Since the terrorist attacks against the United States on 11 September 2001, significant activity and demonstrable gains have been made in the effort to improve U.S. homeland security. First, the Bush White House Security Council outlined a layered approach to prevent, warn about, protect against, contain, and treat future terrorist attacks. Then the newly created U.S. Department of Homeland Security (DHS) developed its four pillars of biodefense for the 21st Century: (a) threat awareness; (b) prevention/protection; (c) surveillance and detection; and (d) response and recovery.
More recently, Rear Admiral Nicole Lurie, M.D., appointed by President Barack Obama to serve as Assistant Secretary of Preparedness and Response (ASPR) of the U.S. Department of Health & Human Services (DHHS),entified the four highest priorities for ASPR as: (a) individual and community resilience; (b) response capacity; (c) healthcare system capabilities; and (d) countermeasures development/delivery. The common thread within these high-level strategic goals is an emphasis on response. When the word “prevention” has been used, it has often referred to the intelligence and law-enforcement activities necessary to thwart terrorist plots.
This same response order of priorities, though, is sometimes a source of frustration for those who practice preventive medicine, in which pre-exposure immunization is a cornerstone of both community health and resilience. A major ongoing concern is that the current anthrax biodefense policy is based primarily on the use of antibiotics (with or without vaccination) following an attack – an approach that appears to ignore and/or downplay the threat posed by multi-drug resistant (MDR) anthrax. In the case of MDR, the planning related to antibiotics opens the door to the possibility of numerous casualties actually caused by failed antibiotics.
There exists abundant data in medical literature documenting the fact that anthrax can be and has been made resistant to antibiotics. One authoritative example: Abed Athamna et al. reported (in the August 2004 issue of the Journal of Antimicrobials and Chemotherapy) that anthrax could be made resistant to 18 different antibiotics designed to treat it. Included on that list are all of the antibiotics currently stored in the Strategic National Stockpile (SNS) for post-exposure response to an anthrax attack.
Similarly, retired Major General Philip K. Russell, M.D., sounded the alarm on MDR anthrax – in a 2007 Clinical Infectious Disease Supplement titled Project BioShield: What It Is, Why It Is Needed, and Its Accomplishments So Far – as “posing a threat to national security.” Russell is the former commander of the U.S. Army Medical Research and Development Command, where he spearheaded the effort to increase the capability of the nation’s armed forces to defend themselves against biological agents. Moreover, the current edition of ASPR’s own Aerosolized Anthrax Response Playbook includes an exhaustive review of the threat posed by MDR anthrax.
Ignoring the Obvious: A Worst-Case Scenario Nonetheless, the continuing emphasis on post-attack antibiotic utilization dominates current planning to such a degree that neither MDR anthrax nor, another credible possibility, the use of preventive immunization, is on the current operational agenda.
Here, a point in fact is the scenario selected, earlier this year, for the 7-8 July deliberations of the National Biodefense Science Board (NBSB) on the use of Anthrax Vaccine Adsorbed (AVA; Biothrax®) to protect children and special-needs populations. At the Board’s 7 July public meeting, in fact, instead of proposing the worst set of circumstances of an attack with MDR anthrax, a much less onerous attack situation was postulated for consideration. More specifically: The scenario selected for the public-meeting deliberations was the potential “wide-area” release of antibiotic-sensitive anthrax.
Today there is no FDA-licensed indication for the use of AVA after exposure in any person of any age, and there also is no FDA-licensed indication for use of the vaccine in children and/or seniors (older than 65) either pre- or post-exposure. AVA is FDA-approved, in fact, only for the pre-exposure prevention of anthrax in persons in the 18-65 age group. Consequently, the NBSB was asked by Lurie to engage all “stakeholders” in the issues involved. Those stakeholders include, but are not limited to, the American Academy of Pediatrics, the American Medical Association, various federal partners from the Department of Homeland Security (DHS), the Centers for Disease Control and Prevention (CDC), the Department of Defense (DOD), and the National Vaccine Program Office – as well as knowledgeable representatives from academia, local and state public health agencies, advocates for children’s rights, and the nation’s biopharmaceutical industry.
The members of those groups, certainly, would be well qualified to ascertain the best approach available to close the existing gaps in knowledge involving the efficacy, immunogenicity, and safety of AVA administered to children and members of the various special populations groups that also need protection. Lurie also specifically requested the NBSB, in fact: (a) to directly address the challenges involved in administering the vaccine under an Investigational New Drug (IND) research protocol after an anthrax event; and (b) to compare those challenges with the ethical considerations involved in attempting to gather sufficient data in the absence of a confirmed anthrax release.
Zero Proof of Zero Benefits Recognizing the type of anthrax likely to be encountered is critically important to properly address the questions posed by Lurie in her request to the NBSB (and to other stakeholders). Any contrarian undercurrent about administering AVA in children – in the absence of either a bonafide imminent threat or a confirmed release of anthrax – is understandable, of course. However, when the lack of a clear and present threat is coupled with an assurance that any anthrax encountered will be sensitive to antibiotics, there is very little, if any, motivation to expose children to what might plausibly seem to be an unnecessary immunization. In other words, no matter how low a risk is assigned to the use of AVA, the risk-to-benefit ratio of vaccination necessarily remains undefined – primarily and perhaps exclusively because the contrarian position is that immunization would be of zero benefit.
However, that calculation changes dramatically if more complete data on the potential anthrax weapon is presented and discussed – which is not what happened at the NBSB public meeting. In MDR anthrax, the contribution provided by antibiotics is, by definition, resisted. For one thing, there is no antibiotic safety net involved – and, without effective antibiotics, even the vaccination of exposed victims might fail because the disease progresses first to toxicity, then to death, much too quickly for the vaccine to be able to provide the protection needed.
If, on the other hand, the threat posed by MDR anthrax is acknowledged, the risk-to-benefit ratio for anthrax vaccination is no longer undefined. The risk numerator remains the rate of adverse events of AVA – but in the case of MDR anthrax the benefit calculated can no longer be responsibly defined as zero. Just the opposite, in fact. In MDR anthrax, the benefit denominator becomes the 93 percent efficacy of protection conferred by immunization. In MDR anthrax, therefore, the risk of vaccination pales in comparison to the probable benefit. In other words, the introduction of MDR anthrax into the equation illustrates the clear benefits of receiving pre-exposure vaccination – even if the only gain (but an extremely important one) is to provide an objective clinical trial that can be used to develop more accurate dosing, efficacy, and safety assessments.
Interestingly, there are several important caveats to consider in calculating the risk-to-benefit ratio of the alternative to preventive vaccination – namely, potential problems related to the cornerstone antibiotics (ciprofloxacin and doxycycline) now planned for use in children. With both of those antibiotics, the safety and efficacy data related to inhalational anthrax is extremely limited. In the case of ciprofloxacin, the FDA reports that: (a) only dosing data are available; and (b) those data are based on only 10 cases. The case of (or for) doxycycline, a tetracycline derivative, is even more problematical, because it is not FDA-licensed for use in children under eight years of age.
Ethical Considerations & the Potter Box Above and beyond these risk-to-benefit calculations, it also is important, as Lurie has requested, to assess the ethical dilemma inherent in the clinical trials carried out on subjects who are unable to make decisions on their own behalf. One practical instrument to assist in the consideration of ethics in the equation is the so-called “Potter Box,” developed in 1965 by Dr. (ThD) Ralph B. Potter Jr., who was then professor emeritus of social ethics at the Harvard Divinity School.
The Potter Box is frequently used by scholars of communication and healthcare ethics as a moral reasoning tool because it incorporates not only a broad spectrum of facts and scientifically objective information but also several morally (and, therefore, politically) important values, principles, and loyalties that can and should be taken into consideration to guide users through the meta-communications required to arrive at a final decision on potentially controversial subjects.
Of particular importance to those using the Potter Box is the collection and consideration of all relevant facts on the question at hand. According to Potter, every known fact relevant to a morally acceptable judgment must be sought, and fully documented, without obfuscation or personal bias to cloud the picture. It is only after every single fact is considered can the politically and mentally difficult work of comparing values, applying ethical principles, and weighing ethical loyalties be adequately undertaken and carried out.
It is in this context that acknowledgment of the factual data related to the use of MDR anthrax should be considered imperative to successful completion of the ethical work assigned to the NBSB – and to all of the other stakeholders involved – relevant to the AVA clinical trials in children.
Currently, an estimated 500,000 doses of Strategic National Stockpile AVA are now wasted every month due to shelf-life expiration. This is despite the fact that the 2010 Final Recommendations of the CDC’s Advisory Committee on Immunization Practices support the offering of preventive immunization to “persons involved in emergency response activities including, but not limited to, police departments, fire departments, hazardous material units, government responders, and the National Guard.”
Today, ten years after the multi-wave, multi-site lethal “anthrax letters” were posted – very shortly after the 9/11 terrorist attacks on the World Trade Center and the Pentagon – there is an ample supply of anthrax vaccine, and indisputable evidence of the dangers related to the use of MDR anthrax. It seems reasonable to suggest, therefore, that there may well be no better time than the present to shift planning from a post-exposure response capability to preventive immunization – especially for those personnel who are needed to preserve civil order and maintain continuity of operations and government.
Thomas K. Zink
Thomas K. Zink, M.D., is an adjunct associate professor of community health in the Institute for Biosecurity at Saint Louis University and a healthcare/biodefense consultant. He graduated from the University of Missouri – Kansas City School of Medicine – and is now an accomplished quality improvement professional, a successful health policy strategist, and an experienced vaccinologist with special expertise in viral hepatitis, pertussis, anthrax, and botulinum toxin. A retired emergency physician, he also is the Founding Director of Project Equal Immunization Policies & Practices (EQUIPP), an organization that has been a catalyst in the formulation of CDC recommendations to support the pre-event anthrax vaccination of U.S. civilian emergency responders.