Biothreat scenario Dennis Klinman, MD/PhD _________________________________________________________________________ "The assertions herein are the private ones of the author, and are not to be construed as official or as reflecting the views of the food and Drug Administration." _________________________________________________________________________ Overview: Bacterial and viral pathogens capable of causing severe disease in Man, animals, and crops can be readily engineered. Using the tools of molecular biology, these pathogens can be modified to resist antibiotic therapy, to avoid immune detection, to secrete toxins, and to mutate rapidly (hindering efforts to control the pathogen's spread). Some but not all biothreat agents can propagate in the host to cause further rounds of infection (depending on initial pathogenicity, method of spread, and replication proficiency). For many pathogens, effective vaccines are not available. It should be appreciated that despite two decades of worldwide effort, there is still no effective vaccine against HIV. Even if an effective vaccine could be produced, it may require a decade or more to develop, test, approve and enter widespread usage. By comparison, bioterrorists could generate mutant pathogens capable of circumventing the effects of a successful vaccine in a matter of months, using in vitro selection methods. It is important to recognize that the production of a biothreat agent is not difficult. It is reasonable to assume that nation states and terrorist organizations with interests inimical to those of the US will have ready access to such technology by 2025. Many have such access today. While it is considered difficult to target and distribute biothreat agents effectively against specific military targets, a more general/widespread attack could succeed. Moreover, it may be possible to identify genetic factors that predispose a particular population to severe infection, and to target a pathogen against that population (HLA type, for example). We should consider the possibility that biothreat agents will be targeted against: 1) soldiers in the field 2) civilians 3) husbandry animals/crops 4) natural resources (particularly oil). Depending on the time line and objectives of the terrorist (injury/death versus de-stabilization of the US politically or economically), one or all of these could be targeted. It should be appreciated that there is a trade-off between the ability of a pathogen to cause rapid disability/death, and its ability to spread to other contacts. An agent that was rapidly lethal would have a limited ability to spread. One that caused only modest disease (at least initially) could be passed and amplified between hosts, resulting in more widespread infection. For example, the HIV virus dose not cause severe disease until several years post infection, which facilitated its successful spread through the human population. Agents capable of infecting husbandry animals, crops or oil would provide terrorist with a means of attacking the US infrastructure. While such an attack would not immobilize an armed force, it could limit our nation's ability to project force over a prolonged period. Such an "attack" would be difficult to detect and it's source identified. The scenario presented below provides one example of a biothreat agent that could be used to directly attack members of the armed forces or the civilian population.In this scenario, the pathogen was engineered to cause an initial flu-like illness. This illness would be relatively mild (sufficient to prevent a soldier from fighting, but not requiring isolation). Pulmonary infection and replication would lead to the rapid spread of the pathogen to uninfected individuals. Over a course of several weeks, the pathogen would lead to more severe disease and/or death. Such an agent could potentially incapacitate an army in the field, overwhelm available medical care, and threaten the civilian population. It should be appreciated that such an attack, if only partially successful, would have major military, social and political implications. These might include changes in tactics (requiring the de-centralization of military personnel stationing and operation), a the threat to political stability, and an enhanced potential for political blackmail. Scenario: In 1918, as strain of influenza virus spread through Europe causing a pandemic that killed millions. The nucleic acid sequence of this virus is in the process of being determined by PCR analysis of stored (frozen) tissue samples. It is assumed that this sequencing will identify the factor(s) responsible for the pathogenicity of this virus (which caused massive lung inflammation and was readily passed from infected to uninfected individuals). Since the DNA sequence of this virus will be released, I assume for the sake of this scenario that an enemy group (hereafter referred to as "Red") uses this sequence to modify an existing strain of flu and make it more pathogenic. Many strains of flu are readily available, and these can be grown to high infectious titers in chicken eggs. Using the techniques of molecular biology, flu can be modified and made more pathogenic. Indeed, "Red" could modify key proteins on the surface of the virus to interfere with the effectiveness of currently available flu vaccines, and/or introduce a gene encoding a toxin that would prevent infected individuals from mounting a protective immune response. Moreover, since "Red" would know the sequence and protein products of this virus, they could produce a vaccine to protect members of their own population. It would take months before the US could replicate such a vaccine, and additional months before adequate stocks of the vaccine could be manufactured and distributed. It should also be appreciated that "Red" could select a pathogen for which no vaccine is available. The scenario would be that "Red" would surreptitiously introduce this pathogen into a small number of individuals. Infected servicemen/civilians would initially develop a flu-like disease. The disease would rapidly spread to other contacts as the severity of the illness in the original targets increased. Issues: 1) It is unlikely that US medical personnel would appreciate the nature of this pathogen when confronted by the first wave of infected patients. Such patients would appear to have conventional flu-like symptoms. Thus, rapid spread of the infection to other servicemen and civilians is likely. 2) Many different pathogens that could be used for bioterrorist purposes. By 2025, techniques in molecular biology and cell culture should allow 'designer' pathogens to be produced and grown. This confronts us with the difficulty of detecting and identifying an unlimited number of potential pathogens, many of which could masquerade as conventional infectious agents (ie, flu). 3) The same techniques can be used to generate pathogens against food crops (soy bean, corn, wheat) or oil. In such cases, recognizing that an "attack" against US interests, much less identifying the point source of the infection, would be extremely difficult. 4) The development of effective countermeasures against such biothreat agents (either antibiotics or vaccines) could take years. Yet modified biothreat agents capable of resisting these countermeasures could be produced in a few months. Thus, the US would always be "behind the curve".