May 22, 2012 | 5
This past week brought news about another successful bioterrorism response drill, effectively delivering hypothetical medicines to protect the citizens of Baltimore from a hypothetical anthrax attack. Frankly, I always shake my head in dismay when I read of such preparedness exercises. I think back to my childhood, with its “duck and cover” Cuban missile crisis school drills and laughable plans to evacuate Washington, D.C. to the hills of West Virginia. I mean, have you seen normal traffic? Even in the ‘60s, this was a ludicrous idea! And I think of the battles I had in Allegany County, when my children were in school, over there being no soap or paper towels in the public school bathrooms. There is where the real threat of germ warfare is imminent.
It was in the same vein that I recently reviewed the plans for pediatric anthrax vaccine trials, preparing for a provocative grand rounds presentation at a military hospital. Let me share what I found with you here.
First, anthrax infections are contracted by inhalation of spores or, infrequently, by skin contact with infected animals or hides. It is not infectious in the sense of being spread person-to-person. Pre-exposure immunization for high-risk workers involves receiving 5 initial doses and then an annual booster. Not a problem if you are in the army; not so likely to happen in regular civilian populations.
For post-exposure prophylaxis: For adults, the CDC and Advisory Committee on Immunization Practice (ACIP) reccommend 3 doses (not 5) of anthrax adsorbed vaccine (AVA) and 60 days Ciprofloxacin, Doxycycline, or Procaine Penicillin G (or Amoxil for kids, if the organism is susceptible).
Evolution of anthrax vaccine
The anthrax adsorbed vaccine (AVA) was first licensed in 1970. It contains purified anthrax antigen proteins, with 1.2 mg/ml aluminum hydroxide as an adjuvant (commonly used to boost the immune response so that a lower dose of the protein can be given) and “25 μg/mL benzethonium chloride and 100 μg/mL formaldehyde, added as preservatives.” There was a single manufacturer, Bioport. In ~2000, the manufacturer had quality control problems at the plant; a new plant built and has been producing the vaccine since 2002. In 2008, Emergent Biosolutions took over the company and, through its aggressive monopoly and lobbying, obtained a lucrative government contract to provide the vaccine for the military.
The 2001 anthrax attacks also created a huge business opportunity; a new bioterrorism response industry burgeoned. The anthrax vaccine became licensed for use in adults 18 to 65 years of age for pre-exposure vaccination (2005); it was not licensed for use as post-exposure prophylaxis (PEP) for any age group.
A number of military veterans complained of serious and lingering side effects from the mandatory vaccination, prompting a study by the prestigious Institute of Medicine (IOM). The IOM report “concluded that AVA is reasonably safe” and did not find link with “Gulf War Syndrome.”
But the package insert on Biothrax (AVA) says:
Serious allergic reactions, including anaphylaxis, have been observed, and notes that birth defects were slightly more common in first trimester-exposed infants (odds ratio = 1.18). There was a >10 % incidence of significant arm pain after injection, with limited range of motion. All adverse events were more common in women.
In 2011, a bioterrorism preparedness exercise, “Dark Zephyr,” was conducted. (This was a coy symbolic name, as Zephyr means “A soft gentle breeze,” and reminded me of spies and intrigue.) The Dark Zephyr exercise found a notable lack of data about the safety or immunogenicity of AVA in those <18 or >65 years old.
Subsequently, the National Biosafety Science Board (NBSB) proclaimed, “Preparation for a national and potentially global threat from the use of B. anthracis spores by terrorists is a major priority for U.S. national security.” This has led to the current bioterrorism exercises and NBSB recommendation to test a pediatric anthrax vaccine. Health and Human Services Secretary Kathleen Sebelius has now referred this issue to the Presidential Commission on Bioethics, which met this past week to begin discussions. Their report will likely be available by year’s end.
But, one might ask, how likely is an attack? What evidence exists of any “national and potentially global threat from anthrax”? Is this really a threat, or another “Weapons of Mass Destruction” ploy such as we saw under Bush/Cheney?
Pediatric anthrax vaccine trials
Under Emergency Use Authorization, the FDA has the authority to allow use of an unapproved product if it has been shown to be safe in that population for which it is intended. Note that most medicines were never tested for dosing or safety in kids. It used to be assumed that kids were just “pint-sized people.” Why would this anthrax vaccine be treated differently?
Since there is no data about AVA in children, the question then became, should we study the vaccine in kids pre-emergency or try to conduct trials during an emergency?
Historically, dosing for children has been extrapolated from that for adults. The NBSB argues that, during an emergency, the planned dosage of vaccine would have to be the same as in adults and that they would not be able to do sequential studies. So the question is whether the limited likelihood and risk of an attack warrants testing a vaccine with significant side effects on healthy children—especially since it is not known whether any antibodies formed would actually be protective, and boosters have to be given annually. (Note: for example, the dose of diptheria and tetanus proteins in vaccines are higher for infants than for adults.) And it is known that antibiotics and post-exposure vaccination are effective for preventing anthrax infection if necessary.
A look at the pediatric trial arguments: (Pro-AVA trial now)
The driving force behind the rush to conduct trials now is “Be Prepared.” Immunized kids might be protected if they are exposed in the future. Parents have more time to consider whether to have their child participate in this clinical trial. Undoubtedly, better data is gained in non-emergent settings. Finally, if needed in an emergency, there would be dose of AVA known to be immunogenic and “safe.”
Counter position on AVA trials
Why the urgency? Even the CDC states: “Vaccination is recommended only for those at high risk, such as workers in research laboratories that handle anthrax bacteria routinely.” Also, the combination of 60 days of antibiotics plus 3 doses of vaccine currently recommended for use in post-exposure prophylaxis is very effective in preventing anthrax disease from occurring after an exposure.
Further, U.S. federal regulations (45 CFR 46, Subpart D) state that children may not be exposed to risk if a medical experiment does not offer them a direct benefit. Since, “Currently, U.S. children are not at immediate risk from anthrax and would not benefit directly from pre-event AVA [anthrax vaccine] administration,” there is only the potential for future benefit.
No vaccine or medicine is without risk. This anthrax vaccine is contraindicated for pregnant women, since it can harm the fetus. There have been cases of anaphylaxis, which is life-threatening. The manufacturer had to stop production and close its plant over quality control issues. While they have re-opened, this is not exactly a reassuring history.
Logistical impracticalities and human nature
Let’s look at some of the logistics of the proposed trial. First, how burdensome is the vaccine trial?
The immunization schedule requires 5 doses of vaccine administered over 18 months. In a scathing analysis, ethicist Art Caplan, mockingly notes:
“How worried are you about an anthrax attack on your family? I suspect it is pretty far down on your “things to worry about” list, far behind getting food on the plate, saving for the college fund, and making sure the kids get picked up after sports. Unless the government is willing to scare the living daylights out of parents, few will bring their kids in to act as subjects in what amounts to a safety study.
Even if you are worried, consider this: The current vaccine requires five shots across 18 months. That alone is going to make it somewhere between very unlikely and absolutely hilariously unlikely that any parent or kid is going to make it through a trial. Even if you offered a lot of money to induce parents to bring their sons and daughters down to the test site, it would take a lot of money to make it worth their time to make five separate visits.”
Caplan further asks: “If there was an attack, would it make sense to have your kid take an untested vaccine whatever its risks? And would your child even have a chance to get the vaccine if an attack does occur?”
While this week’s bioterrorism preparedness exercise demonstrated the feasibility of distributing antibiotics to a large population in case of an emergency, it relied on postal workers, not health care workers trained to administer vaccines. Jonathan Moreno and Tom Daschle note that “33 states and the District of Columbia have cut health funding since 2008, and local health departments have lost 23,000 jobs since then. Among these are the first responders, whom we will rely on during a crisis.”
Who will give the vaccines? If the response to Hurricane Katrina is at all representative, we are in big trouble.
So why the push to do pediatric trials now?
What are the incentives for pursuing trials now? One cynically could begin by playing “Follow the Money.” We’ll start to do that in an upcoming post. Otherwise, this plan for a pediatric anthrax vaccine trial makes no sense to me. My major concern, besides the safety and ethical questions, is that serious allergic side effects will inevitably occur. And when it does, it will fuel the anti-vaccine movement. At a time when the nation is experiencing a record number of cases of measles and pertussis—vaccine preventable diseases—why would we further alienate the public with a vaccine of questionable value?