Anti-toxin Antibodies in Prophylaxis and Treatment of Inhalation Anthrax

Anette Schneemann; Marianne Manchester


Future Microbiol. 2009;4(1):35-43. 

In This Article

Abstract and Anthrax Pathogenesis


The CDC recommend 60 days of oral antibiotics combined with a three-dose series of the anthrax vaccine for prophylaxis after potential exposure to aerosolized Bacillus anthracis spores. The anthrax vaccine is currently not licensed for anthrax postexposure prophylaxis and has to be made available under an Investigational New Drug protocol. Postexposure prophylaxis based on antibiotics can be problematic in cases where the use of antibiotics is contraindicated. Furthermore, there is a concern that an exposure could involve antibiotic-resistant strains of B. anthracis. Availability of alternate treatment modalities that are effective in prophylaxis of inhalation anthrax is therefore highly desirable. A major research focus toward this end has been on passive immunization using polyclonal and monoclonal antibodies against B. anthracis toxin components. Since 2001, significant progress has been made in isolation and commercial development of monoclonal and polyclonal antibodies that function as potent neutralizers of anthrax lethal toxin in both a prophylactic and therapeutic setting. Several new products have completed Phase I clinical trials and are slated for addition to the National Strategic Stockpile. These rapid advances were possible because of major funding made available by the US government through programs such as Bioshield and the Biomedical Advanced Research and Development Authority. Continued government funding is critical to support the development of a robust biodefense industry.

Anthrax Pathogenesis

Bacillus anthracis, the causative agent of anthrax, is a Gram-positive, rod-shaped bacterium that forms highly resistant spores under conditions of environmental stress.[1] Spores represent a dormant, nonreproductive form of the bacterium that is resistant to UV light, desiccation, extreme temperatures and other environmental conditions. Spores can persist in nature for many decades, primarily in soil, and are very difficult to eradicate.

Owing to the soilborne nature of B. anthracis, anthrax mainly affects grazing animals but all mammals are susceptible to the disease. Natural infections of humans are rare in the USA and other countries where vaccination of livestock and people who are most likely to come in contact with diseased animals or their products is implemented. In humans, infection is initiated when spores enter the host by one of three routes: the cutaneous route through a cut or abrasion in the skin, the gastrointestinal route by ingestion of contaminated meat and the inhalational route by breathing in airborne spores.

Inhalation anthrax is the deadliest form of the disease because it is difficult to diagnose in a timely manner and since exposure via the inhalational route has the potential to affect a large number of individuals in the event of a deliberate release. Following inhalation, spores are taken up by alveolar macrophages and transported to the mediastinal lymph nodes. During this process, they germinate to form vegetative bacilli that enter the bloodstream and ultimately cause sepsis. The disease has a typical incubation period of 1-6 days and begins with relatively mild, flu-like symptoms such as malaise, fatigue and slightly elevated temperature. This is followed by respiratory distress, which abruptly and rapidly progresses to respiratory failure and shock despite aggressive antibiotic treatment.[2] Two virulence factors, the capsule, which allows the bacterium to evade phagocytosis, and two AB-type exotoxins, lethal toxin and edema toxin, are associated with anthrax pathogenesis.[3,4] The B moiety, protective antigen (PA), represents the cell-binding component required for the entry of the enzymatic A moieties, lethal factor (LF) and edema factor (EF).[5] LF is a zinc protease that cleaves several mitogen-activated protein kinase kinases leading to blockage of signaling pathways by which immune cells respond to pathogens.[6,7,8,9] EF is a calmodulin-dependent adenylate cyclase that generates unphysiologically high levels of cAMP.[10] This leads to impairment of intracellular signaling pathways, interference with phagocytosis by macrophages and disruption of waterhomeostasis with resulting edema.[11,12,13]


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