anthrax vaccine in the Federal Register, which included an expert review panel's findings. Those findings included the fact that the "Anthrax vaccine efficacy against inhalation anthrax is not well documented," and that "No meaningful assessment of its value against inhalation anthrax is possible due to its low incidence," and that "The vaccine manufactured by the Michigan Department of Public Health has not been employed in a controlled field trial."[7] On December 15, 2005, the FDA re-issued a Final Rule & Order on the license status of the anthrax vaccine.[8]

After reviewing extensive scientific evidence, but failing to address a variety of substantive issues of safety and efficacy raised in the public comments, the FDA again determined that the vaccine is licensed for the prevention of anthrax, regardless of the route of exposure. On October 16, 2006, the Defense Department announced the reinstatement of mandatory anthrax vaccinations for more than 200,000 troops and defense contractors. Then another lawsuit was filed by the same attorneys as before, challenging the basis of the vaccine's license on scientific grounds. The vaccinations will be required for most military units and civilian contractors assigned to homeland bioterrorism defense or deployed in Iraq, Afghanistan or South Korea.[9]

Vaccination schedule

Vaccination with Emergent BioSolutions BioThrax AVA and BioThrax SQ for subcutaneous injections in the deltoid is given at 0, 2, and 4 weeks, with three vaccinations at 6, 12, and 18 months, followed by annual boosters.

As of December 2008, the new BioThrax IM for intramuscular injections in the deltoid was approved by the US FDA which changes the immunity initialization sequence from 6 to 5 shots given at 0 and 4 weeks and then at 6, 12, and 18 months, followed by annual boosters. This prolonged initialization sequence is required with annual booster shots, because the anthrax vaccine's primary ingredient, the Anthrax Protective Antigen, can impair the life-cycle of the human immune system's memory B-Cells and memory T-cells, through inducing the production of immunoglobulin G (IgG) which sequesters furin.

The loss of memory B-Cells leads to declining concentrations of IgG which can sequester APA, and therefore declining tolerance to the presence of anthrax bacteria. There is the potential that other memory B-Cell populations will be adversely affected as well.

Furin is the protein activator for pro-parathyroid hormone, transforming growth factor beta 1, von Willebrand factor, pro-albumin, pro-beta-secretase, membrane type-1 matrix metalloproteinase, gonadotropin, and nerve growth factor. Furin is also essential to maintain peripheral immune tolerance by creating memory T-cells and suppressor T-cells.[10]

Because IgG will cross the maternal fetoplacental blood-barrier, Furin-sequestering IgG can cause severe congenital birth defects during pregnancy.[11]

The approved US FDA package insert for Anthrax Vaccine Adsorbed contains the following notice:

Pregnant women should not be vaccinated against anthrax unless the potential benefits of vaccination have been determined to outweigh the potential risk to the fetus. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this product, the patient should be apprised of the potential hazard to the fetus.[12]

Contraindications

The approved US FDA] package insert for Anthrax Vaccine Adsorbed contains the following notice:

* Severe allergic reaction (e.g., anaphylaxis) after a previous dose of BioThrax&trade.

* Administer with caution to patients with a possible history of latex sensitivity because the vial stopper contains dry natural rubber and may cause allergic reactions.[12]

Adverse reactions

The approved US FDA package insert for Anthrax Vaccine Adsorbed contains the following notice:

The most common (>10%) local (injection-site) adverse reactions observed in clinical studies were tenderness, pain, erythema and arm motion limitation. The most common (>5%) systemic adverse reactions were muscle aches, fatigue and headache.

Serious allergic reactions, including anaphylactic shock, have been observed during post-marketing surveillance in individuals receiving BioThrax&trade.[12]

Drug interactions

The approved US FDA package insert for Anthrax Vaccine Adsorbed contains the following notice:

Immunosuppressive therapies may diminish the immune response to BioThrax.[12]

Adjuvant

The Anthrax Vaccine Adsorbed contains aluminium hydroxide as an adjuvant.[5] Each dose of the vaccine contains no more that 0.83 mg aluminum per 0.5 mL dose. This is near the allowed upper limit of 0.85 mg/dose.[13] The BioPort anthrax vaccine also contains 0.0025% benzethonium chloride as a preservative, and 0.0037% formaldehyde as a stabilizer.[5]

In 2007, tests with mice of the anthrax vaccine using aluminum hydroxide adjuvant were reported as resulting in adverse neuropathy symptoms.[14]

Controversy

The United States Centers for Disease Control (CDC) reported that from 1990 to 2000, more than 1,859,000 doses of anthrax vaccine were distributed in the United States.[15] During that decade, 1,544 adverse events (.08% of total doses) were reported to the Vaccine Adverse Event Reporting System (VAERS), 76 of these events (5%, 0.004% of total doses) were serious ("results in death, hospitalization, or permanent disability or is life-threatening"). Reports to VAERS are not necessarily events that have a cause and effect relationship, and the number of unreported adverse events caused by vaccines is unknown. These figures are intrinsically misleading in as much as the VAERS system is a passive system, meaning that there is no notification process within the military to inform either troops or outprocessing servicemembers of its existence, let alone instructions for completing the paperwork.

Although individuals have expressed health concerns after receiving anthrax vaccine, a congressionally directed study by the Institute of Medicine (part of the National Academy of Sciences) concluded that anthrax vaccine is as safe as other vaccines. The Academy considered more than a dozen studies using various scientific designs, and heard personally from many concerned US military service members.[16]

Concern has been raised that The Pentagon did not inform the United States Congress about more than 20,000 hospitalizations involving troops who had received the anthrax vaccine, because "hospitalizations merely followed vaccinations in time, without documented proof of a cause-and-effect relationship."[17] Independent researchers, David and Mark Geier, published "Anthrax vaccination and joint related adverse reactions in light of biological warfare scenarios" in Clinical and Experimental Rheumatology in 2002 vol. 20 page 119. They also published "Gastrointestinal adverse reactions following anthrax vaccination" in Hepatogastroenterology in 2004 vol. 51 page 762. The Geiers found a very large and statistically significant increase in joint symptoms and gastrointestinal problems following vaccination with anthrax vaccine. These authors concluded that due to the extreme reactogenicity of anthrax vaccine, its general use in the civilian population is undesirable. The safety of the U.S. anthrax vaccine continues to be an active area of study for both government and non-government personnel, but to date no data have been found that have caused the FDA to declare the vaccine anything other than safe and effective.[8]

Controversy in Israel

Beginning in 1998 and running for 8 years, project Omer Two tested an anthrax vaccine on 716 volunteers of the Israel Defense Forces. Adverse multi-symptom illnesses were reported by a group of the volunteers. All were denied disability by the Defense Ministry. In February 2009, a petition from the disabled volunteers to disclose a report about Omer Two was filed with the Israel's High Court against the Defense Ministry, the Israel Institute for Biological Research at Nes Tziona, the director, Avigdor Shafferman, and the IDF Medical Corps. Release of the information could support further action to provide disability compensation for the injured volunteers.[18]

Anthrax and the US military

Main article: Anthrax Vaccine Immunization Program

Development of a new vaccine

While effective in protecting against anthrax, the licensed vaccine schedule is not very efficient, involving a cumbersome six dose injection series. Typically, six injections are given over a period of 18 months in order to induce a protective immune system response. The Centers for Disease Control and Prevention have undertaken a clinical trial to investigate more abbreviated vaccinations schedules for AVA. In addition, in 2004 the U.S. Department of Health and Human Services contracted with Vaxgen Inc. to supply up to 75 million doses of a recombinant anthrax vaccine, for $877 million.[19] To be acceptable to HHS, this vaccine was to be protective against anthrax in three doses or less. On December 19, 2006, HHS voided the contract, because of stability problems with the vaccine, and a failure to start a Phase 2 clinical trial on time.[20] In May 2008, Emergent Biosolutions, the Maryland-based successor to BioPort, both controlled by former Lebanese banker Faud el Hibri, acquired rights to Vaxgen's patents and processes.[21]

Research is being done to develop and test new anthrax vaccines.[22] One possible new type of vaccine would be administered by a skin patch rather than by injection.

Human Genome Sciences announced in 2007 the development of a new anthrax vaccine with the trademark name of ABthrax. The vaccine sensitizes the human immune system to the presence of the Anthrax Toxin Factor. In 2008, HGS reported on testing on 400 human volunteers given ABthrax. In 2009, HGS announced that they had made first delivery of 20,000 doses of ABthrax to the United States Department of Defense.[23]

Licencing and product in the UK

The UK anthrax vaccine, manufactured by the Health Protection Agency, is similar to that made in the U.S. The active ingredient in the vaccine is a sterile filtrate of an alum precipitated anthrax antigen from the Sterne strain in a solution for injection. The other ingredients are aluminium potassium sulphate, sodium chloride and purified water. The preservative is thiomersal (0.005%). The vaccine is given by intramuscular injection and the primary course of four single injections (three injections 3 weeks apart, followed by a 6 month dose) is followed by a single booster dose given once a year.

During Gulf War I, 1990–1991, the UK military were given the UK anthrax vaccine co-commitantly with the pertussis vaccine as an adjuvant to improve the immune response efficacy of the UK anthrax vaccine.

Licencing and Product in India

On February 12, 2009, Emergent BioSolutions announced that the Drugs Controller General of India (DGCI) had approved licensing of BioThrax AVA for distribution by Biological E. of Hyderabad.[24]

Bioterrorism preparedness

Demographic groups, ages 18 to 65, are being considered for preexposure vaccination, for bioterrorism preparedness, included emergency first responders such as police and firefighters, federal responders, medical practitioners, and private citizens. To that end, under the George W. Bush administration, the US established a policy in 2005 to ensure that the Strategic National Stockpile retains a current unexpired inventory of 60 million doses of BioThrax. The US GAO reports that 4 million doses of the inventory will expire every year, requiring vaccine destruction services.

The shelf-life of BioThrax is reported to be three years, requiring non-freezing storage temperatures between 2°C to 8°C (36°F to 46°F). However, given the low risk of exposure to anthrax, vaccination of these groups is not currently recommended by the FDA. In particular, "... Safety and effectiveness of BioThrax have not been established in pregnant women or nursing mothers, or in pediatric or geriatric populations."

Moreover, "... the safety and efficacy of BioThrax for post-exposure setting have not been established.".[12]

The recommended therapy for post-exposure setting is a course of doxycycline, instead of ciprofloxacin, as announced in October 2008 by US Health and Human Services.[25]

Ciprofloxacin is a fluoroquinolone antibiotic, which interferes with cell division (mitosis). Adverse side-effects have been reported including chronic tendonitis, ruptured tendons, and birth defects.

References

  1. ^ NY Dept. of Health - June 2004.
  2. ^ Centers for Disease Control Official CDC Anthrax Web Page.
  3. ^ Ferrari ME, Hermanson G, Rolland A. Development of anthrax DNA vaccines. Curr Opin Mol Ther. 2004 Oct;6(5):506-12.
  4. ^ Holzman, Robert S. M.D. Course:Anthrax
  5. ^ a b c d BioThrax Package Insert
  6. ^ "John Doe #1 v. Donald H. Rumsfeld, et al" (PDF). Military Vaccine (MILVAX) Agency. 2004-10-27. http://www.anthrax.mil/documents/library/AnthraxSJtOrder_Op.pdf. Retrieved 2009-05-06. 
  7. ^ 50 FR 51002 published on Dec. 13, 1985
  8. ^ a b FDA Final Order. Issued December 15, 2005.
  9. ^ Mandatory Vaccine Article - 'Mandatory Anthrax Shots to Return', Christopher Lee, Washington Post (October 17, 2006)
  10. ^ Pesu M, Watford WT, Wei L, Xu L, Fuss I, Strober W, Andersson J, Shevach EM, Quezado M, Bouladoux N, Roebroek A, Belkaid Y, Creemers J, O'Shea JJ (August 2008). "T-cell-expressed proprotein convertase furin is essential for maintenance of peripheral immune tolerance". Nature. doi:10.1038/nature07210. PMID 18701887. 
  11. ^ Ryan, M.A.D., et al. (2008). "Birth defects among infants born to women who received anthrax vaccine in pregnancy.". American Journal of Epidemiology (168): 434–442. 
  12. ^ a b c d e US FDA, Center for Biologics Evaluation and Research CBER, Product Approval Information for Anthrax Vaccine Adsorbed (December 2008)
  13. ^ Aluminum salts in vaccines--US perspective. Baylor NW, Egan W, Richman P. Vaccine. 2002 May 31;20 Suppl 3:S18-23.
  14. ^ Petrik MS, Wong MC, Tabata RC, Garry RF, Shaw CA. (2007). "Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice.". Neuromolecular Med. (9): 83–100. 
  15. ^ CDC.gov - 'Use of Anthrax Vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices', Centers for Disease Control
  16. ^ Review of the Institute of Medicine findings. (PDF file) The Anthrax Vaccine: Is it safe? Does it work?
  17. ^ Dailypress.com - 'An Incomplete Picture: Despite promises that hospitalizations after anthrax vaccinations would be reported, the Pentagon withheld data on more than 20,000 cases', Bob Evans (December 4, 2005)
  18. ^ Yossi Melman (27 January 2009). "Defense attempting to block report about anthrax trial". Haaretz Newspaper. http://www.haaretz.com/hasen/spages/1056673.html. 
  19. ^ Vaxgen anthrax vaccine contract information.
  20. ^ U.S. cancels VaxGen anthrax vaccine contract The Washington Post
  21. ^ [1]"VaxGen sells anthrax vaccine candidate to Emergent BioSolutions", Forbes Magazine (2008)
  22. ^ Taking the sting out of the anthrax vaccine by Laurie Goodman in the Journal of Clinical Investigation (2004) Volume 114 pages 868–869.
  23. ^ BioWatch: HGS shipping anthrax treatment in $150M deal Gazette.Net - Maryland Community Newspapers Online
  24. ^ Emergent BioSolutions Announces That BioThrax (Anthrax Vaccine Adsorbed) Receives Market Authorization in India (Press Release). 12 February 2009. http://www.businesswire.com/portal/site/home/permalink/?ndmViewId=news_view&newsId=20090211006556&newsLang=en. 
  25. ^ Determination and Declaration Regarding Emergency Use of Doxycycline Hyclate Tablets Accompanied by Emergency Use Information, Federal Register, E8-23544, (October 6, 2008)

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