Anthrax, a deadly zoonotic disease due to Bacillus anthracis, has been known since antiquity
. The fifth and sixth plagues in the Bible's book of Exodus may have been outbreaks of anthrax in cattle and humans. Naturally occurring anthrax in humans is acquired from contact with anthrax-infected animals or anthrax-contaminated animal products, which allows one to distinguish agricultural anthrax, a most significant problem in developing countries especially among veterinarians, agricultural workers and butchers, and industrial anthrax, resulting from exposure to contaminated sheep wool or goat hair that are processed into yarns used in the textile and carpet industry, as well as cattle hides that are processed into leather goods, or bones used for the manufacture of gelatin and/or fertilizer.
Anthrax infection in humans occurs by three major routes, the skin, the respiratory tract or the gastro-intestinal tract, generating three different primary forms of the disease, the cutaneous, the inhalational and the gastro-intestinal forms  . Cutaneous anthrax presents as a small pruritic papule that develops within a week into a vesicle usually on an exposed part of the body such as the face, the neck or arm. Edema and erythema often develop around the lesion. The vesicle eventually ruptures, revealing a depressed ulcer crater that develops into a black eschar. The case fatality rate of cutaneous anthrax usually is about 20% if untreated. Inhalational anthrax presents within one to five days with nonspecific symptoms, fatigue, myalgia and slight fever, which are followed by a sudden severe respiratory distress with dyspnea, cyanosis, and stridor leading to a lethal shock syndrome associated with pulmonary haemorrhage and mediastinal edema. Systemic infection with B anthracis resulting from inhalation causes a 100% case fatality rate. As to gastrointestinal anthrax, it develops within 2 to 5 days following ingestion of contaminated meat with nausea, vomiting, fever, abdominal pain and diarrhoea, eventually leading to toxemia, shock and death in 25% to 75% of cases.
The incidence of natural anthrax in industrialized countries remains quite low and the disease is not a major public health problem in the world. Thus, between 1900 and 2005, only 82 cases of inhalational anthrax were reported in the USA . Occasional anthrax epidemics nevertheless did occur, such as the Zimbabwe epidemic in the early 1980s with approximately 10 000 cases reported. The scene changed in 2001 with the bioweapon attacks in the Eastern USA. Modelling studies showed that anthrax spores used as a bioweapon against civilian populations could generate catastrophic consequences  . It was for example estimated that the airborne delivery of 50 kgs of anthrax spores over a large city could lead to 125 000 severe clinical cases of anthrax and 95 000 deaths. This renewed the general interest for the field and prompted the development of new anthrax vaccines.
Control of anthrax in humans and animals is based on control measures in livestock in endemic areas, such as the safe disposal of anthrax carcasses and vaccination of at-risk cattle herds. Incineration of carcasses is a manner to prevent contamination of the surrounding soil. Local conditions in many endemic countries however make these simple control measures difficult to implement. In industrializaed countries, prevention lies in good agricultural and industriual hygiene.
B anthracis, the agent of anthrax, is a large gram-positive, spore-forming, nonmotile bacillus with little if any genetic variability. In tissues, the bacteria are encapsulated and appear singly or in short chains of a few bacilli. The spores are extremely resistant in the environment and may survive for decades in certain soil conditions. They eventually are ingested by cattle or wild animals such as deer
 when grazing on contaminated land.
B anthracis has two major virulence factors that are carried by two distinct plasmids, pX01 which carries the tripartite toxin genes cya (edema factor), lef (lethal factor) and pagA (protective antigen), and pX02, which carries the gene encoding the polyglutamate capsular filaments. The tripartite exotoxin consists of the 83 kD protective antigen (PA), the 90 kD lethal factor (LF), and the 89 kD edema factor (EF)  . PA binds to cellular receptors and mediates the entry into the cytosol of both LF, a Zn+ metalloprotease that cleaves mitogen-activated protein kinase kinases (MAPK), and EF, an adenylate cyclase that converts ATP to cyclic AMP (cAMP) and promotes lethal tissue edema   . The lethal toxin is composed of PA combined with LF while the edema toxin is made from the combination of PA and EF. Both LF and EF inhibit acquired and innate immune responses, allowing the bacteria to replicate unchecked in the host .
The polyglutamate capsule plays a major role as an invasiveness factor. Bacteria which lack plasmid pX02 and therefore are uncapsulated are attenuated for animals and can be used as live attenuated vaccines, as initially demonstrated by Sterne    (For a review, see ).
Anthrax vaccines are available for both animals and humans. However, in humans, their use has been confined to high-risk groups such as occupationally exposed workers and military personnel.
A few live attenuated B anthracis strains have been developed as vaccines, such as the uncapsulated Sterne strain for subcutaneous immunization of domestic animals or the uncapsulated SST-1 strain used in Russia and the Langzhou avirulent strain A16R developed in China. The latter are given by skin scarification as a single or a double immunization followed by yearly booster immunizations .
The human anthrax vaccine licensed in the USA is made from cell-free filtrates of bacterial cultures of an unencapsulated, nonvirulent strain of B. anthracis adsorbed to aluminium hydroxide (Anthrax Vaccine Adsorbed/BioThrax, Emergent BioSolutions Inc).   . To develop and maintain protective immunity in humans, these vaccines must be administered subcutaneously six times over 18 months, followed by yearly booster injections   . A recent study showed that by using the IM route of immunization rather than the SC route, effective immuninization required a three-dose schedule rather than the original four-dose schedule  . Still, these vaccines have shown only partial protection from infection with some strains of B. anthracis in animal models  . After the intentional release of anthrax spores in 2001, it was clear that a more effective, easily administered, and safer vaccine was needed for emergency situations     for both pre- and post-exposure prophylaxis.
While the poly-D-glutamic acid capsule is nonimmunogenic  , the PA component of the toxin has been shown to induce a protective antibody response in numerous studies using animal models of infection     and including inhalational anthrax  . Recent research has focused on the design of a recombinant PA (rPA) vaccine which would eliminate the need for filtered culture supernatants or whole B. anthracis lysates, as well as produce a more consistent immune response. Thus, rPA given to healthy adults in two IM injections four weeks apart with the adjuvant alhydrogel was well tolerated and highly immunogenic  . PA is the main component of the two licensed anthrax vaccines, Anthrax Vaccine Adsorbed (AVA) in the USA and Anthrax Vaccine Precipitated (AVP) in the UK.
Several new human adjuvants have been studied to be included in anthrax vaccines, including monophosphorylated lipid A (MPL A), saponin QS-21, and muramyl tripeptide linked with dipalmitol phosphatidylethanolamine. In recent attempts at developing mucosal anthrax vaccines a variety of other adjuvants were tested including soy phosphatidyl choline, cholera toxin (CT), and CpG oligonucleotides   . The use of soybean oil-and-water nanoemulsions (NEs) (NanoBio Corporation, Ann Arbor, MI) as a mucosal adjuvant appears very promising: the candidate vaccine generated long-term, high-titer neutralizing anti-PA IgAs and IgGs in mucosal secretions and provided significant protection of the animals against intranasal challenge with B anthracis spores after only two intranasal immunizations .
Live recombinant anthrax vaccines using bacterial or vaccinia virus vectors are also being developed, as well as recombinant HBc particles expressing a PA epitope   . The demonstration that spore components could offer additional protection in animal models has moreover lead to the development of a dual component candidate anthrax vaccine that combines rPA with formaldehyde-inactivated spores and was shown to be significantly protective against intra-nasal spore challenge in mice  . In a similar approach, PA was combined with LF and poly-gamma-glutamic acid (gamma PDGA) and administered by the intra nasal route in mice, inducing high level protective bactericidal antibodies  . Similarly, a trivalent vaccine composed of rPA added with inactivated LF and EF induced long-lasting protective immunity in rabbits .