Status: FDA approved; primarily gov’t controlled distribution; new U.S. stockpile contract awarded in Oct. 2008

Organizations involved:

BioPort Corp. – Manuf.; R&D; Tech.; World mark.

Emergent Biosolutions Inc. – Parent

Hollister-Stier Laboratories LLC – Manuf. other

Michigan Biologics Products Institute – R&D; Tech.; Former

Michigan Dept. of Public Health – Former

Joint Vaccine Acquisition Program (JVAP), DOD – USA mark.

U.S. Army Medical Research Acquisition Activity (USAMRAA) – R&D

U.S. Department of Defense – Parent

Biological E. Ltd. – India mark.

Cross ref.: See the Anthrax Vaccine, rDNA entries (#103, #104) for information about recombinant anthrax protective antigen (rPA) vaccines.

Description: Anthrax Vaccine Adsorbed (BioThrax; AVA) is a cell-free suspension of sterile acellular filtrates of cultured avirulent nonencapsulated Bacillus anthracis (anthrax) bacteria complexed and concentrated with aluminum hydroxide (Alhydrogel) adjuvant. AVA is used for pre- and post-exposure prevention of disease (anthrax) due to Bacillus anthracis infection. The primary and active component antigen of B. anthracis and BioThrax is “protective antigen,” a 83 kDa protein common to all disease-causing anthrax strains that evokes protective antibodies when injected into humans.

Anthrax Vaccine Adsorbed is a made from sterile filtrates of microaerophilic (near anaerobic) cultures of an avirulent strain of Bacillus anthracis (nonencapsulated, nonproteolytic strain V770-NP1-R). This strain elaborates protective antigen but no toxins during culture. The bacteria are now reported as grown in a chemically defined protein-free liquid medium consisting of a mixture of amino acids, vitamins, inorganic salts and sugars. [However, as discussed below, the FDA has cited the vaccine as one of the few incorporating bovine-sourced materials potentially from a country with cases of BSE]. The final product is prepared by sterile filtration of the culture fluid, eliminating all cell-sized materials, and adsorption onto aluminum hydroxide gel. Otherwise, the vaccine does not undergo other purification, inactivation or lyophilization processes. Thus, manufacture is rather simple, involving culture/fermentation of the bacteria, harvesting of media, filtration to remove bacterial cells, and formulation with adjuvant. The resulting vaccine is essentially a classic cell-free inactivated bacterial vaccine composed of bacterial protein(s) and other acellular (below cell sized) components suspended or dissolved in the culture media.

Anthrax Vaccine Adsorbed is supplied in 5.2 mL vials containing 10 doses, 0.5 mL each , for subcutaneous injection. The final product is formulated to contain up to 2.4 mg of B. anthracis protective antigen (PA)/0.5 mL dose adsorbed onto aluminum hydroxide (1.2 mg/mL aluminum; added as adjuvant in 0.85% sodium chloride solution. The product also contains 25 µg/mL benzethonium chloride and 100 µg/mL formaldehyde as antimicrobial preservatives. The dating period (shelf life) was originally 36 months when stored at 2-8˚C (refrigerated), with this extended to 4 years in 2009.

Potency of the vaccine is determined by comparison to the U.S. Reference Anthrax Vaccine. For quality assurance, the vaccine is compared to the reference vaccine in guinea pigs. See the Code of Federal Regulations (CFR), Title 21, parts 620.2 through 620.24. Potency is determined by assessing protection against an intradermal challenge with 1,000 B. anthracis spores (Vollum strain).

Although originally developed as an occupational vaccine, e.g., for use by those in close contact with cattle and other ruminants, BioThrax/AVA is now primarily used for bioterrorism/biological warfare preexposure prophylaxis against infection/disease due to inhalational exposure to B. anthracis spores. AVA is may also be used for post-exposure prophylaxis, including against inhalational exposure, e.g., using an accelerated administration regimen of three inoculations every two weeks, combined with antibiotic treatment.

Nomenclature: Anthrax Vaccine [BIO]; Biothrax [TR]; Anthrax Vaccine Adsorbed [FDA]; Vaccine A [SY; as administered to U.S. military personnel during the Persian Gulf war]; AVA [SY]; NDC 64687-0211-05

Biological.: Bacillus anthracis is a Gram-positive, rod-shaped, microaerophilic (tending toward anaerobic or without need for oxygen/air), endospore-forming bacterium. Anthrax, the disease caused by Bacillus anthracis infection, is also known by other names, including woolsorters’ disease and charbon. Bacillus anthracis spores are highly infectious and survive well in the environment, such as in contaminated soil where spores can survive for decades.

Different routes of exposure to B. anthracis spores result in disease of varying severity. Contact with B. anthracis spores, such as handling contaminated carcasses, bones, hides, etc., can result in localized cutaneous disease, which has a much milder course compared to respiratory (inhalation) exposure of spores, which can have a very high (near 100%) rate of mortality. As further discussed below, Bacillus anthracis spores have been developed as biological weapons by multiple countries’ during and after World War II, there are concerns that terrorists and countries may also use anthrax spores as a weapon, the U.S. has experienced anthrax spore attacks (e.g., spore-laden envelopes sent to Congress and a newspaper publisher), and AVA is being used for biological warfare prophylaxis by the U.S. and other militaries.

Anthrax is a naturally occurring disease of plant eating animals (goats, sheep, cattle, etc.) caused by the bacterium Bacillus anthracis. Human anthrax was once common in essentially all areas where livestock were raised. However, intensive livestock immunization programs have greatly reduced the disease among both animals and humans in much of the world. Most outbreaks now occur in areas where immunization programs have not been implemented or have become compromised (primarily Africa and Asia; outbreaks occurred during the mid-1990’s in Haiti and the former Soviet Union).

Infection of humans with B. anthracis can result from: cuts or breaks in the skin from contact with an infected animal or its tissues, resulting in local (cutaneous anthrax) and possibly systemic infection; inhalation of spores resulting in an infection of the lungs (inhalational anthrax; woolsorters disease) with a very high mortality rate; and from eating infected meat, resulting in gastrointestinal infection (gastrointestinal anthrax). Symptoms of anthrax begin after a 1 to 6 day incubation period following exposure. For contact or cutaneous anthrax, itching occurs at the site of exposure followed by the formation of a lesion. Untreated cutaneous anthrax has a fatality rate of 5-20%, but few deaths now occur with modern antibiotic treatment. For inhalational anthrax, symptoms generally involve nonspecific low grade fever, a dry hacking cough, and weakness. Symptoms often briefly improve after 2-4 days. However within 24 hours after this brief improvement, respiratory distress can occur with shock and death following shortly thereafter. An estimated 80% all cases of inhalational anthrax in which antibiotic and other treatment was started after patients exhibited symptoms have resulted in death, regardless of post-exposure treatment. If untreated, inhalational anthrax has a near 100% morbidity rate after inhalation of a sufficient number of spores, and a near 100% mortality rate after development of symptoms.

Cases of anthrax are now very rare in the U.S. Worldwide, incidence is estimated to be from 20,000 to 100,000 cases/year, mostly in agricultural workers, and mostly cutaneous. Anthrax vaccine’s primary use until recent years was for vaccination of veterinarians, slaughterhouse workers, those working with hides or animal products, and others potentially in contact with bovine (cow), ovine (sheep) or other animal carcasses or their products (potentially infected with B. anthracis). Alternatives to anthrax vaccine for prevention of anthrax disease primarily involve post-exposure treatment with penicillin, ciprofloxacin, doxycycline, or other B. anthracis-susceptible antibiotics. Penicillin, doxycycline, or ciprofloxacin may be used to treat symptomatic cases, but effectiveness depends on the route and dose of anthrax spores or bacteria, how early treatment is started, and the antibiotic sensitivity of the particular strain. Vaccination sufficiently prior to exposure to B. anthracis spores, particularly cutaneous exposure, has been shown the be generally effective to prevent active infection and disease.

Since clinical/field efficacy trials are now impossible to perform (unethical and illegal, although other countries and terrorist groups may not be bound by these conventions) for some of the vaccine’s uses, particularly prophylaxis against inhalation anthrax (bioterrorism/biological warfare defense), animal studies provide much of the information relevant to assessing human clinical and field efficacy of the vaccine. This is particularly true for inhalational anthrax. Animal testing indicates that AVA protects non-human primates against a high dose inhalation challenge with spores of the B. anthracis Ames strain (which is non-homologous, or dissimilar, to the vaccine strain). More recent data on animal efficacy was published in summary form by Dr. A. Friedlander, et al., (See Jour. Amer. Med. Assoc., Dec, 8, 1999). This report noted that non-human primates have shown a high level of protection against two other non-homologous strains, in addition to the Ames Strain (supporting the authors’ and federal government’s view of the likely utility of the vaccine for inhalation prophylaxis).

In Jan. 2006, results were reported from two animal studies supporting the efficacy of BioThrax for post-inhalation exposure prophylaxis. BioThrax provided 100% protection against death in anthrax-infected animals treated with BioThrax plus antibiotics, a significant im-provement over antibiotic treatment alone. One study performed by the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) involved non-human primates (monkeys) infected by aerosol exposure with 1,600 times the lethal dose of spores, with the animals receiving post-exposure treatment with BioThrax plus a 14-day course of antibiotics or antibiotics alone. Significant mortality was seen after the antibiotics were discontinued. Antibiotics plus post-infection BioThrax vaccination (using the licensed human schedule) provided protection against death in 100% of the animals tested (10/10). Preliminary results from a similar study performed in rabbits performed by Battelle Memorial Institute indicated the animals were protected against death when treated with BioThrax plus antibiotics after aerosol exposure to anthrax spores, with antibiotic prophylaxis alone only partially protective.

History: Anthrax vaccines have a long history. Louis Pasteur in 1881 demonstrated protective efficacy in farm animals (sheep, cows, a goat) using a live, attenuated vaccine. Inactivated anthrax vaccines were developed in England and the U.S. in the 1950s and early 1960s. The U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID; Fort Detrick, MD) has conducted various anthrax vaccine studies and clinical/field trials since 1950. Merck, Sharp & Dohme (now Merck & Co., Inc.) manufactured an inactivated vaccine for U.S. Army studies in 1950. Use of AVA (from Michigan Dept. of Public Health) by the U.S. Department of Defense (DOD) began under an IND starting in 1965 (and the vaccine was licensed in 1970). A live attenuated vaccine is still used in the former Soviet republics. An inactivated vaccine is currently manufactured by the Centre for Applied Microbiology and Research (CAMR), U.K., which like AVA, is an acellular filtrate (using the Sterne 34F3 capsulating strain) precipitated with aluminum potassium sulfate (alum).

The U.S, U.K., Germany, and Japan experimented with and developed offensive B. anthracis spore-based biological weapons during World War II, but these were never used (although there have been allegations that Japan tested spore-based weapons in China and experimented on prisoners during World War II). Subsequently, other nations have developed offensive anthrax biological weapons, e.g., Iraq, which has admitted manufacture of stocks of weoponized spores in solution for aerosol delivery (although, with the conquest of Iraq by the U.S., these and other weapons of mass destruction had not been found as of 8/2004).

Anthrax is generally presumed to be a likely, probably the most likely, threat in terms of biological warfare. The intelligence community presumes that at least a dozen countries may have or are developing B. anthracis spore-based weapon systems. This has prompted great concern in the U.S. military for the need to vaccinate troops against these widely proliferated biological weapons. It has been widely reported that Russia had developed both a multi-strain anthrax weapon and genetically engineered strains of anthrax for biological warfare use, including strains for which AVA may be ineffective. This and the possibility that other countries, e.g., North Korea, Russia and Iran, have developed strains for which the current U.S. vaccine (AVA) may have little protective efficacy has contributed to the controversy about the wisdom of large-scale vaccination of the U.S. military with the current vaccine for biological warfare defense purposes. However, it is very difficult and there an no examples of development or isolation of vaccine-resistant B. anthracis strains that retain good weapon characteristics.

AVA and vaccination of large numbers of U.S. military personnel have been very controversial in recent years. Some vaccinated military personnel, activists, and others allege that the vaccine has caused various chronic and serious adverse effects. A number of other factors contribute to the controversial nature of the vaccine, including the perceived inadequacy of clinical/field trials with the vaccine, particularly lack of data regarding protection from inhalation exposure; mistrust of the government by many (e.g., experience with Agent Orange); the intimate involvement of the Department of Defense with the current manufacturer, BioPort Corp.; the company’s chronic financial and manufacturing problems; and the controversial nature of biological warfare defense in general. However, six different independent civilian scientific review panels have confirmed the presumed efficacy and safety of AVA; including the Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC).

As noted by Colonel Engler, U.S. Army, “The beginnings of this vaccine were perhaps in a scientifically more naive or clinically more naive period.” Problems associated with perceptions of the vaccine continue to plague BioThrax. If the vaccine were presented as a new product to FDA and other regulatory authorities for widespread use, e.g., availability to the general public for anthrax prophylaxis, it very well might not receive approval. AVA is the only aluminum-adsorbed vaccine administered subcutaneously rather than intramuscularly (a route associated with less serious local reactions), and its manufacture does not include purification (essentially just sterile filtration of the culture media used).

By conventional standards, particularly its use for protection against inhalational anthrax (bioterrorism/biological warfare preexposure prophylaxis), available clinical and field studies are generally considered to be suboptimal. Clinical trials demonstrated about 93% reduction in risk for anthrax disease after a full course of six doses. However, this was primarily demonstrated against cutaneous, not respiratory, exposure and manifestations of anthrax. The incidence of exposure to inhaled B. anthracis spores, as might occur from use for biological warfare, is too low to determine prophylactic efficacy in this context, and there have been no published clinical or field trials of the vaccine involving intensional human inhalation exposure to B. anthracis spores. Prophylactic efficacy of AVA is presumed to last for about one year after completion of a full course of vaccination, but this has not been firmly established for inhalation exposure.

The initial clinical trials with AVA were conducted by Dr. P.S. Brachman et al., during the 1950’s (see “Field Evaluation of a Human Anthrax Vaccine,” Amer. J. Pub. Health, Vol. 52, p. 632-645, 1962), and by the Centers for Disease Control (CDC) in the 1960’s. The Michigan Department of Public Health (MDPH; now BioPort) manufactured four lots of the vaccine used in the CDC study. On April 14, 1966, CDC submitted an IND for anthrax vaccine to the Division of Biologics Standards, then part of the National Institutes of Health (NIH), later transferred to FDA (now CBER). The DBS issued a product license (PLA) to MDPH to manufacture anthrax vaccine on Nov. 10, 1970.

A CBER, FDA advisory panel review of available data in 1985 recommended that the anthrax vaccine manufactured by MDPH be classified as a Category I product (safe, effective and not misbranded) and that licenses be continued based upon substantial evidence of safety and effectiveness of the product. These findings were published in the Federal Register (Dec. 3, 1985, Vol. 50, No. 240 p. 51002-51117).

Starting in the early 1990s, particularly during and after the Persian Gulf War (1st Iraq war), the U.S. military initiated large-scale vaccination programs to inoculate U.S. troops against potential biological warfare inhalation exposure to B. anthracis spores. The U.S. Department of Defense (DOD) has become, by far, the largest purchaser and user of AVA, purchasing and using millions of doses. DOD currently purchases the vaccine through the Joint Vaccine Acquisition Program (JVAP), DOD. Some critics allege that an AVA batch produced in 1993 and improperly recertified by the manufacturer may have contributed to illnesses and chronic health problems in Gulf War veterans. However, multiple civilian review panels have found no clear evidence for such a link.

In Dec. 1997, DOD announced U.S. intensions to vaccinate all U.S. military personnel against anthrax. In May 1998, DOD proceeded with its previously announced plan (Anthrax Vaccine Immunization Program or AVIP) to vaccinate all active-duty personnel and Selected Reserves, a total of about 2.4 million persons, using AVA, the only FDA-approved anthrax vaccine. The Joint Program Office for Biological Defense, DOD, contracted with Mitretek Systems, Inc., MITRE Corp., to oversee and report on supplemental testing (repetition of release tests) requested by DOD to be performed by BioPort. Supplemental testing of the anthrax vaccine stockpile began in Jan. 1998. All lots of vaccine distributed by DOD since approval of the Accelerated AVIP in March 1998 have passed supplemental testing by BioPort, and been cleared (released) by CBER, FDA.

The FDA inspected the Michigan Biologics Products Institute facilities in Feb. 1998 and reported “significant deviations” from current GMP. In Sept. 1998 (only weeks after BioPort took over the business from the State of Michigan), the Joint Vaccine Acquisition Program (JVAP), DOD, awarded BioPort a sole source $29 million (maximum), 26-month contract for manufacture, testing, bottling and storage of anthrax vaccine. The contract also included contingency plans for quantities exceeding the current production capacities, and contained an option to renovate and upgrade BioPort’s production facilities to fulfill possible requirements. This was the first major contract for BioPort, which reported that it earns “most of its revenue from sale of anthrax vaccine to the Department of Defense and from its plasma fractionation services,” with its plasma fractionation business now abandoned.

In Aug. 1999, DOD announced that is was increasing the price paid to BioPort from $4.36/dose to $10.64/dose, in order to assure continued and sufficient supplies of the vaccine. The total cost of the contract with BioPort was increased from $25.7 million to $49.8 million to keep the company financially stable. BioPort asserted that the increased cost was needed to cover its debts and costs, including facilities and manufacturing improvements required to retain FDA approval of the vaccine. The DOD considered maintaining BioPort’s production of vaccine to be essential for military readiness. However, AVA production was not restarted by the relatively new owners, BioPort. Rather, the company continued with a major DOD-funded renovation and expansion of manufacturing facilities. The FDA inspected and declined to approve the company’s new facilities in Dec. 1999. This was then expected to delay restart of production for up to (or more than) a year.

In April 2000, an audit by the DOD inspector general reported that BioPort Corp. had wasted millions on office renovations and travel fees (although these were fully legal and allowed by DOD), and that the company expected to end the year with an $18 million shortfall, if not bailed out by DOD. Critics noted that DOD had already helped the company, paying about double the prior price for the vaccine than originally agreed upon, and that DOD provided the bulk of funds for construction and validation of the new vaccine manufacturing facilities (which had not yet received FDA approval). At the time, DOD reported that about 1 million doses of AVA (from the old plant) were stockpiled for use (after approval for release by CBER), and that CBER/FDA lot release approval of another million doses was expected within three months. Subsequently, CBER/FDA rejected the three remaining batches of AVA previously manufactured by BioPort. The DOD estimated it was then using 75,000 doses/month. At this rate, with the BioPort having halted manufacture of the vaccine for renovations planned since 1994 and with existing stocks not releasable, only a few months of released vaccine were in storage or available for use.

Faced with nearly depleted stocks of vaccine, in summer 2000, DOD announced it was limiting administration of the vaccine to military staff at high risk, e.g., stationed in areas of high biological warfare threat potential, e.g., South Korea and Middle East. Only about 175,000 doses remained to vaccinate those who have started the six-shot series against anthrax or were at high risk, e.g., being posted to high risk areas. The potency of these remaining doses was in doubt. An estimated 15,000 doses were being administered monthly, down from an earlier rate of about 75,000/month. [See the Companies and Status sections below for more recent information].

Companies.: AVA was originally developed and manufactured by the Michigan Department of Public Health, later the Michigan Biologics Products Institute (MBPI), CBER/FDA est. no. 0099. MBPI was acquired on Sept. 4, 1998 from the state of Michigan by BioPort Corp. after the company won a public auction for purchase of MBPI. BioPort is now a subsidiary of Emergent Biosolutions Inc. BioPort and Emergent Biosolutions are privately-held, and the related limited access and disclosure of information has contributed to the controversies involving AVA/BioThrax. The Joint Program Office for Biological Defences, DOD, is the primary purchaser of the vaccine (for the Army and other U.S. military services).

BioThrax is marketed in India by Biological E. Ltd.

BioPort was founded by Mr. F. El-Hibri, a naturalized U.S. citizen (formerly a resident of Germany and of Lebanese extraction) and a former investor/officer in Porton International plc. Other major holders of BioPort stock include his wife and a Netherlands Antilles company controlled by his brother. Mr. El-Hibri recruited retired Admiral W.J. Crow, Jr., former Chairman of the Joint Chiefs of Staff (highest military position in DOD), to serve as Chairman of Bioport. Admiral Crow owns (at one time) 22.5% of a holding company that effectively controls BioPort through ownership of just over 50% of its stock, effectively holding 12%-13% of the company.

On Dec. 31, 2003, the Department of Defense (DOD) signed a 3-year, $245 million contract with BioPort for supply of BioThrax. The number of doses to be ordered was not disclosed, but this should purchase in the range of 100 million doses (at recent prices, see next paragraph). DOD has flexibility in the amounts it orders, including the ability to increase its purchases over the three years. Other federal agencies may purchase BioThrax through the DOD contract.

On May 6, 2005, the Department of Health and Human Services (DHHS) awarded BioPort Corp. a $122.7 million contract for the manufacture and delivery of 5 million doses of BioThrax (ave. $24.54/dose). BioPort completed deliveries of the initial 5 million doses in February 2006, eight months ahead of schedule. This was purchased under the Project BioShield program, for addition to the Strategic National Stockpile for use in the event of a bioterror/biological warfare anthrax incident.

In May 2006, DHHS issued a $120 million modification to BioPort’s 2005 contract (for 5 million doses, delivered in Feb. 2006), with an order for an additional 5 million doses. Fulfillment of this procurement will result in a combined total delivery of ten million doses of BioThrax to the civilian Strategic National Stockpile,

In Feb. 2006, BioPort/Emergent BioSolutions received a package of financial incentives, mostly tax breaks, from the State of Michigan as an incentive (reward or pay-off) for locating a new manufacturing facility on its Lansing, Michigan campus (vs. going to another state offering an incentives package), where manufacturing is presently located. The facility being constructed will have a maximum capacity to manufacture 80 million doses per year of BioThrax. In late 2004, the State of Maryland granted the company a similar financial incentives package for expansion of product development and manufacturing capacity in a 150,000 sq. ft. facility in Frederick, MD. This will be multi-product manufacturing facility, not dedicated to BioThrax manufacture, as are the Lansing facilties.

In July 2006, Emergent BioSolutions “dedicated” (laid the corner stone for) its new BioThrax manufacturing facilities in Lansing, MI. Construction of the 50,000-square-foot, three story facility began in Feb. 2006, is scheduled for completion in early 2007, and FDA approval is expected in 2008.

Although BioThrax has been ruled by FDA and evaluated by other respected organizations as being safe (relatively) and effective (likely), the repeated financial support and sole source contracts given to BioPort/Emergent BioSolutions remain controversial. Critics note that starting with an apparent ~$4.5 million investment, in just a short span, the company went from pleading poverty to announcing $100s million in acquisitions, including other companies, and building new manufacturing facilities, with the company’s major source of income being BioThrax sales through contracts with the U.S. government. Details of the company’s finances are not disclosed, since it is privately held. Some allege a pattern of “Tell the Pentagon or Congress that it doesn’t have the money to keep going, negotiate a new deal, then count the extra cash rolling in;” and that the company is a prime example of the problems inherent with sole source federal and defense contracting. With the company allegedly making excessive use of insider connections, lobbyists and public relations efforts, some question whether the vaccine’s federal support is due to this, rather than being supported by scientific findings and prudent public policy. Others are not concerned, or cite “national security,” with AVA/Biothrax acquisitions being well within the norm for defense contracting and simply part of what is required to maintain sufficient defense manufacturing capacity/infrastructure [If companies were not subsidized or given what they need to survive, they would not continue as government contractors (an inherently risky business); and, ultimately, it is often cheaper and more effective to let companies prosper, even if the government has to give them what amounts to subsidies, rather than either have the government do something, e.g., make biodefense vaccines, itself or have to pay even more for new or additional contractors to establish manufacturing capacity, with this also resulting in intolerable delays]. By defense procurement standards, BioPort/Emergent BioSolutions appears to be doing a good job of providing a product critical for U.S. security.

In April 2007, the Department of Health and Human Services (DHHS) and the Department of Defense (DOD) issued two separate notices of intent to procure up to a combined total of 22.75 million doses of BioThrax. DHHS intends to procure 10.4 million doses of BioThrax for the Strategic National Stockpile (SNS) with options for up to an additional 8.35 million doses. DOD intends to issue a sole source contract award to procure a minimum of 4 million doses of BioThrax, over a base period and 3 optional ordering periods.

In Sept. 2007, DHHS (HHS) awarded Emergent Biosolutions a $448 million three year contract. This included $400 million firm fixed-price for delivery of 18.75 million doses of BioThrax for inclusion in the Strategic National Stockpile (SNS); $34 million ($21.33/dose) for receipt of regulatory approval of 4-year expiry dating for BioThrax payable through a combination of a lump-sum payment reflecting a price per dose increase for certain doses delivered prior to approval and an increase in the per dose price to be paid for doses delivered following approval; up to $11.5 million in milestone payments in connection with advancement towards a post-exposure prophylaxis (PEP) indication for BioThrax; and $2.2 million for logistics services and other related support. HHS will purchase an aggregate of 18.75 million doses of BioThrax through Sept. 2010 for a firm, fixed-price of $400 million. The company anticipated making deliveries for ~6 million doses under this contract by year-end 2007. In the event the company receives FDA approval of its then pending supplemental BLA to extend the shelf life of BioThrax from three years to four years, the company will receive a lump sum payment reflecting a price per dose increase for certain doses delivered prior to approval and an increase in the price per dose to be paid for doses delivered following the date of approval, with a total value of ~$34 million. If FDA approval of 4-year expiry dating is not received during the term of the contract, the company will not be entitled to receive any of the $34 million. The company submitted its supplement for 4-year expiry dating to the FDA in Dec. 2006. The contract was funded through the Project BioShield Special Reserve Fund, which was created by an act of Congress in May 2004.

In Nov. 2007, the Department of Defense (DOD) inconcluded a collaborative arrangement with the Department of Health and Human Services (HHS) to facilitate the use by DOD of stockpiled doses of BioThrax (to prevent future waste of government funding and resources. DOD cance.led its previously announced request for proposal (RFP). DOD's actions were in response to a recent Government Accountability Office (GAO) report (discussed in the Status section) in which it was recommended that HHS and DOD develop a single integrated inventory system to improve efficiency.

In Oct. 2008, DHHS (HHS) awarded Emergent Biosolutions a second/follow-on new, multi-year, firm fixed price contract for manufacture and delivery of 14.5 million doses of Biothrax for inclusion in the Strategic National Stockpile (SNS), worth as much as $404 million. The total value of this follow-on contract was between $364 and $404 million, with the higher amount tied to the delivery of product having four-year expiry dating. First deliveries of BioThrax under this new contract are scheduled to begin in 3Q 2009, immediately following the scheduled completion of deliveries under the company's then ongoing $448 million contract to supply 18.75 million doses of BioThrax to the SNS. Final product deliveries under this new contract was anticipated in 3Q 2011. For Emergent Biosolutions, the new contract allowed for " seamless transition" and unterrupted manufacture of BioThrax.

In Jan. 2009, Emergent Biosolutions formed a joint venture with Ninebio Sdn. Bhd. (9Bio; Malaysia) for development and supply of biodefense countermeasures, including BioThrax. , and other medical and complementary products and services to the Government of Malaysia. Besides that Government of Malaysia, "It is anticipated that the joint venture will also supply such products and services to certain member countries of the Organisation of the Islamic Conference (OIC) and other countries within Asia. 9Bio is a Malaysian Government owned company and one of the National Institutes of Health under the Ministry of Health. 9Bio is fully funded by the Government of Malaysia."

In Dec. 2009,

In July 2010, Emergent BioSolutions signed a contract valued at up to $107 million with the Office of the Biomedical Advanced Research and Development Authority (BARDA) of the Department of Health and Human Services (HHS), to develop and obtain regulatory approval for large-scale manufacturing of BioThrax(in Building 55 at the company's vaccine manufacturing facility in Lansing, Michigan. This cost plus fixed fee development contract had a total value of $107 million and consisted of a two-year base period of performance valued at $54.6 million and three option years that, if exercised by BARDA, would increase the contract value to up to $107 million. The contract award was based on a technical proposal provided to BARDA that projected an annual large-scale manufacturing capacity of 26 million doses in Building 55, a significant increase from the company's current capacity of approximately 7-8 million doses/year. The contract also includes regulatory activities in support of the submission to FDA of a sBLA for BioThrax at the expanded scale.

Also in July 2010, Emergent BioSolutions completed separate international sales and deliveries of BioThrax to governments of several allied nations for a total of $2.3 million.

In Sept. 2010, Emergent BioSolutions signed a contract valued at up to $28.7 million with the National Institute of Allergy and Infectious Diseases (NIAID), NIH, for advanced development of the company's third generation anthrax vaccine candidate. The award of this contract increases to over $58 million the total potential development funding from NIAID for this product. This product candidate, one of two third generation vaccines being developed as part of Emergent's anthrax franchise, consists of BioThrax in combination with a novel immunostimulatory compound, CPG 7909 (VaxImmune). This 4-year development contract consisted of a two-year base, valued at $9.1 million, and milestone-based options that if exercised, would increase the total contract value to up to $28.7 million. The base contract funds activities related to manufacturing and stability studies of Phase II clinical trial lots, process characterization and assay validation, and clinical trial preparation. The milestone-based options include continued stability testing of Phase II clinical trial lots and a clinical study to evaluate safety and immunogenicity of the product candidate. The Phase II clinical trial was anticipated to begin in the first quarter of 2012. This new contract was awarded to expand the development efforts being conducted under a Biomedical Advanced Research and Development Authority (BARDA)/NIAID contract awarded in Sept. 2008, which provides for funding of up to $29.7 million. Thus, with this new contract, the potential funding from the U.S. government for this third generation anthrax vaccine candidate increased to over $58 million.

In May 2011, Emergent BioSolutions signed a modification to its current procurement contract (200-2009-30162) with the U.S. government to supply an additional 3.42 million doses of BioThrax. This modification to the contract is valued at up to $101 million for the delivery and shipping of additional doses of BioThrax beginning 3Q 2011. Delivery of these doses commences immediately following early completion of final delivery of the original 14.5 million doses of BioThrax under the contract prior to this modification. Emergent anticipated completing all deliveries of these additional 3.42 million doses of BioThrax during 2011.

In Oct. 2011, Emergent BioSolutions received an award in response to solicitation RFP-2011-N-13414to supply the U.S. government with 44.75 million doses of BioThrax over a period of five years for a total value of up to $1.25 billion. Initial deliveries began in 2011 with 8.5 million doses scheduled to be delivered during the first contract year. Deliveries are scheduled to continue, subject to availability of funding, through Sep. 2016. The company retains the ability to modify the timing of deliveries depending on manufacturing yields and other factors.

Manufacture: Limited information is available regarding the manufacture of Anthrax Vaccine Adsorbed. Bio-Port reports that largely due to national security concerns, it is “not aware of any publications that specifically detail our facilities and manufacturing process in the public domain.” However, the basics of the manufacturing process, which predates consideration of anthrax vaccine as a strategic defense commodity, have been reported.

Bacillus anthracis (nonencapsulated, nonproteolytic strain V770-NP1-R) cultures are grown in a synthetic liquid medium (similar to Puziss-Wright 1095) under conditions with little oxygen (microaerophilic). This strain is nontoxigenic (does not produce anthrax toxin). The culture fluid (supernatant) is filtered to remove bacterial cells. The filtrate is adsorbed onto aluminum hydroxide (Alhydrogel from Superfos), yielding an opaque suspension. This is formulated to contain 0.85% sodium chloride to make the product isotonic with body fluids. Multi-dose vials also contain <0.02% formaldehyde and <0.0025% benzethonium chloride as antimicrobial preservatives. All fermentation steps, bulk formulation and adsorption, and filling are sterile, aseptic processes. The manufacturing is controlled by stringent quality control measures (information not available). The potency of the vaccine is assayed by protection of vaccinated guinea pigs against challenge with 1,000 spores of the virulent Vollum strain of anthrax (21 CFR 620.20 through 620.24). Filling of vials is performed under (sub)contract by Hollister-Stier Laboratories LLC.

FDA class: Biologic PLA

Approvals: Date = 19701110; first approval, PLA; granted to Michigan Department of Public Health

Date = 19981112; PLA/ELA revoked from Michigan Biologics Products Inst. and reissued to new owner, BioPort Corp.

Date = 20020131; BLA supplements (essentially reapproval of the vaccine), including use of Hollister-Stier Labs. as contract manufacturer for filling, and update of labeling

Date = 20040429; BLA supplement; Indication = increased the dating period to 24 months at 2-8˚C (refrigerated)

Date = 20050427; BLA supplement; Indication = increased the dating period to 36 months at 2-8˚C

Date = 20081211; sBLA; Indication = include a change in schedule from 0, 2, 4 weeks and 6, 12 and 18 months to 0, 4 weeks, and 6, 12, and 18 months, and a change in route of administration from subcutaneous to intramuscular.

Date = 20090600; supplemental BLA; Indication = shelf life extension from 3 to 4 years

Date = 20120517; supplemental BLA; Indication = change the administration schedule to a three-dose primary series of intramuscular injections at 0, 1, and 6 months. The booster series consists of intramuscular injections at 12 and 18 months after initiation of the primary series, and at 1-year intervals thereafter for those who remain at risk. Individuals are not considered protected until they have completed the three-dose primary immunization series.

Indications: [full text of "INDICATIONS AND USAGE” section of insert/labeling]:

BioThrax is indicated for the active immunization against Bacillus anthracis of individuals between and 65 years of age who come in contact with animal products such as hides, hair or bones that come from anthrax endemic areas, and that may be contaminated with Bacillus anthracis spores. BioThrax is also indicated for individuals at high risk of exposure to Bacillus anthracis spores such as veterinarians, laboratory workers and others whose occupation may involve handling potentially infected animals or other contaminated materials. Since the risk of anthrax infection in the general population is low, routine immunization is not recommended. The safety and efficacy of BioThrax in a post-exposure setting has not been established.

Status: See the History and Companies sections for prior background and further information.

As of Jan. 2006, the Dept. of Defense has immunized more than 1.3 million military personnel with AVA/BioThrax.

Mr. Elengold, then Deputy Director, Operations, Center for Biologics Evaluation and Research (CBER), FDA, noted in Congressional testimony, Oct. 3, 2000, that FDA had inspected the AVA manufacturing facility on many occasions during the past decade and identified a number of deficiencies requiring correction. In particular, FDA conducted a surveillance inspection of MBPI in Nov. 1996. FDA documented numerous significant deviations from FDA regulations and current Good Manufacturing Practices (GMPs). FDA issued a Notice of Intent to Revoke (NOIR) letter to MBPI in March 1997. The letter stated that if MBPI’s corrective actions proved to be inadequate, the facility would run the risk of license revocation. MBPI responded to the NOIR with a “Strategic Plan for Compliance” presented to FDA in April 1997.

In Jan. 1998, MBPI halted production of anthrax vaccine sublots (prior to the sale of MBPI to BioPort) to begin a comprehensive renovation of the anthrax production facility. In Feb. 1998, FDA conducted a follow-up inspection of the MBPI facility to evaluate compliance with its strategic plan. The inspection disclosed significant deviations from cGMP regulations. FDA also noted that MBPI had made progress in achieving its compliance goals, but additional work remained in order to correct the deviations related to manufacture. Pursuant to its purchase of the troubled MBPI facility in Sept. 1998, BioPort agreed to abide by the strategic plan and other commitments for corrective actions made by the management of MBPI. During an Oct. 1998 inspection of BioPort, FDA found some improvements.

FDA conducted a pre-approval inspection of BioPort in Nov. 1999. This inspection was more focused in scope and purpose than the Feb. and October 1998 surveillance inspections. BioPort received a Form FDA 483 with observations and possible GMP deviations in some of the following areas: validation, failure to investigate, manufacturing deviations, deviation reporting, aseptic processing, filling operations, standard operating procedures, stability testing, and environmental monitoring. All observations on the Form FDA 483 must be addressed adequately before FDA could approve BioPort’s pending supplemental application for resumption of AVA manufacture and approval of its renovated facilities.

In Dec. 2000, CBER/FDA reported that AVA was one of the relatively few vaccines being manufactured using bovine-derived material of unknown/undocumented origin, possibly from countries on the official USDA list of countries known to have cattle with BSE. BioPort resolved this situation, including generating new intermediate and working seed stocks. See the Status section of the Vaccine Products (#400) entry for further information about bovine materials and BSE/TSE concerns with vaccines.

BioPort subsequently had another FDA inspection and received a citation with 18 observations, most involving the filling and packaging suite. Bioport decided to seek a contractor (Hollister-Stier Labs.) to assume these tasks.

In late August 2000, FDA approved ciprofloxacin (Cipro), an antibiotic, for treatment of inhalation anthrax. This provided the first approved drug treatment explicitly for inhalational exposure, such as would likely occur with use of B. anthracis for biological warfare or terrorism. Approval allows DOD and other government agencies to adopt and stockpile the antibiotic. With the vaccine then unavailable, approval of Cipro for inhalational anthrax exposure provided an option for treatment (and prevention, if used off-label) of inhalational anthrax, including biological warfare/bioterrorism. However, antibiotics are not particularly useful for preexposure prophylaxis in most of DOD’s scenarios.

In Oct. 2001, a series of letters laden with weaponized-grade (finely milled, nonaggregated) anthrax spores were sent through the U.S. mail to several high visibility targets, including a major tabloid newspaper and several Congressmen. This resulted in the death of five persons from inhalational anthrax, and contaminated Congressional and other offices and postal facilities. After these anthrax-related terrorist attacks, approximately 10,000 persons, including Congressional and postal workers, were recommended to receive a 60-day regimen of antimicrobial prophylaxis with ciproflaxin (Cipro) or other oral antibiotic treatment for suspected or confirmed exposure to B. anthracis spores. However, adherence to the recommended 60-day antibiotic regimens was as low as 42%. Because studies of the 2001 terrorist attacks suggest that some persons might have been exposed to B. anthracis spores in excess of those studied in animal models, the effectiveness of antimicrobial prophylaxis alone in such persons is considered unclear. Only about 200 persons received a course of BioThrax vaccination. Despite the low level of postexposure prophylactic treatment, no deaths from anthrax occurred in persons recommended to take antimicrobial prophylaxis after the attacks of 2001.

In Dec. 2001, the Centers for Disease Control and Prevention (CDC) obtained 220,000 doses of BioThrax for potential emergency use in civilians (then for use under an IND, if needed), enough to fully vaccinate 36,000-73,000 people. With the vaccine then lacking full approval, the CDC developed extensive informed consent and patient monitoring procedures in collaboration with FDA.

In Jan. 2002, CBER/FDA essentially (re)approved vaccine manufactured in BioPort’s new facilities, releasing (approving distribution of) three lots of BioThrax or about 209,000 doses. This allowing the DOD to resume vaccine purchases and active vaccination of military personnel. The product insert/labeling was also modified with more explicit warnings about adverse effects. This vaccine had been manufactured in 2001, and these were the first lots of vaccine manufactured by the renovated facilities. In Feb. 2002, DOD decided that the current anthrax vaccine will continue to be used on a limited basis to protect the 2.4 million U.S. military personnel, but only until other options, including the possibility of a new vaccine, are fully explored. This allowed the DOD to resume active vaccination of military personnel.

In March 2002, an Institute of Medicine (IOM), National Academy of Sciences (NAS), study concluded that AVA appears effective for prevention of inhalational anthrax, including bioterrorism/biological warfare use of weaponized anthrax spores. No unexpected risks were found to be associated with AVA, with injection site soreness and redness in about one-third to 50% of recipients, and more serious adverse effects, e.g., fever and malaise, far less common. AVA was considered impractical for public use, and development of improved vaccines, e.g., requiring few injections and shorter time for immunity, was recommended. Long-term AVA safety studies were also recommended.

In Dec. 2003, the Advisory Committee on Immunization Practices, Centers for Disease Control (CDC), issued supplemental recommendations for using anthrax vaccine in response to bioterrorism. This included recommendations for laboratory workers and other at risk to receive pre-exposure vaccination. For postexposure prophylaxis (PEP), a course of three injections (0, 2, 4 weeks) combined with antibiotic treatment is recommended. This would be administered under an Investigational New Drug (IND) application filed by CDC with FDA for AVA use in unvaccinated persons at risk for inhalational anthrax (since AVA is not approved for postexposure use in preventing anthrax).

In Aug. 2004, it was reported that despite pledges to do so, the federal government had failed to develop and maintain a biodefense stockpile for civilian use. Only 159 vials of anthrax vaccine had been set aside for civilian use according to congressional and administration officials. At the time, BioPort was storing (for DOD) enough BioThrax to fully vaccinate more than 330,000 people, and the Dept. of Health and Human Services (DHHS) had not purchased any vaccine from BioPort (perhaps, hoping it would be transferred at no cost by DOD, or looking forward to contracting for purchase of a recombinant vaccine, as it later did).

In Dec. 24, 2003, the U.S. District Court for the District of Columbia ruled in a class action lawsuit brought by six military personnel having refused AVA vaccination. The judge concluded that AVA should be classified as “investigational” and an off-label/unapproved indication with regard to protecting against inhalation anthrax, and that there was no justification for the DOD considering Anthrax vaccination to be mandatory. The judge concluded that AVA was only approved for the prevention of cutaneous anthrax, despite the product insert/labeling stating it is effective against anthrax irrespective of route of exposure. With this ruling, military use of the vaccine was temporarily halted.

On Dec. 31, 2003, one week later, FDA issued its “Final Rule and Final Order Regarding Safety and Efficacy of Anthrax Vaccine.” FDA ruled the vaccine was safe and effective, independent of route of exposure, with this in line with conclusions from a 2002 Institute of Medicine study that concluded the vaccine is effective “for the protection of humans against anthrax, including inhalation anthrax, caused by all known or plausible engineered strains of Bacillus anthracis.”

On Dec. 31, 2003, on the same day as the Final Rule allowing restart of vaccination was promulgated by FDA supporting BioThrax, the Department of Defense (DOD) signed a 3-year, $245 million contract with BioPort for supply of BioThrax (confident that the court-ordered halt to mandatory military anthrax vaccination would soon be lifted). The number of doses to be ordered was not disclosed. DOD has flexibility in the amounts it orders, including the ability to increase its purchases over the three years. Other federal agencies may purchase BioThrax through the DOD contract.

On Jan. 6, 2004, the court granted a motion by Justice Department seeking reinstatement of the governments’ vaccination program, except for the six plaintiffs having filed the class-action lawsuit; and DOD immediately reinstated its mandatory anthrax vaccination program.

In March 2004, the government of Taiwan purchased an undisclosed amount of BioThrax for immunization of laboratory workers and to create a stockpile for emergency use. This was the BioPort’s first commercial sale of the vaccine. Many other commercial sales, i.e., sales to foreign militaries, are likely to follow.

In March 2004, the Department of Homeland Security and the Department of Health and Human Services announced their intention to purchase 25,000 million doses of BioThrax for near term civilian (not military) contingency use against bioterrorist or biological warfare.

In April 2004, a full monograph for BioThrax was published in the U.S. Pharmacopeia (USP) National Formulary (NF), issue 27-NF 22 supplement.

As of June 2004, ~1.1 million persons, nearly all in the U.S. military, had received BioThrax, a total of >4 million doses, since 1998. BioThrax remains the only licensed anthrax vaccine worldwide. The U.S. government (DOD) has reportedly spent ~$1.4 billion on AVA and Bioport.

On July 1, 2004, the DOD formally announced that all troops deployed to areas managed by U.S. Central Command, stretching from North Africa to Pakistan, as well as South Korea, and selected other groups, will be vaccinated against anthrax (and also smallpox).

On Oct. 27, 2004, the U.S. District Court for the District of Columbia (the Court) issued an opinion overturning FDA’s finding in Dec. 2003 that AVA/BioThrax is effective to prevent inhalation anthrax regardless of the route of exposure. The court did not suspend or revoke the vaccine’s approval for the prevention of anthrax disease and the vaccine remains licensed. However, an injunction ordering halt of the Anthrax Vaccine Immunization Program (AVIP) by DOD was issued, and vaccination was halted. This new injunction was based on a conclusion by the Court that FDA was required by its regulations to solicit additional public comments before finalizing its conclusion that anthrax vaccine is safe and effective for protection against inhalational anthrax. At this point, about 1.2 million U.S. citizens, primarily in the military, had received anthrax vaccination since 1998.

On Jan. 14, 2005, the Dept. of Health and Human Services (DHHS) issued an Emergency Use Authorization (EUA), authorizing DOD to restart vaccination of members of the armed services for anthrax under an emergency provision included in the Project BioShield Act of 2004 (once the U.S. District Court removes its injunction against vaccination) (See Fed. Reg., 2/2/2005). The EUA is essentially comparable to an IND or limited approval. Prior to the EUA and needed to implement it, the DOD ruled that a significant potential for a military emergency exists, involving heightened risk for certain U.S. military forces from attack with anthrax spores. The FDA stated that, under the approved product labeling, anthrax vaccine may be used to immunize against anthrax caused by any route of exposure, including inhalational anthrax. The authority for issuing an EUA is a provision of the Federal Food Drug, and Cosmetic Act, as amended by the Project BioShield Act of 2004. The BioShield Act allows the FDA to approve biodefense pharmaceuticals that have not been fully tested in the event of an emergency or for critical biodefense needs. Under BioShield, anthrax vaccinations must be voluntary and service members must be informed about the vaccine and its potential side effects.

In April 2005, the U.S. District Court modified its earlier injunction against mandatory anthrax vaccinations by DOD, ruling that inoculations can proceed as long as service men and women are fully informed of the risks involved and are allowed to forego vaccination without fear of reprisal. Subsequent to the prior ruling that use of BioThrax for inhalation anthrax prophylaxis was essentially illegal since it was never approved by the FDA for this indication, the Bioshield Act had been signed into law in the prior year, with this explicitly allowing such vaccinations. Thus, vaccination of U.S. military personnel resumed. Technically, they may refuse vaccination.

As of May 2005, BioPort was supplying the Department of Defense (DOD) with an undisclosed number of doses of AVA/BioTrax under a 3-year, $245 million contract signed in Dec. 2003; and BioPort was supplying the Department of Health and Human Services (DHHS) with 5 million doses for the civilian biodefense stockpile under a $122.7 million contract awarded in May 2005.

In Aug. 2005, FDA extended the emergency-use authorization (EUA) for U.S. military use of the BioThax in individuals who face a heightened risk of exposure. The EUA, which was issued in Jan. 2005 (see above), will remain in effective for the duration of the declaration of emergency (probably, until rPA vaccine become available).

In Oct. 2005, the same U.S. federal judge (E. Sullivan) who had stopped the mandatory DOD anthrax vaccination program in 2004 issued an order that military personnel receive detailed instructions (informed consent) and the opportunity to refuse vaccination before receiving voluntary anthrax vaccination.

In the Dec. 15, 2005 Federal Register, FDA published an updated, 73-page, Final Order concluding that anthrax vaccine (BioThrax) is safe and effective against all routes of exposure, including inhalation anthrax. “After review of the comments and finding no additional scientific evidence to alter the proposed categorization, FDA accepts the Panel’s recommendation and adopts Category I as the final category for AVA and determines AVA to be safe and effective and not misbranded.” This allowed DOD vaccinations to continue as it had since April 2005 (on a voluntary basis, for the same eligible people; technically, until DOD completes its own policy review). With this, DOD resumed its prior vaccination programs. The order was based on a full analysis of available clinical data and adverse event reports on AVA/BioThrax, as well as review of approximately 350 comments submitted during the public review process. The ruling was supported by more than 20 scientific studies in 27 peer-reviewed journals, and numerous expert panels, notably the Institute of Medicine’s Committee to Assess the Safety and Efficacy of the Anthrax Vaccine, the Anthrax Vaccine Expert Committee established by the Department of Health and Human Services, the CDC’s Advisory Committee on Immunization Practices, and the Panel on Review of Bacterial Vaccines and Toxoids convened by FDA. Regarding allegations that BioThrax was approved illegally/improperly, FDA stated, “We disagree. AVA has been legally licensed since November 1970.”

With the FDA ruling in support of the vaccine and with no court-ordered injunctions in force, the vaccine is again being administered by DOD, primarily to troops going to or in Korea, the Middle East, and South Asia, and to researchers and others working with B. anthracis.

On May 6, 2006, the Dept. of Health and Human Services (DHHS) granted a $120 million, five year contact to BioPort for supply of an additional 5 million doses ($24/dose) of BioThrax for addition to the civilian biodefense (Project BioShield) stockpile by Sept. 2007. Combined with another 5 million dosed delivered in early 2006, this 10 million doses was expected to bridge the period until expected approval of recombinant Bacillus anthracis protective antigen vaccine, but which has been abandoned its contractor (rPA from VaxGen; see #103). By Dec. 2006, over 4 million doses from the 5 million dose order had been delivered.

In 2006, Emergent BioSolutoins signed a contract amendment with DOD for the delivery of about 1 million additional doses of BioThrax, with final delivery scheduled by Sept. 2007.

In Aug. 2006, BioThrax received certification and designation as a “qualified anti-terrorism technology” (QATT) under the “Support Anti-Terrorism by Fostering Effective Technology Act” (SAFETY Act) by the Department of Homeland Security. BioThrax is the first vaccine to receive this recognition. Designation provides the seller of a QATT with several benefits, including exclusive jurisdiction in federal court, limitation of liability to a specified amount of insurance coverage, and a bar on punitive damages. “Certification” confers status as an “Approved Product for Homeland Security” and enables the seller to invoke a rebuttable presumption that the government contractor defense applies, with this designed (untested) to eliminate liability for claims arising from terrorism.

In Oct. 2006, the DOD announced it was resuming manditory vaccination with BioThrax, but only for troops in Iraq, Afghanistan and South Korea, where there was presumed to be a credible threat for exposure to anthrax spores as a biological/bioterrorist weapon.

In Feb. 2007, FDA granted BioThrax fast-track designation for a sBLA seeking approval for used in combination with antibiotics as a treatment for people after they have been exposed to B. anthracis spore inhalation (post-exposure prophylaxis), using a three-dose regimen administered two weeks apart. Current presumptions by DOD and other vaccine supporters are that BioThrax is and will be effective for post-infection/post-exposure prophylaxis/treatment when used in combination with antibiotics, with the vaccine alone not effective for post-exposure use. However, this is largely based on a single spore inhalation study in monkeys (discussed above), and will likely be controversial. For example, in Nov. 2005, Dr. A. Friedlander, one of the original developers of AVA with USAMRIID, stated that ”The vaccine alone doesn’t protect and we wouldn’t expect it to protect” those already exposed anthrax.” Most use (inoculations) of the vaccine is for pre-exposure prophylaxis, like most other vaccines, with stocks (millions of doses) stockpiled for emergency use to prevent, not treat, anthrax in those potentially exposed.

In April 2007, the Department of Health and Human Services (DHHS) and the Department of Defense (DOD) issued separate notices of their intent to order up to a combined 22.75 million doses of BioThrax needed to maintain the government’s stockpile (with vaccine being used by the military and supplies aging). DHHS in its Presolicitation Notice stated its intent to procure 10.4 million doses of BioThrax for the country’s strategic national (civilian) stockpile, with options for up to an additional 8.35 million doses. DOD is its Special Notice announced an anticipated contract to order a minimum of 4 million doses of the vaccine.

With the demise of the recombinant anthrax vaccine that VaxGen had been developing and manufacturing under contract in late 2006 and early 2007, BioThax is the only vaccine available in the near term for U.S. and other governments’ procurement.     

In May 2007, Emergent BioSolutions nonexclusively licensed use of VaxImmune vaccine adjuvants from Coley Pharmaceutical Group, Inc. Emergent intends to utilize VaxImmune in the development of new anthrax vaccines, i.e,. reformulate BioThrax. VaxImmune is a Toll-like receptor 9 (TLR9) agonist designed to induce both an enhanced antibody response and a potent killer T cell immune response to infectious microorganisms. A trial jointly conducted by Emergent and Coley, with funding from the Defense Advanced Research Programs Agency (DARPA), DOD, in 2005 showed that VaxImmune significantly boosted immune responses to BioThrax. Some critics have speculated that, faced with eventual competition or replacement by recombinant B. anthracis protective antigen (rPA) vaccines, Emergent is trying to extend the life of BioThrax by reformulating and improving it with a potent adjuvant system.

As of May 2007 (simply stated), since 1998, BioPort Corp./Emergent BioSolutions had filled orders from the U.S. government for about 19 million doses of Biothrax/AVA (at ≤$25/dose).

IN Oct. 2007, the Government Accountability Office (GAO) issued a report concerning the governments stockpiling of anthrax vaccine. Findings included that at the time about $12 million of anthrax vaccine in the Strategic National Stockpile (NS) had expired. The vaccine was then being kept for use in an emergency, even though FDA regulations prohibit expired vaccines from being administered. Starting in 2008, about $100 million of the stockpiled vaccine would go out of date each year. The GAO also said that because the Defense Department buys its vaccine separately, having two programs was wasteful; and the Department of Health and Human Services' (HHS) effort to replace that vaccine with one easier to use and with fewer side effects has been hobbled by unrealistic expectations. This was after HHS had abandoned a $877.5 million contract with VaxGen of California to develop a recombinant anthrax vaccine (rPA). The GOA asserted that the government rushed into the contract with VaxGen, setting unrealistic standards and timelines that would have been difficult for even a large firm to meet.

In March 2008, a U.S. District judge dismissed the class-action lawsuit that had been filed by six military personnel challenging the Pentagon's policy of compulsory anthrax vaccinations for certain troops. The military personnel had argued that they should not be forced to take the vaccine because there is no scientific proof that it is effective for humans. The class-action lawsuit had asked the court to block the DOD from inoculating the plaintiffs and to rule that the vaccine was improperly licensed by FDA. Judge R.M. Collyer ruled that the FDA "did not act arbitrarily or capriciously" and granted the government's request to dismiss the case. The plaintiffs are pursuing an appeal.

In Oct. 2008, BioThrax was designated by HHS as a covered countermeasure to a public health emergency under the Public Readiness and Emergency Preparedness Act, with this providing Emergent BioSolutions with considerable protection from liability suits.

In Dec. 2008, FDA approved a change in schedule from 0, 2, 4 weeks and 6, 12 and 18 months to 0, 4 weeks, and 6, 12, and 18 months, and a change in route of administration from subcutaneous to intramuscular. This essentially changed the vaccination series by allowing removal of the 2 week dose and supported the safety and effectiveness of the new 5 dose regimen. This was a change from the originally licensed 6 dose regimen. The route of administration changed from a subcutaneous injection over the deltoid to an intramuscular injection in the deltoid. The route change to IM had been shown to significantly reduce the local reactions and discomfort at the injection site and still afford the same level of protection against anthrax as with the previous SC injections.

     On Feb. 12, 2009, Emergent BioSolutions received approval from the Drugs Controller General of India (DCGI) for BioThrax for prevention of anthrax infection.

In late 2011, Emergent reported it had delivered a total of over 55 million doses of BioThrax to the U.S. government and continues to deliver additional doses under active procurement contracts. Since 1998, over 10 million doses of BioThrax had been administered to more than 2.6 million military personnel.

In April 2012, the Homeland Security Department and the Centers for Disease Control and Prevention (CDC) announced plans to make unused federal stocks of anthrax vaccine available to certain nonmilitary emergency personnel in a trial program. Select first responders at the state and local level have the option to receive a federally funded course of anthrax vaccination doses. The CDC Advisory Committee on Immunization Practices helped clear the way for the pilot program in 2010 by recommending that emergency personnel have the option to obtain anthrax vaccine voluntarily if they are "engaged in response activities that might lead to exposure" to the bacteria through the air. Officials did not indicate when the program would launch or how much vaccine would be made available.

In May 2012, FDA approved a new administration schedule. This sBLA was based on a Final Study Report from a large multi-center study initiated by the CDC in 2002. This study was designed to evaluate whether as few as three doses of BioThrax administered over six months, with booster doses to follow, would confer an adequate immune response. CDC completed the study in 2009, and Emergent submitted the sBLA in 2010.

In June 2012, Emergent BioSolutions reached an agreement with the Biomedical Advanced Research and Development Authority (BARDA) to conduct a non-interference study to be used to support a Post-Exposure Prophylaxis (PEP) indication for BioThrax. This agreement provided the company with up to $8.43 million in additional funding. The non-interference trial, targeted to commence in the fourth quarter of 2012, involves 120 healthy volunteers to demonstrate non-interference of BioThrax when administered in conjunction with antibiotics. Approval of a PEP indication would enable BioThrax to be used in combination with antibiotics in people suspected to have been exposed to anthrax spores. Currently, BioThrax only has a pre-exposure prophylaxis indication. Immune protection in this setting is important because of the potential for residual anthrax spores to germinate and cause disease after the currently recommended 60-day course of antibiotic treatment has stopped. Separately, under its development contract with BARDA, Emergent had completed dosing and the last subject visit in a pivotal PEP immunogenicity and safety study evaluating a three-dose vaccination schedule for BioThrax. Data from this study, which involves 200 healthy volunteers, will also be used by the company in support of a PEP indication for BioThrax.

Trials: Original approval was largely based on a well controlled trial of anthrax vaccine in U.S. mill workers processing imported animal hair. During the trial, 26 cases of anthrax were reported at the mills - five inhalational and 21 cutaneous cases. Of the five inhalation cases, two had received the placebo and three were in the observational group. Four of the five people who developed inhalation anthrax died. No cases of inhalation anthrax occurred in vaccine recipients. The authors calculated a vaccine efficacy level of 92.5%. There is much other field experience supporting the efficacy of AVA for prevention of occupationally-contracted anthrax.

The Centers for Disease Control and Prevention (CDC) is sponsoring ongoing clinical trials with BioThrax. This includes a trial in 1,300 volunteers testing four and five (vs. current 6) injection regimens and intramuscular, rather than subcutaneous, injection. CDC is also sponsoring primate studies to determine optimal dosage, and to find a way to link primate and human efficacy data. An epidemiological study is studying long-term safety among 1,300 or more textile mill workers having received AVA at plant that has required vaccination of all employees for over 30 years. Other safety studies are examining military vaccination records.

In the Feb. 19, 2007 issue of Vaccine, it was reported that serum anti-protective antigen (PA) concentrations in Marines who had not completed a full vaccination series of six injections with BioThrax still provided a significant antibody response, and that six doses provided no significant advantage over four doses. The investigators examined Marines having partially completed their vaccination regimens after DOD suspended vaccination in late 2004. The CDC’s reactive threshold of 3 µg/ml was used to define a positive antibody response to vaccination.

Medical: With the Dec. 2008 approval, the primary anthrax vaccine series schedule in the U.S. changed. Anthrax vaccinations are now given as a series of five 0.5-ml intramuscular doses, optimally at 0, 4 weeks, 6 months, 12 months, and 18 months, with annual boosters given to maintain immunity. Doses of the vaccine should not be administered on a compressed or accelerated schedule. The originally-approved primary 6 dose schedule of 0, 2 weeks, and 4 weeks, 6 months, 12 months, and 18 months may still be used.

Primary immunization consists of subcutaneous injections, 0.5 mL each, at 0, 2 and 4 weeks, with boosters given at 6, 12, and 18 months (total of 6 inoculations. If immunity is to be maintained, subsequent booster injec-tions of 0.5 mL at one year intervals are recommended. Although protection levels increase as shots in the series are given, the entire six-shot series is required (recommended) for full protection, as approved by the FDA and implemented by DOD. The vaccine is not recommended for use in persons <18 years of age (since no adequate studies have been performed in these populations). AVA is the only aluminum-adsorbed vaccine administered subcutaneously rather than intramuscularly, a route associated with fewer serious local reactions.

Mild local skin reactions at the site of injection are common (in about 30% of recipients). These generally occur within 24 hours and start to resolve by 48 hours. The most common side effects reported after injection are mild discomfort (localized swelling and redness at the site of injection), joint aches, and in a few cases, nausea, loss of appetite, and headaches. Many of these symptoms are not all that uncommon after injection of other inactivated bacterial vaccines. Con-tra-indications: for use of the vaccine include prior anthrax infection. Various other adverse events, many serious, have been associated with AVA, and the safety and use of the vaccine, particularly within the U.S. military, continues to be controversial.

In Oct. 2001, it was reported that about 521,000 persons (out of about 2.4 million) in the U.S. military had received one or more AVA inoculations since 1998, a total of 1.2 million doses administered. Among these, 1,628 reported adverse effects, mostly local redness and swelling, but including 10 cases of massive swelling of the arm requiring hospitalization and 15 cases of anaphylaxis. Also, the Centers for Disease Control and Prevention (CDC) reported finding no patterns of unexpected local or systemic adverse events linked to AVA among military personnel. Out of 409,000 people vaccinated with more than 1.5 million doses, only 620 adverse events had been reported, including 26 people who were hospitalized, and only six cases were related to the vaccine (see MMWR, Vol. 49, No. 16, p. 341).

Since the beginning of FDA’s Vaccine Adverse Event Reporting System (VAERS) in 1990, through Sept.15, 2000, 1,561 reports of adverse events associated with use of the anthrax vaccine had been reported to VAERS. During this period, approximately 2,000,000 doses of the vaccine had been distributed. Of those reports, 76 (4.9%) were considered serious events (either fatal, life threatening, or resulting in hospitalization or permanent disability). These reports are for diverse conditions, and FDA reports there are no clear patterns emerging at this time. Most reports were limited to injection site reactions, e.g., local hypersensitivity, edema, and pain, with other reports of headache, joint pain and pruritus (itching). None of these events, except for the injection site reactions, can be attributed to the vaccine with a high level of confidence, nor can causation by the vaccine be entirely ruled out.

For its original primary use, as a commercial vaccine for civilians potentially occupationally exposed to anthrax, the vaccine has compiled an overall excellent safety record. From 1971-1978, the FDA (VAERS) received only 1 report of an adverse reaction (and this reaction was attributed to the use of dirty needle to inject the vaccine). However, reports of adverse events substantially increased with the DOD large-scale vaccination efforts and associated publicity and controversies.

In Dec. 2008, FDA approved a change in schedule from 0, 2, 4 weeks and 6, 12 and 18 months to 0, 4 weeks, and 6, 12, and 18 months, and a change in route of administration from subcutaneous to intramuscular.

Market: First-half 2013 sales were reported to be $88 million.

In 2007, Emergent BioSolutions reported, "Product sales for 2007 consisted of BioThrax sales to HHS of $141.6 million, sales to DoD of $26.2 million and aggregate international and other sales of $2.0 million."

In 2006, Emergent BioSolutions reported total product sales of $148.0 million, up from $127.3 million in 2005, with essentially all of this from sales of BioThrax, particularly delivery of 6 million doses to DHHS and DOD in 2006. The company reported, “ Product sales in 2006 consisted of BioThrax sales to HHS of $109.8 million, sales to DoD of $37.4 million and aggregate international and other sales of $0.8 million.”

The price paid by the federal government for BioThrax is on the order of up to $25/dose.

The 2007 Average Wholesale Price (AWP), i.e., for those few sales to the private sector for those occupationally to anthrax, is $1,331.19/10-dose vial (unchanged from 2004) (Red Book, 2007).

In Feb. 2009, Emergent BioSolutions reported, "Since 1998, the U.S. government has procured nearly 33.5 million doses of BioThrax. During that time period, nearly 8.4 million doses have been administered to more than 2.1 million military personnel."

Ongoing: CDC has been conducting studies, including comparing intramuscular vs. intradermal administration of BioThrax to see if this provides increased safety (decreased reactogenicity) and comparable efficacy.

Emergent is developing BioThax-based vaccines incorporating VaxImmune adjuvants (see above).

          On Sept. 26, 2008, Office of the Biomedical Advanced Research and Development Authority (BARDA) of the Department of Health and Human Services (HHS) and the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), awarded Emergent BioSolutions a contract valued at up to $29.7 million to fund the further development of AV7909, one of the company's rPA vaccine candidates. AVA7909 is composed of BioThrax and the immunostimulatory oligodeoxynucleotide compound CPG 7909 (VaxImmune) developed by Coley Pharmaceutical Group (purchased by Pfizer Inc. in 2007). The three-year contract provides up to $24.9 million for manufacturing of clinical lots, for non-clinical safety and efficacy studies, and for stability studies to further demonstrate that the vaccine candidate does not need refrigeration during storage, a key requirement of this vaccine development initiative. In addition, the contract provides up to $4.8 million for a Phase I clinical trial, to be funded as an option that, if exercised, would increase the value of the contract to $29.7 million.

Competition: In 1999, well before the terrorist attacks of 9/11/2001 and several incidents shortly thereafter of weaponized anthrax spores sent through the U.S. mail, Congress appropriated $20 million to the Centers for Disease Control and Prevention (CDC) for anthrax vaccine research and development, particularly clinical trials.

Post 9/11/2001 (after the Al Queda attacks on several major U.S. icons/buildings), with the increased threat of bioterrorist/biological warfare use of anthrax spores, the increased recognition of the need for better anthrax vaccines, increased federal R&D funding and contracts, implementation of the BioShield Act of 2004, and with hopes of large contracts and subsidies (e.g., those provided to BioPort), a number of organizations are developing new anthrax vaccines (with a few examples below). This includes recombinant B. anthracis protective antigen (rPA)-based vaccines. See the Anthrax Vaccine, rDNA entries (#103, #104) for further information about rPA vaccines.

The Centre for Applied Microbiology and Research (CAMR; U.K.) is currently manufacturing an AVA/Biothrax-like anthrax vaccine for the British Ministry of Defense (and perhaps other countries) using new manufacturing facilities. The U.K. government may be purchasing the vaccine through Ipsen S.A. (formerly a partner in the DynPort Vaccine biodefense vaccine joint venture), which holds/held rights to market products from CAMR.

In July 2004, Vical Inc. (San Diego, CA) initiated a Phase I trial with a cationic lipid-formulated bivalent DNA plasmid-based anthrax vaccine.

In July 2004, Cerus Corp. (Concord, MA) received a $3.8 million grant from the National Institute of Allergy and Infectious Diseases (NIAID), NIH, for development of a psoralen-inactivated anthrax vaccine.

Crucell N.V. concluded a Cooperative Research and Development Agreement (CRADA) with the Naval Medical Research Center, U.S. Navy, in Oct. 2005 for development of adenovirus vector vaccines cultured in PER.C6 cells, AdVac, vaccine against anthrax and plague, and testing in non-human primates.

In Oct. 2007, Ichor Medical Systems, whose advanced electroporation system is being used worldwide to increase the effectiveness of DNA drug and vaccine delivery, was awarded a 2-year contract valued at over $2.3 million by the Defense Threat Reduction Agency (DTRA). Ichor will assist the Biological Defense Research Directorate (BDRD) of the Naval Medical Research Center (NMRC) in the development of a DNA vaccine for anthrax and plague..

See also the Anthrax Immune Globulin entry for further anthrax antibody-based therapeutics development.

Ref.: a) DOD Web sites – www.anthrax.osd.mil; and www.defenselink.mil/specials/Anthrax, “Countering the Anthrax Threat. b) Anthrax Vaccine: Evidence for Safety and Efficacy Against Inhalational Anthrax, Friedlander, A.M., et. al., Journal of the American Medical Association (12/08/99) Vol. 282, No. 22, p. 2104; c) Consensus Statement by the Working Group on Civilian Biodefense, Journal of the American Medical Association, vol.. 281, no. 18, p. 1735, May 12, 1999; d) Transcript of presentation/Q&A by Colonel Dr. Friedlander, U.S. Army Medical Institute of Infectious Diseases (USAMRIID), Conference for Biological Warfare Defense Immunization, May 1999; e). Field Evaluation of a Human Anthrax Vaccine, Brachman, P.S., et. al., Amer. J. Pub. Health, 52:632-645, 1962; f) Advisory Committee for Immunization Practices. Adult Immunization, Morbidity and Mortality Weekly Report, 33(15):33-34, 1984; g) Hambleton, P, et al., Anthrax: The Disease in Relation to Vaccines, in Vaccine, vol. 2, p. 125-132, 1984. Special thanks to LTC J.D. Grabenstein, Ph.D., Anthrax Vaccine Immunization Agency, U.S. Army, for information and comments.