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Oct 15, 2007 (Vol. 27, No. 18)

Preparedness for Bioterrorism

Hastening Development of Counteragents and Production Techniques Are Key Issues

  • While less than a decade ago the concept of terrorism felt distant and like something that would never happen in America, 9/11 changed everything. Still, when most of us think of terrorist attacks we think big: car bombs, airplane hijackings, and atomic blasts quickly come to mind. Some of the deadliest weapons for terrorists, however, might be so tiny that the human eye cannot even see them.

    Unlike traditional warfare, bioterrorism, a terrorist attack that deploys viruses, bacteria, or other germs as weapons for the intent of massive human destruction, can be quietly insidious. With preparation, the worst biological agents could spread through air, water, and food supplies. Days might pass while germs spread rampantly without anyone knowing.

    Just six years ago attackers delivered anthrax as a powder in letters sent through the U.S. mail. Unfortunately, this was not the first time that humans manipulated microbials and viruses with harmful intent. In the past, smallpox (a virus) and plague (a bacterium) have also been agents for biological warfare.

    The nature of these miniature biological powerhouses has led the U.S. government to believe there is an increased need for preparedness and surveillance. Preparations are well under way to counter a biological attack. Much is on the horizon to hasten the development of counteragents using new technologies such as the breeding of transgenic rabbits to make human polyclonal antibodies and finding new uses for old antibiotics.

    The DoD hopes to decrease the spread of viruses and deadly bacteria by leveraging accelerated manufacturing techniques that rapidly produce huge quantities of vaccines and antibodies. The goal is to create an accelerated manufacturing platform that can produce as many as three million doses in 12 weeks. The ability to respond rapidly and with such large quantities represents an enormous technological advance for society.

  • A Brief History

    Some countries developed research programs in bioterrorism as early as the 1930s. Japan had an offensive biological warfare program and performed human experiments. Many believed Germany was experimenting with biological agents for purposes of war at the same time.

    In 1942, the British conducted biological warfare experiments, dropping bombs full of anthrax spores off the coast of Scotland. Their tests proved that anthrax could survive and spread through an explosion and that the spores would be sustained in the soil for decades.

    The U.S. responded by starting an offensive biological plan in 1943. It weaponized seven biological agents such as anthrax that could kill or incapacitate humans. The program was renounced by President Nixon in 1969.

    The Soviet Union also had a 4,000-person, 30-building facility located in Koltsovo, Novosibirsk. The site had biosafety level 4 laboratories, and botulinum toxin was one of several agents tested.

    In October 2001, 22 people developed symptoms and five died from the intentional distribution of letters laced with anthrax. Thousands of panicked people clogged hospital emergency rooms, which revealed the unanticipated logistical problems of diagnosis and treatment of the worried well. Before that anthrax was only an agent of concern for biological warfare but it is now at the top of the bioterrorism list.

    According to the Centers for Disease Control and Prevention, there are three main categories of biological threat: A, B, and C. Category A is the highest priority, since this class of bugs spreads effortlessly from human to human, resulting in high mortality rates. Included in this category are anthrax (Bacillus anthracis), botulism (Clostridium botulinum toxin), plague (Yersinia pestis), smallpox (Variola major), tularemia (Francisella tularensis), and viral hemorrhagic fevers (e.g., filoviruses like Ebola and Marburg and arenaviruses such as Lassa and Machupo). These represent a major public health concern as they can cause, in addition to death and disability, panic and social disruption.

    Category B biological agents are a lower priority than Category A. These control germs spread relatively easily, have moderate morbidity, and exhibit low mortality rates. While they require enhanced diagnostic capability and disease surveillance, they are less threatening than Category A. Category C pathogens are emerging biological agents that are readily available and spread easily but are uncommon. Still, if engineered, their threat potential could increase, pushing them to a higher category.

  • Counteragent Development

    While the pathogens that humans could weaponize are well defined, the market for counteragents and vaccines is less clear. However, various government agencies are providing contracts to nonprofit and for-profit companies to support development.

    For example, the Defense Advanced Research Projects Agency contracted with Neugenesis (www.neugenesis.com), which in turn has subcontracted with SRI International (SRI; www.sri.com) to help speed the discovery and development process and rapid response or just-in-time production capability for vaccines and therapeutics. Ideally, this will decrease the need to stockpile vaccines. Rapid production capabilities would promote enhanced U.S. military response to biological threats.

    In another example, Bavarian Nordic (www.bavarian-nordic.com) received several large contracts to provide an attenuated smallpox vaccine. SRI has worked with Bavarian Nordic to win and implement grants that helped develop the vaccine to a stockpilable status.

  • Flu Vaccines

    Currently the Biomedical Advanced Research and Development Authority (BARDA) is focusing on the acquisition of flu vaccines and antiviral drugs, as the current thought is that the flu is the highest-threat pathogen today. This work focuses on acquiring flu vaccines from U.S. and foreign sources and adding various adjuvants to reduce the dose needed and extend the number of doses in the nation’s stockpiles.

    While there is a dearth of information about the next stockpile target, there will likely be much more focus on diagnostics in the future, as well as a strong call for broad-spectrum therapeutics instead of one-bug, one-drug technology.

    Yet there remains notable uncertainty in the market. There is a perception of low profitability, and acquisition budgets are small even with the BARDA legislation passed. This is partly because BARDA is entirely a procurement effort applicable only to drugs or vaccines already evaluated in Phase I trials, which means that it does not fund any drug discovery or development. As a result, the NIH must fund the basic R&D activities and even the clinical trials themselves.

  • Best Practices

    Collaborations that bring together new technology and trusted knowledge have the most potential for success in rapid drug development. For example, licensed drugs could have unanticipated activity against a biothreat agent. Discovery of this potential second use of a drug can lead to rapid approval for the new application through an ANDA for either repurposing or relabeling to extend patents.

    The advantage to this approach is that there already is existing data on the drug (e.g., safety, pharmacokinetics, pharmacodynamics, and bioavailability). As a result, repurposing can be a quick path to approval for a new indication.

    At the same time, the development of new technologies is important. Groundbreaking work currently under way to develop transgenic rabbits that make human proteins could permit rapid antibody production, since rabbits breed quickly and produce a potent polyclonal antibody. Likewise, transgenic fungi could help accelerate manufacturing and lead to massive replication in a short time.

    Collaborations that combine the competencies of multiple organizations and shared resources make tremendous sense because complex capabilities are rare in one company. Additionally, government contracts for these projects are complicated.

    Both DoD and NIH contracts, more so than grants, are difficult for small biotech companies to win and handle. A small company might provide innovative basic drug discovery capability, but the point is to create collaborations between organizations with different areas of expertise to accelerate the discovery and development process to proof-of-principle and into the clinic.

    Moving forward, medical countermeasures to combat biological weaponry will rely on the ability of scientists to develop potent vaccines and therapeutics that have broad activity and to do so rapidly. Technology that uses alternatives to mammalian cells to replicate proteins quickly, such as transgenic rabbits and fungal cells, will help make rapid production a reality. So will the repurposing of licensed drugs for which scientists already have a great deal of information.

    Collaboration between organizations will help ensure broad capability and shared resources, but the hand-off between them must be seamless. Watchfulness and preparedness will be important if bioterrorism becomes increasingly attractive as a tool for terrorists.

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