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 adsorbed 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. 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) flight surgeon Maj. Timothy Ballard (right) administers the final shot in the six-dose series of anthrax vaccine adsorbed to
Chairman of the Joint Chiefs of Staff Gen.
Henry Shelton There were no published studies of anthrax vaccine adsorbed's safety in humans 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. Adverse events following anthrax vaccine adsorbed administration were assessed in several studies conducted by the DoD in the context of the routine anthrax vaccination program. Between 1998 and 2000, at
U.S. Forces, Korea, data were collected at the time of anthrax vaccination from 4,348 service personnel regarding adverse events experienced from a previous dose of anthrax vaccine. Most reported events were localized, minor, and self-limited. After the first or second dose, 1.9% reported limitations in work performance or had been placed on limited duty. Only 0.3% reported >1 day lost from work; 0.5% consulted a clinic for evaluation; and one person (0.02%) required hospitalization for an
injection site reaction. Adverse events were reported more commonly among women than among men. A second study, also between 1998 and 2000, at
Tripler Army Medical Center,
Hawaii, assessed adverse events among 603 military health-care workers. Rates of events that resulted in seeking medical advice or taking time off work were 7.9% after the first dose; 5.1% after the second dose; 3.0% after the third dose; and 3.1% after the fourth dose. Events most commonly reported included muscle or joint aches, headache, and fatigue. However, these studies are subject to several methodological limitations, including sample size, the limited ability to detect adverse events, loss to follow-up, exemption of vaccine recipients with previous adverse events, observational bias, and the absence of unvaccinated control groups. By 2000, some 425,976 US service members had received 1,620,793 doses of anthrax vaccine adsorbed.
The IOM review (2000–2004) In October 2000, a committee of the
Institute of Medicine (IOM) of the
National Academy of Sciences was asked by the
US Congress to review anthrax vaccine adsorbed according to the best available evidence. It issued its study in March 2002. The IOM panel noted that human data on inhalational anthrax prevention is limited due to the natural low incidence of disease and that therefore animal model data are the best we are ever likely to have. Primates and rabbits were considered the best models for human disease. As regards vaccine effectiveness, "The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, show that anthrax vaccine adsorbed as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by all known or plausible engineered strains of
B. anthracis." With regard to safety, "The committee found no evidence that people face an increased risk of experiencing life-threatening or permanently disabling adverse events immediately after receiving anthrax vaccine adsorbed, when compared with the general population. Nor did it find any convincing evidence that people face elevated risk of developing adverse health effects over the longer term, although data are limited in this regard (as they are for all vaccines)." Side effects of anthrax vaccine adsorbed were found to be "comparable to those observed with other vaccines regularly administered to adults". The committee concluded that anthrax vaccine adsorbed is "safe and efficacious" for pre-exposure prevention of inhalational anthrax. It also asserted that a new and improved anthrax vaccine might have greater assurance of consistency than anthrax vaccine adsorbed and recommended licensure of a new vaccine requiring fewer doses and producing fewer local reactions. In the months after the
October 2001 anthrax letters attacks, Washington and New York area mail sorters were advised to receive prophylactic vaccination with anthrax vaccine adsorbed. Owing to the controversy surrounding the administration of the vaccine to military personnel, however, some 6,000
US Postal Service employees balked at this, preferring to take their chances with the risks of residual anthrax spores in the workplace. BioPort changed its name to
Emergent BioSolutions in 2004.
Injunctions and FDA re-reviews (2004–2006) Despite the positive IOM assessment, mandatory vaccinations of military personnel were halted due to an injunction ordered by a judge for the U.S. District Court for the District of Columbia due to a 2003 lawsuit brought against Donald Rumsfeld, et al. in that court. The injunction became effective on 27 October 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 on 30 December 2003, which came "suspiciously" (as the District Court judge stated) only weeks after filing of the suit. The court found that FDA's incomplete rulemaking from 1985 rendered the anthrax vaccine program illegal. The basis of the suit was the never finalized FDA Proposed Rule. In that rulemaking the FDA published, but never finalized (until mere weeks into the 2003 suit), 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 15 December 2005, the FDA re-issued a Final Rule & Order on the license status of the anthrax vaccine. After reviewing the extensive scientific evidence and carefully considering comments from the public, the FDA again determined that the vaccine is appropriately licensed for the prevention of anthrax, regardless of the route of exposure. Also in 2005, the
George W. Bush administration established a policy to ensure that the
Strategic National Stockpile retains a current unexpired inventory of 60 million doses of anthrax vaccine adsorbed. (The US
GAO reports that 4 million doses of the inventory will expire every year, requiring vaccine destruction services.) These would be used for pre- or post-exposure vaccination — of emergency first responders (police, firefighters), federal responders, medical practitioners, and private citizens — in the event of a
bioterrorist anthrax attack.
Reinstatement of the AVIP (2006–2016) On 16 October 2006, the DoD announced the reinstatement of mandatory anthrax vaccinations for more than 200,000 troops and defense contractors. (Another lawsuit was filed by the same attorneys as before, challenging the basis of the vaccine's license on scientific grounds.) The reinstated policy required vaccinations for most military units and civilian contractors assigned to homeland bioterrorism defense or deployed in
Iraq,
Afghanistan or
South Korea. A modification of previous policy allowed military personnel no longer deployed to higher threat areas to receive follow up doses and booster shots on a voluntary basis. As of June 2008, over 8 million doses of anthrax vaccine adsorbed had been administered to over 2 million US military personnel as part of the AVIP. In December 2008, the FDA approved Biothrax for intramuscular injections thus reducing the immunization schedule from a total of 6 shots to 5 shots (see below). In February 2009, Emergent BioSolutions announced that the
Drugs Controller General of India (DGCI) had approved licensing of Biothrax for distribution by Biological E. of
Hyderabad. In 2011, Biothrax was approved for sale in
Singapore by the Singapore Health Sciences Authority.
Building 55 approval (2016) The FDA approved the company's license (officially called a supplemental
Biologics License Application, or sBLA) to manufacture Biothrax in a large building in Lansing, Michigan known as "Building 55." According to
Homeland Preparedness News, "The use of Building 55 to manufacture Biothrax could expand manufacturing capacity to an estimated 20 to 25 million doses annually." The US federal government has a goal to stockpile 75 million doses of anthrax vaccines. The new facility and its capacity will help Emergent meet the government's security needs. ==Administration==