Anthrax vaccine adsorbed, sold under the brand name Biothrax among others, is a vaccine intended to provide acquired immunity against Bacillus anthracis.
Anthrax vaccine adsorbed originated in studies done in the 1950s and was first licensed for use in humans in 1970. In the US, the principal purchasers of the vaccine are the Department of Defense and Department of Health and Human Services. Ten million courses (60 million doses) of the vaccine have been purchased for the US Strategic National Stockpile in anticipation of the need for mass vaccinations owing to a future bio-terrorist anthrax attack. The product has attracted some controversy owing to alleged adverse events and questions as to whether it is effective against the inhalational form of anthrax.
Medical uses Anthrax vaccine adsorbed (Biothrax) is indicated for the active immunization for the prevention of disease caused by Bacillus anthracis in people aged 18 through 65 years of age. It is approved for both pre-exposure prophylaxis of disease in persons at high risk of exposure and also for post-exposure prophylaxis (PEP) of disease following suspected or confirmed Bacillus anthracis exposure, when administered in conjunction with recommended antibacterial drugs.
Anthrax vaccine adsorbed, adjuvanted (Cyfendus) is indicated for post-exposure prophylaxis of disease following suspected or confirmed exposure to Bacillus anthracis in people aged 18 through 65 years of age when administered in conjunction with recommended antibacterial drugs.
Description Anthrax vaccine adsorbed was developed by Emergent Biodefense Operations.
Antigen Anthrax vaccine adsorbed is classified as a subunit vaccine that is cell-free, meaning it lacks any whole or live anthrax bacteria.Biothrax Package Insert The antigen (immunologically active) portions are produced from culture filtrates of a toxigenic, but avirulent, nonencapsulated mutant — known as V770-NP1-R — of the B. anthracis Vollum strain. (The Vollum strain was the same one weaponized by the old U.S. biological warfare program.) As with the Sterne (veterinary) anthrax vaccine strain and the similar British anthrax vaccine (known as AVP), anthrax vaccine adsorbed lacks the capsule plasmid pXO2 (required for full virulence) and is composed chiefly of the anthrax protective antigen (PA)Leppla SH, Klimpel KR, Singh Y, et al (June 1996), "Interaction of anthrax toxin with mammalian cells", Salisbury Medical Bulletin, Special Supplement #87, pg 91. with small amounts of edema factor (EF) and lethal factor (LF) that may vary across vaccine production lots. Other uncharacterized bacterial byproducts are also present. Whether or not the EF and LF contribute to the vaccine's efficacy is not known. Anthrax vaccine adsorbed has smaller amounts of EF and LF than AVP.
Adjuvant Anthrax vaccine adsorbed contains aluminium hydroxide (alhydrogel) to adsorb PA as well as to serve as an adjuvant (immune enhancer). As such it is believed to stimulate humoral, but not cell-mediated, immunity. Each dose of the vaccine contains no more than 0.83 mg aluminum per 0.5 mL dose. (This is near the allowed upper limit of 0.85 mg/dose.) It also contains 0.0025% benzethonium chloride as a preservative and 0.0037% formaldehyde as a stabilizer. The mechanism of action of the adjuvant is not entirely understood.
Potency/immunogenicity Vaccination of humans with anthrax vaccine adsorbed induces an immune response to PA. More than 1/3 of subjects develop detectable anti-PA IgG after a single inoculation; 95% do so after a 2nd injection; and 100% after 3 doses. The peak IgG response occurs after the 4th (6 month) dose. The potency of anthrax vaccine adsorbed vaccine lots is routinely determined both by the survival rates of parenterally challenged guinea pigs and their anti-PA antibody titres as measured by an enzyme linked immunosorbant assay (ELISA). The shelf-life of anthrax vaccine adsorbed is reported to be three years when stored between and never frozen.
History
Initial research and development (1954–1970) The vaccine efficacy of anthrax vaccine adsorbed in humans was initially established by Philip S. Brachman of the United States Public Health Service (USPHS) in a controlled study undertaken between 1954 and 1959. The study field sites were four wool-sorting mills in the northeastern United States where employees were sometimes exposed to anthrax spores in the course of their work. Over the five years, 379 vaccinees were compared against 414 unvaccinated control subjects. There were 23 cases among controls (5 of them inhalation anthrax) compared with 3 cases among vaccinated (0 inhalation cases). The vaccine was judged to have a 92.5% vaccine efficacy against all types of anthrax experienced. Subsequently, there were no controlled clinical trials in humans of the efficacy of anthrax vaccine adsorbedBrachman PS and Friedlander AM (1994), "Anthrax", In: Plotkin SA and Mortimer EA (eds): Vaccines, 2nd ed.; Philadelphia, WB Saunders, pg 729. due to the rarity of the condition (especially in the inhalational form) in humans and the ethical inadmissibility of conducting dangerous challenge studies in human subjects. Supportive animal challenge studies were done, however, showing that unvaccinated animals uniformly die whereas vaccinated animals are protected. About 95% of rhesus monkeys (62 of 65) survived challenge, as did 97% of rabbits (114 of 117). Guinea pigs (which are a poorer model for human anthrax than are monkeys or rabbits) showed a 22% protection (19 of 88).
Licensure and limited occupational use (1970–1991) In 1970, anthrax vaccine adsorbed was first licensed by the USPHS for protection against cutaneous anthrax to a state-owned facility operated by the Michigan Department of Public Health. In 1973, the US Food and Drug Administration (FDA) first published standards for making, using and storing anthrax vaccine adsorbed.21 CFR Section 620.20. In the mid-1980s, the FDA approved it specifically for two limited preventive indications: 1) individuals who may come in contact with animal products or high-risk persons such as veterinarians and others handling potentially infected animals; and 2) individuals engaged in diagnostic or investigational activities involving anthrax spores. In 1985, the FDA published a Proposed Rule for a specific product review of the anthrax vaccine adsorbed, stating that the vaccine's "efficacy against inhalation anthrax is not well documented" (a statement quoted controversially many years later). For many years, anthrax vaccine adsorbed was a little known product considered to be safe for pre-exposure use in the US in at-risk veterinarians, laboratory workers, livestock handlers, and textile plant workers who process animal hair. In 1990, the State of Michigan changed the name of its original production plant facility to the Michigan Biologic Products Institute (MBPI) as it gave up state ownership and converted it to a private entity. The same year (as later revealed) MBPI changed both the fermenters and the filters used in manufacturing anthrax vaccine adsorbed without notifying the FDA, thus reportedly causing a 100 fold increase in the PA levels present in vaccine lots.
Only several thousand people had ever received the vaccine up to 1991 when — coincident with Saddam Hussein's invasion of Kuwait and the subsequent Gulf War — MBPI and the U.S. Army entered into an agreement for the manufacture of the vaccine. Later that year, the Army awarded MBPI the Commander's Award for Public Service for their efforts in supplying the US military with increased amounts of anthrax vaccine adsorbed for use during the conflict in which the use of anthrax bio-weapons by Iraq had been anticipated.
Initial use in US military (1991–1997) Use of anthrax vaccine adsorbed expanded dramatically in 1991, when the US military, concerned that Iraq possessed anthrax bioweapons, administered it to some 150,000 service members deployed for the Gulf War. Hussein never deployed his bio-weapons, but subsequent confirmation of an Iraqi bioweapons program — including 8,500 liters of concentrated anthrax spores (6,500 liters of it filled into munitions) — came in 1995 and later when the Iraqi government began to fully disclose the scope and scale of the effort, which it had pursued since the 1980s.
Meanwhile, MBPI fell afoul of FDA inspectors and reviewers when it failed inspections (1993, 1997) and received warning letters (1995) and Notices of Intention to Revoke (1997) from the agency. At issue were a failure to validate the anthrax vaccine adsorbed manufacturing process to the FDA's satisfaction and various quality control failures, including reuse of expired vaccine, inadequate testing procedures, and use of lots that had failed testing. All of these developments vexed the Army, not only in its efforts to obtain sufficient vaccine for the troops, but in its desire to have anthrax vaccine adsorbed validated and fully licensed for prevention of inhalational anthrax, which is the expected weaponized form of the disease (as opposed to the cutaneous form for which the vaccine had been licensed in 1970). In 1995, the Army contracted with the Science Applications International Corporation (SAIC) to develop a plan to obtain FDA approval for a license amendment for anthrax vaccine adsorbed in order to add inhalational anthrax exposure to the product license thus enabling the manufacturer to list on the product license that the vaccine was effective against that form of the disease. The following year, MBPI submitted an IND application to modify the product's license to add an indication for inhalation anthrax, thus formally establishing anthrax vaccine adsorbed as an investigational vaccine when used to prevent anthrax via the inhalation form.
In 1996, the US Department of Defense (DoD) sought and received permission from the FDA to begin vaccinations of all military personnel without obtaining a new licensed indication for anthrax vaccine adsorbed. It announced a plan the following year for the mandatory vaccination of all US service members. Under the plan all military personnel, including new recruits, would begin receiving what was then a six-shot series of inoculations in the following fashion: Phase 1: Forces assigned now, or soon rotating, to high threat areas in Southwest Asia and Korea; Phase 2: Early deploying forces into high threat areas; Phase 3: Remainder of the force and new recruits; and Phase 4: Continuation of the program with annual booster shots.
The AVIP and initial mandatory military use (1997–2000)
There were no published studies of anthrax vaccine adsorbed's safety in humansBrachman (1994), Op. cit., pg 729. until the advent of the Anthrax Vaccine Immunization Program (AVIP). This program, initiated by the Clinton administration and announced by Secretary of Defense William Cohen in 1997, made the vaccine mandatory for active duty US service personnel. Vaccinations began in March 1998 with personnel sent to high-risk areas, such as South Korea and Southwest Asia. Also in 1998, MBPI was purchased by BioPort Corporation of Lansing, Michigan (jointly with former MBPI laboratory directors) for approximately $24 million. The same year, a particularly damning FDA report was issued resulting in the temporary suspension of anthrax vaccine adsorbed shipments from the production plant. Much controversy ensued due to the FDA infractions, the mandatory nature of the program, and to a public perception that anthrax vaccine adsorbed was unsafe — possibly causing sometimes serious side effects — and might be contributing to the highly politically charged malady known as "Gulf War syndrome". Hundreds of service members were compelled to leave the military (some of them court-martialed) for resisting the inoculations during the first six years of the program.