Friday, February 3, 2012

My submission to the Presidential Commission for the Study of Bioethical Issues

Public Commentary -- for meeting on February 2-3, 2012
Presidential Commission for the Study of Bioethical Issues
1425 New York Avenue NW, Suite C–100
Washington, DC 20005
Re:  Pediatric anthrax vaccine trial
Dear Members of the Presidential Commission for the Study of Bioethical Issues:
In this statement, I want to share with you the evidence that underlies my conviction that the proposed trial of anthrax vaccine in children represents an experiment whose risks far outweigh any possible benefits.
My name is Meryl Nass, M.D., and I have been involved in the study of anthrax and bioterrorism for the past 23 years.  I wrote one of the first reviews of the current vaccine.[1]  I have spoken about anthrax vaccine before 3 Congressional committees and 2 Institute of Medicine committees.  Apart from the clinicians at the military Vaccine Healthcare Centers network and Deployment Health Clinical Center, I have probably treated more servicemembers who became ill and/or disabled following anthrax inoculations than anyone in the US. These servicemembers have developed a range of disorders, which most often resemble the Gulf War syndrome—fibromyalgia—chronic fatigue syndrome pattern.  I invite you to contact physicians at the military centers noted above for additional information on anthrax vaccine safety.  I have remained engaged with this issue because I have met so many people whose health was destroyed by this vaccine.
The US human anthrax vaccine has been in development from the 1950s to the 2000s. There have been many changes to its manufacturing process over 60 years.  The Department of Health, Education and Welfare requested the manufacturer to conduct a human efficacy study in workers occupationally exposed to anthrax at the time of licensure
in 1969[2] (this is normally required prior to licensure) but there is no evidence the study was ever done.
All US human anthrax vaccines were named “Anthrax Vaccine Adsorbed” or AVA until 2002.  Subsequently, anthrax vaccine has been named “Biothrax.”

Vaccine effectiveness
The only direct human efficacy study for a US anthrax vaccine was conducted in the 1950s at 4 goat hair mills by Philip Brachman, MD et al. for the Army and CDC.[3]  Workers at these mills were exposed to imported anthrax spores in the course of their work.  The study used two vaccines that were very different from those used in 1970 or today.[4]  Brachman’s study demonstrated efficacy for cutaneous anthrax but not inhalation anthrax, although this distinction was disputed four decades later.  It is an important distinction, because route of exposure can be a critical determinant of vaccine efficacy.  Two other bioterrorism vaccines (plague[5] and Venezuelan equine encephalitis[6]) yielded evidence of protection from infection transmitted by insect bites, but protection for exposure via inhalation was lacking. There is a further important distinction:  deliberate use of anthrax for bioterrorism is likely to expose victims to orders of magnitude more spores than were inhaled in mills. 
At the time of Brachman’s study, neither of the two subjects who had received a placebo vaccine and were believed to develop inhalation anthrax had positive evidence of anthrax infection by culture, serology or pathologic examination, making the diagnosis of anthrax questionable.  One of the two recovered, which was unusual for inhalation anthrax.  Brachman himself wrote, “When inhalation anthrax is considered, the limited experience with this form of the disease makes the data less significant in showing effectiveness of the vaccine.” [7]
Later vaccine studies have used surrogate markers to infer immunity, although for anthrax vaccine this approach is fraught with uncertainty. No surrogate markers have been validated in humans; there is no clear relationship between antibody levels and survival rates in animals.[8] [9] Probably only a subset of measured antibodies are protective, but the understanding of this is at an early stage.[10]  Toxin neutralizing antibodies have been thought to better represent immunity than simple antibody levels.[11]  However, a recent study of sera from anthrax-vaccinated subjects found that only 46% of the 200 subjects had toxin neutralizing antibodies greater than unvaccinated controls, and only 20.5% of the subjects had greater than 50% in vitro toxin neutralization.[12]  In other words, the measurable degree of immunity was weak in most vaccinated subjects.

Vaccine Safety
In terms of safety, the Brachman trial only looked for adverse events up to 48 hours after subjects were vaccinated.  There were no obvious safety issues. Later versions of the vaccine have had a variety of safety evaluations.  The quality of these studies has varied considerably.  Many involved Colonel John Grabenstein, PhD, RPh, who oversaw the military vaccine program.
Each study that he supervised claimed a high degree of vaccine safety. However, Dr. Grabenstein, who is a member of the National Biodefense Science Board, had and continues to have a financial conflict of interest in propagating the claim that the vaccine is safe.  Dr. Grabenstein has been a consultant for several vaccine companies and is currently a scientist at Merck Vaccine, which produced anthrax vaccine for the US government in the 1960s and is today a major US vaccine manufacturer.
For example, a 1998-2000 study was designed to use active surveillance for long-term side effects and to determine their duration, according to principal investigator Colonel Glenn Wasserman.[13]  But when the study was published in 2003, with Colonel Grabenstein as second author, information on prolonged or late onset adverse events was not disclosed.  Eleven women who had been vaccinated while pregnant, mentioned by Wasserman in oral presentations, failed to be mentioned in the published paper.  Half the subjects were lost to follow-up by the end of the study.  The exit questionnaire was not designed to capture specific information about vaccine-related adverse events and their duration, and did not mention anthrax vaccine.  The paper claimed that only local reactions could be linked to vaccinations, dismissing vaccine causality for other reactions without explanation.  And although “women in the immunized cohort were more likely to report that their general health was “poor or fair” (6.6%) compared with the unimmunized cohort (1.5%) (RR 4.4; 95% CI 1.3-15.1)” the report concluded, “The findings of this study support the relative reactogenicity [local side effects] of AVA immunization but do not reveal any serious adverse events or effects on health.”[14]
A 2001 unpublished Navy study of women vaccinated for anthrax during pregnancy revealed a small but statistically significant increase in birth defects.  The research results led to several actions, according to the IOM[15]:
  • FDA changed the pregnancy warning in the vaccine label to category D, indicating evidence of fetal harm, in 2002.  (The Navy study was not published until 2008,[16] after expanding the original database, which diluted the fetal effect somewhat.  I wrote a commentary on it.[17] )
  • CDC added a pregnancy warning to the informed consent document for its 2001 IND trial of post-exposure anthrax vaccinations. 
  • The Assistant Secretary of Defense for Health Affairs issued a memorandum and press release requiring all military services to check for pregnancy before administering anthrax vaccinations. 
FDA closed the anthrax vaccine manufacturing plant in 1998 due to manufacturing problems, finding “the manufacturing process for anthrax vaccine is not validated.”[18]  Despite sale of the plant and a rebuild of the anthrax vaccine facility, the new plant continued to fail FDA inspections and was not allowed to open.  The Defense Department’s stock of vaccine was almost entirely consumed by mid 2001.  However, following the anthrax letters attack in late 2001, DHHS Secretary Tommy Thompson announced to the country that the plant would be relicensed.  In January 2002 FDA issued a new license with a new vaccine label.
The new label provided a higher systemic adverse event rate (5-35%) than the prior label (0.2%).  It also noted, without using the term “Gulf War,” that illnesses meeting CDC’s case definition for Gulf War illness[19] had been reported.[20]  It may be of interest that some
survivors of inhalation and cutaneous anthrax reported similar, lingering medical problems, “such as chronic fatigue, inability to concentrate and joint pain.”[21]
In 2007, a Government Accountability Office report noted, “Officials from the VHC (Vaccine Healthcare Centers) Network and CDC estimate that between 1 and 2 percent of immunized individuals may experience severe adverse events, which could result in disability or death."[22]  The report made clear, in a page 3 footnote, that it was addressing issues related only to anthrax vaccine.  The Assistant Secretary of Defense for Health Affairs concurred with the report’s findings.
CDC conducted a multicenter trial of Biothrax in 1563 subjects, 83% of whom received anthrax vaccine, between 2002 and 2007.  Two hundred twenty-nine serious adverse event reports were filed with the federal Vaccine Adverse Event Reporting System during the 43-month trial.  About 12% of subjects experienced a serious[23] adverse event.  But only a preliminary report on the first seven months and first 1000 subjects in the trial was published,[24] in 2008.  There has been no final report, nor any publicly available accounting of these adverse events.
Simultaneously in 1998, the US, UK, Canada and Australia began vaccinating troops deploying to the Gulf region with anthrax vaccine.  Within several years, the UK, Canada and Australia ended their anthrax vaccinations of troops.  Only the US persisted with them.
Federal District Judge Emmett Sullivan pulled the vaccine’s license in 2004 due to failures in the licensure process, including inadequate evidence of efficacy.[25] [26]  One year later, after a required review, FDA issued a reapproval for the vaccine (without more data) and the new license was upheld in court.
Hundreds of Israeli troops were given (both US and Israeli) anthrax vaccines in experiments beginning in the 1990s, funded by the US.[27]  Dozens are said to remain ill.  Sixty-four have sued for information about the trials and to get their medical care compensated.[28]  A report by the Israeli Medical Association, which recently investigated the trial, said, “No scientific justification was found for the experiment, scientific background was lacking, the experiment's design and execution did not suit its goals, and no result would have justified those goals. Also, conventional guidelines were not followed, risks and possible side effects were not thoroughly investigated, and a follow-up mechanism to keep track of participating soldiers was not set up.”[29]
According to Les Baillie, PhD, former head of anthrax vaccine research at Porton Down, UK, “…concerns over the toxicity of the current vaccines have driven the development of second-generation products.”[30] (emphasis added)
That the current vaccine is unsatisfactory is tacitly acknowledged by the Defense Department and other federal agencies, which continue to fund work to develop a more effective and safer anthrax vaccine. For example, US Army researchers at USAMRIID published a 2012 study of an entirely new candidate vaccine that uses the anthrax capsule, rather than the currently used ‘protective antigen,’ as its primary immunizing agent.[31]

Vaccine Necessity

Anthrax vaccine is not an emergency treatment for anthrax exposure.  It takes 2 or 3 vaccine doses, administered over 28 days, before what is thought to be a sufficient immune response is generated at about day 40. 
True emergency treatments for anthrax exposure include antibiotics, monoclonal antibodies and anti-anthrax antisera, all of which have been stockpiled by the US government.  These treatments are likely to be more effective than vaccination, even after day 40, due to the questionable levels of immunity evoked by the vaccine.  Antibiotics were 100% successful at preventing anthrax in those who received them prior to the onset of clinical disease, following exposure to the anthrax letters in 2001.
The current justification for post-exposure anthrax vaccine is the need for late immunity if inhaled spores germinate in the lungs after antibiotics are stopped.  This is a tenuous theory, based on limited animal data of anthrax deaths 2-3 months after a deliberate exposure.  However, a prolonged antibiotic course is more likely to be effective than vaccination with Biothrax.
Another justification for vaccination after exposure is to allow people to inhabit an area contaminated with anthrax spores. But given the expected  illnesses/deaths of many animals and some humans living in an area with a high level of spore contamination (for no antibiotic or vaccine is 100% protective in everyone) the theory that humans would want to remain in such areas is tenuous.
A third justification for vaccination is the possibility that anthrax used in an attack could be antibiotic resistant.  True:  but it can also be made vaccine resistant, as demonstrated by a Soviet scientist who came to work for NIH.[32]
The anthrax vaccine is not licensed for those under 18, nor for those over age 65.  No studies to test the efficacy, safety and dosing of the vaccine in the elderly have been proposed.  Yet in light of historically poor efficacy of influenza vaccine in those over 65, a high potency flu vaccine (containing 5 times more antigen than standard vaccines) was approved for elders two years ago.  How will the elderly be dosed with anthrax vaccine?  Shouldn’t those over 65, who can provide informed consent, be tested to determine dosing, before children?  However, given the lack of a reliable surrogate marker for the current vaccine, how valid will any tests of dosing be?
Despite questions about the utility of post-exposure vaccinations, the vaccine’s manufacturer has sold nearly two billion dollars’ worth of Biothrax to the federal government to be stockpiled for civilian use, post-exposure.  This stockpile is in addition to vaccine sold to the military for pre-exposure use.  Questions have been raised about the very high profit margin for these sales, said to be on the order of 300%.[33] 
The vaccine manufacturer, Emergent Biosolutions, has had on its payroll a former head of the Joint Chiefs of Staff, a former Secretary of DHHS, a former assistant secretary of DHHS, a former Assistant Secretary of Defense for Health Affairs, a former US Surgeon General, a former Army Surgeon General, and others who had responsibility for biodefense procurement in their former roles in government.
Vaccine Ethics
In 2001 CDC offered anthrax vaccinations to children after possible exposure to the anthrax letters.  To my knowledge there were no takers.  In 2005 the NIH proposed a trial of anthrax vaccine in 100 healthy children. Senator Bingaman, chairman of the Senate Health, Education, Labor and Pensions committee, noted as part of a detailed critique sent to DHHS Secretary Leavitt:
The Institute of Medicine's report Ethical Conduct of Clinical Research Involving Children (2004), which I requested as part of the "Best Pharmaceuticals for Children Act of 2002" (P.L. 107-109), points out, "...when proposed research involves a minor increase over minimal risk and does not offer the prospect of
direct benefit, the research must be limited to children with a disorder or condition and must be expected (among other criteria) to generate vital knowledge about the disorder or condition" (45 CFR 46.406; 21 CFR 50.53).
The IOM report adds, "For research that involves a control group of healthy children (and the anthrax study is to include healthy children) without a disorder or condition and without prospect of direct benefit from the research, the research procedures for that group would have to involve no more than minimal risk."
Subpart A of the HHS regulation defines "minimal risk" as meaning "that the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests" (45 CFR46.102(i); 21 CFR 50.53(k)).[34] 
The NIH withdrew the proposed trial ten days later.[35] 
The Code of Federal Regulations (46.407) is clear regarding the protection of underage human subjects.  Their participation in research must only occur if “the research presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children.”  The language of the regulation does not indicate that a serious potential problem would meet this standard.
Furthermore, 46.407 requires the assent of both parents and children.  A true informed consent, in which the serious outstanding questions about efficacy, safety and necessity were explained to families and understood by them, would result in few, if any, subjects volunteering for the vaccine study.
An IRB, if made aware of the questions about efficacy, safety and necessity, could not ethically approve such a trial.  However, the US government and manufacturer have successfully obfuscated the facts surrounding anthrax vaccine for soldiers. Given this history, the facts will no doubt be concealed from an IRB reviewing a protocol for a pediatric trial of Biothrax.
Anthrax vaccinations are mandatory for all soldiers deploying to the Afghan, Gulf or Korean theaters of operation.  Since 1998, approximately 3 million soldiers have received a required course of anthrax inoculations.  Soldiers are a vulnerable group in our society, required to accept vaccines and other medical treatments ordered by the military, exposed to noxious agents, frequently placed in harms’ way, and soldiers come predominantly from the poorer strata of society.
Will the children selected for a proposed anthrax vaccine trial come with a similar demography?  Whose children will be used to test a vaccine that will provide them no benefit, but a certain risk of harm?
Harvard professor Jerry Avorn, MD wrote:  “The design of the Tuskegee experiment was so loathsome that its legacy became a touchstone for medical researchers all over the world.  If a question of potential harm to patients arose in the design or conduct of a clinical trial, someone might underscore an objection by warning, “We don’t want another Tuskegee.”’[36]
The decision your Commission makes will determine whether anthrax vaccine research on children takes place, research intended to expand the anthrax vaccine license to those under 18.  Will your Commission approve another Tuskegee?  Please consider the many complex issues surrounding the use of the current anthrax vaccine, and make a determination that meets our highest ethical and legal standards.
Thank you very much for your attention.  I would be happy to provide additional information or documents at any time.
Sincerely yours,
Meryl Nass, M.D.

Nass M. Anthrax Vaccine:  Model of a response to the biologic warfare threat.  Infectious Disease Clinics of North America 1999; 13(1):187-208.
Pittman M., Memorandum to S. Gibson, Assistant Director for Licenses and Inspections, NIH. February 10, 1969.
Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M and Ingraham NR. Field Evaluation of a Human Anthrax Vaccine. Am J Public Health 1962; 52(4): 632-645.
GAO T-NSIAD-99- 148, "Medical Readiness: Safety and Efficacy of the Anthrax Vaccine" (Apr 29, 1999).
CDC, "Prevention of Plague: Recommendations of the Advisory Committee on Immunization Practices (ACIP)", MMWR, Dec 13, 1996 / 45 (RR-14); 1-15
[6] Jahrling PB and Stephenson EH. Protective efficacies of live attenuated and formaldehyde-inactivated Venezuelan Equine Encephalitis virus vaccines against aerosol challenge in hamsters. J Clin Microbiology 1984; 19: 429-31.
[7] Brachman, op. cit.
[8] Nass, op. cit.
[9] Turnbull PCB. Anthrax vaccines: past, present and future. Vaccine 1991 Aug; 9(8):533-9.
[10] Crowe SR, Ash LL, Engler RJM, Ballard JD, Harley JB, Farris AD, and James JA. Select human anthrax protective antigen (PA) epitope-specific antibodies provide protection from lethal toxin challenge. J Infect Dis. 2010; 202: 251–260.
[11] Ngundi MM, Meade BD, Lin T-L, Tang W-J, and Burns DL. Comparison of Three Anthrax Toxin Neutralization Assays. Clin Vaccine Immunol 2010; 17(6): 895-903. 
[12] Crowe SR et al. op.cit.
[13] Wasserman G. Tripler Army Medical Center Survey. First Annual Department of Defense Conference for Biological Warfare Defense Immunizations. May 26, 1999. Fort Detrick, Maryland. Transcript.
Wasserman GMGrabenstein JDPittman PRRubertone MVGibbs PPWang LZGolder LG. Analysis of adverse events after anthrax immunization in US Army medical personnel. J Occup Environ Med. 2003 Mar;45(3):222-33
National Research Council. The Anthrax Vaccine:  Is it Safe? Does it Work? Washington, DC: The National Academies Press, 2002. Pages 171-2
Ryan MAK, Smith TC, Sevick CJ et al. Birth Defects among Infants Born to Women Who Received Anthrax Vaccine in Pregnancy. Am. J. Epidemiol 2008. 168(4): 434-442.
[18] FDA Inspection Report of Michigan Biologics Products Institute for February 4-20, 1998. Obtained through FOIA request to FDA.
[19] Fukuda K, Nisenbaum R, Stewart G et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. JAMA 1998; 280: 981-8.
January 2002 anthrax vaccine label: “Infrequent reports were also received of multisystem disorders defined as chronic symptoms involving at least two of the following three categories:  fatigue, mood-cognition, musculoskeletal system.”
Center for Counterproliferation Research. Working Paper:  Anthrax in America. A chronology and analysis of the fall 2001 attacks. November 2002. Page 12. The paper cites: William J. Broad and Denise Grady, “Science Slow to Ponder Ills that Linger in Anthrax Victims,” The New York Times, 16 September 2002, p. A1; Shelley Emling, “Anthrax Victims Feel Forgotten in 9/11 Honors,” The Atlanta Journal-Constitution, 29 September 2002, p. 15A; Deborah Sharp, “Survivors Still Wrestle With Pain, Fatigue, and Shortness of Breath,” USA Today, 1 October 2002, p. 4A.
GAO-07-787R DOD’s Healthcare Centers Network
Marano M, Plikaytis BD, Martin SW et al. Effects of a Reduced Dose Schedule and Intramuscular Administration of Anthrax Vaccine Adsorbed on Immunogenicity and Safety at 7 Months. JAMA 2008; 300(13): 1532-1543.
[30] Baillie L. Is new always better than old? The development of human vaccines for anthrax. Hum Vaccine 2009 Dec; 5(12):806-16.
[31] Chabot DJ, Joyce J, Caulfield M, Cook J, Hepler R, Wang S, Vietri NJ, Ruthel G, Shoop W, Pitt L, Leffel E, Ribot W, Friedlander AM. Efficacy of a capsule conjugate vaccine against inhalational anthrax in rabbits and monkeys. Vaccine 2012 Jan 20;30(5):846-52.
[32] Pomerantsev APStaritsin NAMockov YuVMarinin LI. Expression of cereolysine AB genes in Bacillus anthracis vaccine strain ensures protection against experimental hemolytic anthrax infection. Vaccine 1997 Dec; 15(17-18): 1846-50.
Center for American Progress. (Scott Lilly). Getting Rich on Uncle Sucker:  Should the federal government strengthen efforts to fight profiteering? October 2010.
[36] Avorn J. Powerful Medicines: The benefits, risks and costs of prescription drugs. Borzoi (Alfred A Knopf) 2004. NYC. Page 32.

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