Anthrax vaccine

Anthrax vaccine is a vaccine against the infectious disease, anthrax. Anthrax is caused by the spore-forming bacterium Bacillus anthracis, that most commonly occurs in wild and domestic mammals. 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.

History
Louis Pasteur and William S. Greenfield 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.

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 BioPort Corporation in Lansing, Michigan. The parent company of BioPort is Emergent BioSolutions. The anthrax vaccine is produced from culture filtrates of an avirulent, nonencapsulated strain known as V770-NP1-R. No living organisms are present in the vaccine. 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 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, 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 of 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." On December 15, 2005, the FDA re-issued a Final Rule & Order on the license status of the anthrax vaccine.

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.

Vaccination schedule
Primary vaccination consists of three subcutaneous injections at zero, two, and four weeks, and three vaccinations at six, twelve, and eighteen months followed by annual boosters. For prolonged protection, annual boosters are recommended.

Adjuvant
The BioPort anthrax vaccine contains aluminium hydroxide as an adjuvant. 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. The BioPort anthrax vaccine also contains 0.0025% benzethonium chloride as a preservative, and 0.0037% formaldehyde as a stabilizer. To maintain immunity, the manufacturer recommends an annual booster injection.

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. During that decade, 1,544 adverse events were reported to the Vaccine Adverse Event Reporting System (VAERS), 76 of these events (5%) 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.

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." 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.

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. 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.

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

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.

Bioterrorism preparedness
Demographic groups initially considered for preexposure vaccination, for bioterrorism preparedness, included emergency first responders, federal responders, medical practitioners, and private citizens. However, vaccination of these groups is not currently recommended.