Biological Warfare and the Fifth PlagueAnthrax
COMMENTARY
The Lord said to Moses, "Go into Pharaoh’s presence and say to him, These are the words of the Lord the God of the Hebrews: "Let my people go in order to worship me." If you refuse to let them go and still keep your hold on them, the Lord will strike your grazing herds, your horses and asses, your camels, cattle, and sheep with a terrible pestilence." And . . . "The next day the Lord struck. All the herds of Egypt died . . . " Exodus 9.1-7
The fifth plague of the book of exodus, a striking example of biological warfare of divine, rather than human, origin, may well have represented an outbreak of anthrax in domesticated ruminants. The number of humans who developed anthrax is, unfortunately, not recorded. However, Bacillus anthracis, the first bacterium demonstrated (by Robert Koch, in 1877) to be responsible for a specific disease (animal anthrax) has long been identified as a prime candidate for killing animal and human populations in the service of war.
In response to this potential, the Pentagon recently announced that it would vaccinate every member of the armed forces against anthrax. This amounts to approximately 1.4 million active duty troops and 1 million reservists. Active duty troops in the Persian Gulf and on the Korean peninsula will be the first to be vaccinated.
In this, anthrax may have won the historical competition against a number of alternative agents (Cole LA. Scientific American 1996;275:60-65). Romans dumped bodies into enemy water supplies in an attempt to contaminate them. During their 1346 A.D. siege, Tatars catapulted the cadavers of plague victims into the walled city of Kaffa, a Crimean Black Sea port now called Feodosiya. During the French and Indian war, an English officer named Ecuyer, possibly at the suggestion of Sir Jeffrey Amherst, the commander of British forces in North America, gave blankets from the smallpox hospital at Fort Pitt to Indians at Fort Carillon, which was later renamed Fort Ticonderoga. The Japanese tested anthrax and other bacteria on Chinese prisoners of war and, perhaps, civilians during the 1930s and 1940s, with at least 10,000 resulting deaths. The central unit for these activities was "Water Purification Unit 731." Field trials with these agents tested included delivery by spraying from aircraft. After the defeat of Japan, the individuals responsible for these atrocities, Shiro Ishii and Kitano Misaji, were granted immunity for war crimes prosecution in return for disclosure of information to the United States, which had instituted its own research in biologics in 1942. A list of agents that were stockpiled or actually "weaponized" by the United States prior to their destruction in 1971-1973 are listed in the Table (Christopher GW, et al. JAMA 1997;278:412-417).
Prior to that destruction, however, the U.S. Army surreptitiously tested means of aerosolization dispersal of what it believed to be non-pathogenic organisms in American cities, including New York and San Francisco. One of these "non-pathogens" was Serratia marcescens.
Not all biological attacks have been military in origin. In 1986, Ma Anand Sheela, the chief of staff for Bhagwan Shree Rajneesh during their Oregon ashram days, confessed to placing Salmonella typhimurium in the salad bars of four local restaurants, resulting in illness in at least 751 people, 40 of whom were hospitalized (Torok TJ, et al. JAMA 1997;278:389-395). More recently, muffins and doughnuts served in the staff lounge of a Texas Medical Center hospital laboratory were deliberately contaminated with Shigella dysenteriae (Kolavic SA, et al. JAMA 1997;278:396-398). Raids on the Aum Shinri Kyo after their release of sarin in the Tokyo subway discovered large caches of Clostridium botulinum, whose toxin presents a strong competitor to anthrax as a devastating biological weapon.
Anthrax has remained a prime biological warfare candidate for a number of reasons, including its easy compact storage in spore form, its potential for aerosol delivery, its ability to affect both animals and man, and the availability of a vaccine that could potentially protect the troops of the aggressor. Its use is within the reach of any group interested in biological warfare, and many countries have, in the past, developed stocks of anthrax spores. In April 1979, an explosion occurred at a military facility in Sverdlovsk, USSR (now Ekaterinburg, Russia); at least 66 deaths from anthrax ensued among individuals living or working within a distance of 4 km in a narrow zone paralleling the direction of the northerly wind which prevailed at the time (Meselson M, et al. Science 1994;18:1202-1208).
Table
Biological Agents Weaponized by U.S. and Destroyed in 1971-1973
Lethal Agents
Bacillus anthracis Botulinum toxin Francisella tularensis
Incapacitating Agents
Brucella suis Coxiella burnetii Staphylococcal enterotoxin B Venezuelan equine encephalitis virus
Adapted from Christopher GW, et al. JAMA 1997;278:412-417.
Among the downsides of the use of the anthrax Bacillus is its persistence in the environment. Biological warfare testing on the island of Gruinard off the northwest coast of Scotland in the 1940s resulted in persisting contamination of the soil with B. anthracis spores for four decades.
Anthrax is classified as cutaneous, gastrointestinal, and pulmonary. Descriptions of animal and human anthrax are scattered in ancient Hindu, Greek, and Roman literature. A 17th century epidemic of "black bane" swept through animals and humans in Europe. The cutaneous form of the disease subsequently received the name "malignant pustule."
The organism is susceptible in vitro to penicillin, ciprofloxacin, and doxycycline, and the cutaneous form is usually readily treatable. The pneumonic form, however, is usually fatal even if treated, although antibiotic therapy begun one day after inhalational exposure is protective in monkeys (Friedlander AM, et al. J Infect Dis 1993;167:1239-1243).
When administered as an aerosol, the infectious dose appears to be 8000-50,000 spores. Thus, aerosol dispersal of spores not only allows broadcast over a large area, which could be amplified by appropriate wind currents, but also carries with it a high mortality even if the disease and its victims are recognized and treated. It has been reported that a Special Operations unit of the U.S. Army dropped a light bulb filled with non-pathogenic Bacillus spores in front of a moving New York subway in July 1966, and was able to find spores dispersed widely in the subway system shortly thereafter.
The virulence of B. anthracis is due to several bacterial products. All virulent strains possess a poly-D-glutamate capsule that protects the organism against phagocytosis and, perhaps, killing. Virulent strains also possess a complex exotoxin called the anthrax toxin that is comprised of three thermolabile proteins, termed Factors I, II, and III, with molecular weights of approximately 80 kDa each and encoded by plasmid DNA. Factor I, the "edema factor," is an adenylate cyclase, similar to the pertussis adenylate cyclase toxin. Factor II, the "protective antigen" (so-called because it elicits protective antibodies in guinea pigs), is the binding domain of the anthrax toxin. Factor III is the "lethal factor." Thus, Factor II binds to a glycoprotein receptor on target cells where it is cleaved by a proteinase with resultant release of a 20 kDa fragment and activation of its remaining portion. This activation then allows binding and internalization of Factors I and III.
The anthrax vaccine that will be provided to U.S. military personnel is produced by the Michigan Biologic Products Institute of Michigan’s Department of Health (phone: 513-335-8119). It was approved by the FDA in 1971 based on the results of a single study performed in the 1950s of New England millworkers exposed to potentially contaminated imported animal products (Brachmann PS, et al. Am J Public Health 1962;52:632-645). While the efficacy rate was calculated as 92.5%, the confidence intervals (not calculated) are likely to be wide. Since only five cases of inhalational anthrax were observed, no estimate of the prevention of this potentially lethal form of the disease could be made. Protective efficacy rates in guinea pig challenge studies have ranged from as high as 100% to as low as 4% (Turnbull PCB. Vaccine 1991;9:533-539).
Despite these uncertainties, this vaccine is commonly used by individuals who work with livestock and many veterinarians. Anthrax vaccine has been used selectively in the past by the U.S. military and at one dose was administered to approximately 150,000 soldiers during the Gulf War; it is administered to special units trained to respond to biological attacks.
The vaccine consists of alum-precipitated formalin-inactivated supernatant from fermenter cultures of an attenuated strain of B. anthracis designated V770-NP1-R (Brachmann PS, et al. Am J Public Health 1962;52:632-645). Complete vaccination requires multiple injections followed by annual boosters. The primary series consists of six individual 0.5 mL subcutaneous doses given at 0, 2, and 4 weeks, and then at 6, 12, and 18 months. Eighty-five percent to 95% of recipients develop antibodies by two weeks after the second dose; thus, the first dose must be given at least four weeks prior to exposure. As indicated above, although experimental evidence indicates it is effective against infection produced by cutaneous inoculation, its efficacy against inhalational infection is uncertain. Mild local reactions at the site of injection occur in about 5-30% of recipients. More severe local reactions occur infrequently (< 4%), and systemic reactions are rare (0.2%) (Package insert, anthrax vaccine, adsorbed. Lansing: Michigan Department of Public Health; 1979).
Individuals with known or imminent exposure to B. anthracis should be given ciprofloxacin (500 mg po bid) or doxycyline (100 mg po bid). If exposure is confirmed, the antibiotic should be continued for four weeks while vaccination is instituted, in those not previously immunized, with three 0.5 mL doses over 30 days. Exposed, but previously vaccinated individuals should be given a booster dose of vaccine unless they had received the initial three doses of the vaccination schedule in the previous six months.
Which of the following is correct?
a. The anthrax vaccine currently available in the United States requires only a single injection for full immunity.
b. Anthrax spores may persist in the environment for decades.
c. Bacillus anthracis exotoxins are coded for by chromosomal DNA.
d. Virulent Bacillus anthracis are unencapsulated.
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