In the early part of the 20th century, the advent of microbiology provided the scientific basis for the development of biological weapons and programs began to be developed by some countries, so-called state actors, as part of their warfare armamentarium. For example, Germany instituted a biological weapons program during World War I and conducted attacks of unknown effectiveness against animals (i.e., horses, mules, sheep, cattle) being shipped by neutral countries to the Allies.³⁰

The use of chemical weapons by both sides of the conflict during World War I was considered appalling and led to the Geneva Protocol for the Prohibition of the Use in War of Asphyxiating, Poisonous or Other Gases and of Bacteriological Methods of Warfare (Geneva Protocol).³¹ This treaty was drawn up and signed under the auspices of the League of Nations in 1925 and entered into force in 1928. Although the Geneva Protocol (which has been ratified, acceded to, or succeeded to by 137 State Parties as of March 15, 2013³²) banned the use of biological weapons, it did not proscribe the research, production, or possession of biological weapons, and many of the State Parties to the treaty reserved the right to retaliate in kind should they or their allies be attacked. In addition, no provision was made for verification and compliance was voluntary. A number of countries agreeing to the Geneva Protocol began or continued biological weapons programs after becoming treaty signatories. These included Belgium, Canada, France, Germany, Italy, Japan, the Netherlands, Poland, the United Kingdom, and the Soviet Union.¹⁷ The United States did not ratify the Geneva Protocol until 1975 after it had ended its biological weapons program.²⁵

Despite the list of countries agreeing to the Geneva Protocol, biological weapons are known to have been used during World War II by some who had signed the treaty, including Japan and possibly the Soviet Union.¹⁷ The Japanese biological weapons program was a vast enterprise. It consisted of a major center in Pingfan, Manchuria, termed Unit 731 with more than 3000 scientists plus smaller units at a number of other sites in China. Another center (Unit 100) worked primarily with animal and plant diseases, including glanders, sheep and cattle plague, red rust, and mosaic plant diseases. More than 10,000 prisoners died as a result of experimental infections or execution after experimentation.^25,33 At least 11 cities in China were attacked during World War II using, variously, anthrax, cholera, Shigella, Salmonella, and plague organisms to contaminate food and water supplies. For example, fleas were infected with plague bacteria and released by aircraft over cities. Data regarding the success of Japan’s efforts to infect civilian populations is sketchy. Large outbreaks of cholera and plague are known to have occurred, but it is believed that transmission in any given area was not long sustained. The extent and sophistication of the Japanese program came to be known after the war when Japanese scientists were offered amnesty from war crimes prosecution for the information provided. This information served as an impetus for the expansion of biological weapons programs in a number of countries, including the United States, United Kingdom, Australia, France, and Canada.

In the United States, the principal biological weapons research site was located at Fort Detrick, Maryland; a production facility was constructed at Pine Bluff, Arkansas.²⁵ The studies conducted were wide-ranging. Examples of human disease–associated organisms or toxins that were weaponized and stockpiled include B. anthracis; botulinum toxins; Francisella tularensis; Brucella suis; Coxiella burnetii; staphylococcal enterotoxin B; and Venezuelan equine encephalitis. In conjunction with these activities, medical countermeasures were developed, including vaccines and antibiotics, to protect scientists and military personnel; technical advances were made that permitted large-scale fermentation and storage of agents. Studies of animal responses to infection were conducted at Fort Detrick, in atolls in the Pacific, and at desert sites in the United States. Experiments using aerosolized simulant organisms were conducted in a number of cities to study survival time of organisms and patterns of dispersal.³⁴

Over time there was increasing international concern that the Geneva Protocol did not ban the research, production, or possession of biological weapons and lacked the means to verify adherence by signatory countries. Accordingly, in 1969, draft proposals for a new protocol were submitted to the Committee on Disarmament of the United Nations.¹⁷ Meanwhile, President Nixon unilaterally terminated the U.S. offensive biological weapons program in 1969 by National Security Decision Memorandum (NSDM) 35, followed by the toxin weapons program in 1970 by NSDM 44.^35,36 Then in 1972, the Convention on the Prohibition of the Development, Production and Stockpiling of Bacteriological and Toxin Weapons and on their Destruction—commonly referred to as the Biological Weapons Convention or the BWC—was opened for signature.¹⁸ State Parties to the BWC—which entered into force in 1975—are obligated to not develop, produce, stockpile, or otherwise acquire or retain microbial or other biological agents or toxins of types and in quantities that have no justification for prophylactic, protective, or other peaceful purposes. They may not use any means of delivery of such agents or toxins for hostile purposes and must take necessary measures to prohibit or prevent such activities in their territories. Further, State Parties should destroy or divert to peaceful purposes all agents, toxins, weapons, equipment, and means of delivery and not transfer to any recipient or in any way assist, encourage, or induce to manufacture or otherwise acquire biological agents, toxins, weapons, equipment, or means of delivery.

The BWC—which has 169 State Parties³⁷—has no formal verification protocol to monitor compliance. Accordingly, verifying adherence to and compliance with the BWC by State Parties has proven challenging. For example, the Soviet Union became a State Party to the BWC in 1975. However, in the late 1980s and early 1990s serious concerns arose regarding the biological weapons capability of the Soviet Union.¹⁷ Through defectors, it was learned that the Soviet Union maintained a biological weapons program that was far more extensive and sophisticated than any had imagined at the end of the Cold War.^38–40 After the establishment of the BWC in 1972, the Soviet Union created a civilian research program called Biopreparat to conduct—under the guise of legitimate research—offensive biological weapons–related research not permitted under the BWC. The program included a system of 18 research laboratories and centers employing up to approximately 60,000 staff at its height. One of the larger and more sophisticated of its facilities, the Vector State Research Center of Virology and Biotechnology, referred to as VECTOR, was a 4000-person, 30-building complex with high-security biological facilities for laboratories and isolation of human cases. It was at VECTOR where, during the 1980s, the technical problems were solved for the large-scale production of smallpox virus intended to be used as an offensive weapon.

Another facility of concern was the Soviet Union’s principal production center for smallpox virus located near Moscow, at Sergiev Posad. It was reportedly able to produce upwards of 20 tons of smallpox virus annually, primarily for delivery via intercontinental ballistic missile (ICBM) as a strategic weapon.³⁹ Currently, the site houses the Russian Federation’s Ministry of Defense Microbiology Scientific Research Institute, a laboratory research complex known to maintain a national collection of dangerous pathogens, including Ebola, Marburg, and Lassa viruses.⁴² In 1992, Russian officials confirmed the existence of a biological weapons program it had inherited from the Soviet Union and committed to dismantling it.⁴³ The dissolution of the Soviet Union in 1991 and the halting of the inherited Soviet offensive biological weapons program by Russian President Yeltsin in 1992 resulted in profound reductions in Biopreparat funding and personnel raising concerns that former biological weapons scientists may sell the expertise to states or groups seeking such knowledge.⁴⁴ In 2000 it was estimated that approximately 15,000 Biopreparat scientists remained employed within the system, which could pose a proliferation risk.⁴⁵

Another example that illustrates the challenges of verifying compliance to the BWC is the case of Iraq, which signed the BWC in 1972. After the first Gulf War (Operation Desert Storm) in 1991, U.N. Security Council Resolution 687 established, among other things, the U.N. Special Commission (UNSCOM) to carry out on-site inspections of Iraq’s biological, chemical, and missile capabilities and to oversee their destruction, removal, or procedures to render them harmless.⁴⁶ In April 1991 under its initial declaration (as required under U.N. Resolution 687), Iraq declared that it did not have a biological weapons program and in August 1991 declared to the first biological weapons inspection team only that it had conducted “biological research activities for defensive military purposes.”⁴⁷ It was not until July 1995, after 4 years of UNSCOM investigations and “in the light of irrefutable evidence” that Iraq admitted for the first time that it had an offensive biological weapons program.⁴⁷ However, Iraq initially denied weaponization. It took a defector to begin to uncover the full extent of the Iraqi program. In August 1995 General Hussein Kamel, who had responsibility for all of Iraq’s weapons programs, defected to Jordan and began cooperating with UNSCOM. Subsequently, Iraq admitted to “a far more extensive biological warfare programme” than previously admitted including weaponization.”⁴⁷ U.N. Resolution 687 invited Iraq to ratify the BWC, which it did in 1991.⁴⁸

Verifying adherence to the BWC remains a challenge. A 2011 assessment by the U.S. Department of State found that China, Iran, and Russia—all State Parties to the BWC—engaged in biological research activities in 2011 with potential dual-use applications; however, available information did not establish that any of these countries is engaged in activities prohibited by the BWC.⁴³ In addition, it remains unclear if Russia has fulfilled its obligations under the BWC with respect to the items specified in Article I of the BWC that it inherited from the former Soviet Union. Furthermore, the State Department noted that the United States has judged that North Korea—also a State Party to the BWC—might still consider the use of biological weapons an option and continues to develop its research and development capabilities without declaring relevant developments as part of the BWC confidence-building measures. Finally, the State Department noted the United States’ concern that Syria—a signatory but not State Party to the BWC—may be engaged in activities that would violate its obligations under the BWC if it were a State Party.

Non–State Actors

Non–state actors, including individuals and groups (e.g., terrorist groups, criminal networks), present a unique, complex, and growing challenge with respect to the development and use of biological weapons. For example, there were 185 documented cases of biological weapon use by non–state actors during the 20th century—85% of which occurred from 1990-1999.² Twenty-seven of these cases were by terrorists, 56 by criminals, and 97 were by other/uncertain actors. A notable case occurred in September 1984, when members of a religious cult, the Rajneeshees, deliberately contaminated salad bars located along a stretch of an Oregon interstate highway with Salmonella typhimurium (now Salmonella enterica subsp. enterica serovar Typhi). Although there were no deaths among the 751 persons who became ill, 45 were hospitalized.⁴⁹ The public health investigation of this incident initially failed to determine how the salad bars became contaminated. It was not until 1 year after the outbreak that dissension among the perpetrators led law enforcement officials to discover the contamination was deliberate with the ultimate goal of disrupting a local election.² This episode illustrates the difficulty in differentiating an ordinary foodborne outbreak from a small-scale biological weapons attack conducted by non–state actors.

In late 2001 multiple letters containing anthrax spores were sent through the U.S. mail, resulting in 22 cases of anthrax—11 inhalational and 11 cutaneous.⁷ Five of the victims died. A lengthy investigation by the Federal Bureau of Investigation (FBI), the U.S. Postal Inspection Service, other law enforcement agencies, and federal prosecutors from the District of Columbia and the Justice Department’s Counterterrorism Section determined that the late Dr. Bruce Ivins acted alone in planning and executing the 2001 anthrax attack.⁵⁰ A review of the scientific approaches used in the investigation was conducted by a committee of the National Research Council (at the request of the FBI). It determined, among other things, that the available scientific evidence was insufficient to reach a definitive conclusion as to the origins of the anthrax spores used in the attack, leading some to continue to question whether Dr. Ivins was the culprit.^51,52

In response to increasing concerns regarding the risk that non–state actors might acquire and use biological, chemical, and nuclear weapons and the fact that the BWC does not explicitly address non–state actors, U.N. Security Council Resolution 1540 was appended to Chapter VII of the U.N. Charter by unanimous vote on April 28, 2004.⁵³ Chapter VII sets out the U.N. Security Council’s powers to maintain peace. Resolution 1540 adds the requirement that all member states develop laws with regulatory enforcement measures aimed at preventing the creation, proliferation, delivery, and spread of chemical, biological, and nuclear weapons by non–state actors. The desired intended outcome is to reduce the threat of non–state actors gaining access to and disseminating these weapons. The objectives of this Resolution were reiterated, and the mandate was extended under U.N. Security Council Resolutions 1673, 1810, and 1977 with the 1540 Committee mandate extended to 2021 to ensure full implementation of the original resolution through capacity building and technical assistance.⁵⁴

Smallpox

Smallpox, a disease caused by variola virus (see Chapter 135), was declared eradicated by the WHO in 1980.⁵⁸ The VECTOR laboratory and the CDC in Atlanta are the only two repositories designated by the World Health Organization (WHO) to maintain stocks of the smallpox virus. Both institutions continue to do research on smallpox, albeit under the close scrutiny of the WHO Advisory Committee on Variola Virus Research.⁴¹ It is difficult to ascertain whether clandestine repositories exist. A release of smallpox today could result in a public health catastrophe. Smallpox spreads directly from person to person, causing death in approximately 30% of those infected; although there is no approved drug, an antiviral candidate, Arestvyr (USAN tecovirimat; aka ST-246), is in development and has been placed in the Strategic National Stockpile for use in an emergency.⁵⁹ Vaccination against smallpox, once widely practiced, stopped in 1980 coincident with the declaration that smallpox had been eradicated. Few persons younger than 35 years have been vaccinated; vaccine immunity among those who are older is waning. The United States now has a large stockpile of vaccine, but most countries have little or none and worldwide production capacity is minimal.

Anthrax

Anthrax, caused by B. anthracis (see Chapter 209), was one of the principal biological weapons in the arsenal of former state-run programs, including the former Soviet Union and Iraq.^17,60 Non–state actors have also pursued anthrax for weapons purposes. For example, the Aum Shinrikyo cult’s attempts to develop an anthrax weapon in Japan went undetected for 5 years until the cult’s sarin gas attack in the Tokyo subway system in 1995 attracted the attention of authorities.² In addition, Al-Qa’ida was pursuing biological weapons capabilities, including anthrax, before the U.S. invasion of Afghanistan in 2001.^17,61,62 The organism, found in nature and responsible for enzootic disease (including in the United States), is reasonably readily available, easy to produce in large quantity with a minimum amount of technical skill and supplies, and extremely stable in its spore form. Methods to grow MDR anthrax have been published in the scientific literature.^63,64 Whether such strains maintain virulence is unknown.

Botulism

Botulinum neurotoxins, produced by Clostridium botulinum (see Chapter 247), were one of the principal weapons in the arsenal of the former Soviet Union and are known to have been produced as a weapon by Iraq.⁶⁵ These neurotoxins are among one of the most toxic substances known, posing a significant bioweapon threat due to their potency, potential lethality, and relative ease of production. Those exposed to these neurotoxins may require prolonged intensive care and ventilatory support while receiving treatment with antitoxin.

Glanders and Melioidosis

Glanders is caused by infection with the bacterium Burkholderia mallei (see Chapter 223), and melioidosis is caused by Burkholderia pseudomallei (see Chapter 223).⁶⁶ Melioidosis is endemic in Southeast Asia and northern Australia. The disease is associated with a high mortality due to the speed with which septicemia develops, particularly in immunocompromised hosts, and the inherent resistance of the bacteria to several classes of antibiotics. Prolonged courses of antibiotics are required to treat melioidosis. Despite prolonged antimicrobial therapy, recurrent disease is common. Glanders is primarily a zoonotic disease in Africa, Asia, the Middle East, and Central/South America. Although human susceptibility to B. mallei infection has not been studied in depth, the organism is highly infectious in the laboratory setting. As with melioidosis, prolonged antimicrobial therapy is required to treat it and to prevent its relapse.

Ebola and Marburg Hemorrhagic Fever

Ebola and Marburg hemorrhagic fever viruses (see Chapter 166) are considered to be a significant threat for use as biological weapons due to their potential for causing severe illness and death.⁶⁷ These viruses are highly infectious, spread easily from person to person, and are associated with high mortality. No treatments are available.

Tularemia

Tularemia is a zoonotic disease found in many countries, including the United States. It is caused by the bacterium Francisella tularensis (see Chapter 229).⁶⁸ It is a hardy organism capable of surviving for weeks in the environment.⁶⁹ The bacterium was developed into an aerosol biological weapon by several countries in the past. It is considered to be a serious potential bioterrorist threat because it is one of the most infectious pathogenic bacteria known—inhalation of as few as 10 organisms can cause disease—and may lead to serious illness and death.

Epidemic Typhus

Epidemic typhus is caused by Rickettsia prowazekii (see Chapter 191), a bacterium carried and transmitted by body lice.⁷⁰ Although naturally occurring disease is typically associated with war, famine, and other poor hygiene environment due to lice infestation, the bacterium is easily aerosolized. Mortality is low with prompt antimicrobial therapy, but diagnosis may be a challenge given the nonspecific clinical manifestations of the disease.

Plague

Plague is caused by Yersinia pestis (see Chapter 231), a bacterium that was developed as a bioweapon by several countries in the past.⁷¹ Primary pneumonic plague would result from an aerosol exposure and lead to a rapidly progressive and lethal infection; this form is transmissible to others. A zoonotic infection in many areas of the world, including the United States, Y. pestis is relatively simple to grow and disseminate.

Event Epidemiology

The challenges associated with responding to a biological attack are uniquely different from those associated with responding to an explosion or to the release of a chemical agent. The effects of the latter are readily apparent, allowing early approximations to be made as to the geographic extent of the problem and the number and nature of casualties to be expected. Needed response efforts can thus be gauged and initiated immediately. For biological weapons, however, the incubation period of biological agents means there is an inherent delay from the time a covert attack is launched until the realization that an attack has occurred—most likely by the identification of sick patients. The varying incubation periods of the disease inevitably mean a delay in gauging the magnitude and scope of the attack and deploying appropriate response efforts on the basis of the epidemiology of the ensuing outbreak. However, the epidemiology of a disease outbreak from a biological attack can differ greatly from a natural disease outbreak, which can complicate event investigation and response efforts. For example, simultaneous attacks with an aerosolized biological agent in several locations could generate a large, complex geographic distribution of cases complicating efforts to develop an epidemic curve. In addition, exposure to a large inoculum of aerosolized biological agents could result in atypical disease presentations and clinical courses (e.g., shorter incubation periods, compressed and severe disease course). Furthermore, on the basis of experiences after the anthrax attacks, it is to be expected that there will be widespread apprehension, fear, and concern about the possibility of further cases—either from the spread of a contagious agent and/or from sequential attacks. Many may live in fear that they or their families will be the next victims. Experience shows that this inevitably complicates event investigation and response efforts.^8,9,74,75 For example, in the 2001 anthrax attack it was not until more than 2 weeks after the initial anthrax-laden letters were sent through the U.S. Postal Service that the index case was diagnosed and reported.^7,76 By that time nine cases of anthrax had actually occurred (two inhalational and seven cutaneous). As health and law enforcement authorities subsequently worked to determine what had happened and to implement appropriate response measures, additional anthrax-laden letters were sent (3 weeks after the initial letters), resulting in an additional 13 cases of anthrax (nine inhalational and four cutaneous).