The Anthrax Vaccine Immunization Program: History, Controversy, and Legal Issues

By Michael A. D’Annunzio*

I.  Introduction	1
II. The Anthrax Vaccine	2
A. Description	2
B. Medical Trials and Animal Studies of AVA	3
C. Approval (Biologics Review)	6
D. Indications and Risk Balancing	7
E. Manufacturer’s Regulatory Problems	9
III. History of the AVIP	13
A. Motivation	13
B. Implementation	15
1. Supplemental Testing	15
2. Tracking System	17
3. Communication and Implementation Plans	20
4. Independent Review	21
C. Controversy	24
1. Squalene	24
2. Rate of Refusals	29
3. Refusal Legal Issues	30
4. Experimental Drug Defense	31
5. Defense that the Vaccine is Not Sufficiently Related to Military Duty	33
6. Refusal Case Histories	36
IV. Current Status	39
A. Program Implementation Schedule	39
B. Congressional Report	39
C. 2nd Generation (recombinant) Vaccine	42
V. Conclusion	49

I.  Introduction

	On December 15, 1997, Secretary of Defense William S. Cohen announced plans to vaccinate all U.S. military personnel against the biological warfare agent anthrax.  This decision came after a three year study.  The goal of the vaccination program is “to vaccinate everybody in the force so they will be ready to deploy anywhere, anytime.”  The Anthrax Vaccine Immunization Program (AVIP), as it came to be called, has since generated controversy.  By March 24, 1999, this controversy rose to the level of a hearing before the Subcommittee on National Security, Veterans Affairs and International Relations, of the House Committee on Government Reform (the “Subcommittee”).  Representative Christopher Shays, in opening that hearing, summarized the questions it sought to address:
We begin with questions:  Why now?  Why this vaccine?  Why a mandatory program?  And why would active duty, Reserve and National Guard personnel jeopardize their military careers, and even their liberty, rather than take the vaccine?  … The missing element of the mandatory anthrax vaccine program is trust.  Radiation testing, Agent Orange, the reckless use of experimental drugs and mysterious Gulf War illness have made military men and women understandably distrustful of the Pentagon on medical matters.
	This paper documents the issues that make the AVIP so controversial.  It summarizes the current knowledge about the safety and efficacy of the anthrax vaccine, including the vaccine manufacturer’s history with FDA regulators.  It summarizes the analysis that led DoD to balance the risks and benefits of the anthrax vaccine in favor of universal, mandatory vaccination.  It includes a description of DoD efforts to achieve successful implementation of the program, as well as the setbacks that have arisen.  This collection of observations about the Anthrax Vaccine Immunization Program is relevant for: any attorney prosecuting or defending a member accused of refusing the vaccine; for any servicemember concerned about taking the vaccine; and for member of the general public who wants to know the context of the current controversy.
	There is one proposition on which everyone seems to agree.  Regardless of one’s opinion of the Anthrax Vaccine Immunization Program, it is quite clear that modern medical science has the capacity to develop a better, second-generation anthrax vaccine.  Such a vaccine would better serve the goals of Force Protection.

II. The Anthrax Vaccine
A. Description
	The vaccine employed in the DoD Anthrax Vaccine Immunization Program (AVIP) is Anthrax Vaccine, Adsorbed.  It is prepared with a culture of an avirulent strain of Bacillus anthracis, which is alum-adsorbed, preserved with benzethonium chloride and stabilized with formaldehyde.  The vaccine is made by a method developed before the advent of molecular biology, and is therefore commonly referred to as a “first generation” type vaccine.  It is not highly purified, and its manufacturer requires a dedicated facility because B. anthracis is a spore-forming organism.  
	All strains of anthrax bacteria cause human disease by the same mechanism, anthrax toxin.  Anthrax toxin is composed of three components, none of which is individually toxic.  Those components are edema factor (EF), protective antigen (PA), and lethal factor (LF).  The combination of PA with LF or PA with EF is toxic.  Protective antigen is therefore the common component of all anthrax toxin.  Protective antigen is the predominant component in the anthrax vaccine.  The vaccine induces anti-PA antibodies to prevent disease and death.  Since PA is common to all naturally occurring anthrax toxin, the vaccine should theoretically protect against all strains.

B. Medical Trials and Animal Studies of AVA
	In order to evaluate the merits of the AVIP, one must first review the medical studies on which the DoD bases its assertion that the vaccine is safe and effective.  There is one human efficacy study, the “Brachman Study,” originally published in 1962.  The Brachman Study and subsequent monitoring of vaccinated workers with industrial exposure to anthrax are the only direct studies of AVA’s effectiveness in humans.  Both of those trials demonstrate protection against cutaneous anthrax infection.  The efficacy of the vaccine against inhalation anthrax was not well documented, nor is it amenable to study in humans, because the low incidence of inhalation anthrax makes field trials impossible.  
	The Brachman Study was a placebo-controlled field trial in mills processing goat hair where anthrax infection was an industrial hazard.  The incidence of anthrax in non-vaccinated participants was significantly higher than in vaccinated individuals.  The study was conducted in a population of 1200 mill employees, of whom 40 percent received the vaccine and the remainder received a placebo or nothing.  During the trial, 26 cases of anthrax infection occurred.  Of these, 21 occurred in patients who had received no vaccine, four in patients who had incomplete vaccinations, and one in a completely vaccinated person.  The authors of the study analyzed these data and reported an estimated 93% protection against cutaneous anthrax (the lower 95% confidence figure being 65% effectiveness).  
	The CDC monitored the performance of the vaccine from 1962 to 1974 and observed no cases in fully immunized workers in at risk industrial settings.  For its safety data, the advisory panel cited the data accumulated by the Centers for Disease Control in its investigational trials of the vaccine.  In the CDC’s experience, the vaccine is fairly well tolerated with the majority of reactions consisting of minor local irritation.
Since the Brachman study, the industrial anthrax hazard that made the study possible has largely disappeared.  Inhalation anthrax has always been very rare in the United States.  There have been 18 cases of inhalation anthrax in humans reported in the United States since 1900.  Of course, it is not possible to conduct clinical trials by exposing humans to anthrax.  
Recent studies use animal models to evaluate the efficacy of the anthrax vaccine.  Since the Brachman study established that the anthrax vaccine is effective in humans, the recent animal studies have focused on comparing its effectiveness against inhalation challenges with various potentially “vaccine resistant” strains of anthrax.  
	One concern about the DoD use of AVA is that it may be possible for an adversary to identify or develop anthrax that is able to resist or overcome the protection of the vaccine.  In 1986, in a study using two different types of vaccine in guinea pigs, the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) identified 9 of 27 tested strains as “vaccine resistant.”  The article observed that while most efficacy studies challenge immunized animals with the Vollum strain or one of its derivatives, some vaccines that protect effectively against those strains do not protect against other strains.  The DoD position is that since all strains require protective antigen, then AVA, as a PA-based vaccine, is likely to protect against all strains.  Little and Knudson concluded, however, that “other antigens may play a role in active immunity.”  The DoD specifically cites the Ames strain of anthrax as “one of, if not the most, lethal strain” and asserts that AVA has proven effective against it.  In the Little and Knudson study, however, all six guinea pigs inoculated with AVA died after challenge with the Ames strain (and one of the six control animals challenged with that strain survived).  A follow-up to the Little and Knudson study, published in 1994, again observed that AVA provides significantly less protection against Ames than against the Vollum 1B strain of anthrax.  The observed difference between the two strains was not as dramatic, however.  
	Among the explanations for the better protection against the Ames strain observed by Ivins et al is “variations among individual lots of MDPH-PA.”  The article cites one author’s unpublished data showing that “lots of MDPH-PA vary significantly in their efficacy in guinea-pigs.”  The article also observes that vaccine production changes in 1990 may have resulted in “higher levels of toxin antigen component in both the supernatant and the final vaccine.”   This improvement is offered to explain why the more recent study achieved better immunity to the Ames strain.

C. Approval (Biologics Review)
	The anthrax vaccine has existed since the 1960s.  The product license for AVA was issued by the Division of Biologics Standards to MDPH on November 10, 1970.  As a biologic product, it was subject to the Biologics Review provisions of 21 C.F.R. §601.25.  That provision required a review of the safety, effectiveness, and labeling of biological products previously licensed under § 351 of the Public Health Service Act.  For these reviews, the FDA appointed an advisory panel, which then reviewed the available information concerning safety and effectiveness of the product and made recommendations in a report to the commissioner of the FDA.
The report concerning the anthrax vaccine was published in the Federal Register in December 1985.  The advisor panel relied heavily on the Brachman Study to establish the efficacy of the vaccine.  It concluded that “there is sufficient evidence to conclude that anthrax vaccine is safe and effective under the limited circumstances for which this vaccine is employed.”  Those limited circumstances are “solely for immunization of high risk of exposure industrial populations such as individuals who contact imported animal hides, fur, bone meal, wool, hair (especially goat hair), and bristles … also … laboratory investigators handling the organism.”  The Biologics Review Panel also observed that “This vaccine is recommended for a limited high-risk of exposure population along with other industrial safety measures designed to minimize contact with potentially contaminated material.  The benefit-to-risk assessment is satisfactory under the prevailing circumstances of use.”  The panel did not consider any animal studies in evaluating efficacy.

D. Indications and Risk Balancing
	The labeling and regulatory approval of every drug is a matter of balancing the risks and benefits of that drug.  Normally the FDA does that balancing, and approves indicating the drug in those cases where its benefits outweigh its risks.  In the case of anthrax, however, a key element of the risk balancing process is outside the reach of FDA analysis.  That is the likelihood of exposure.
	The package insert recommends AVA for “individuals who may come in contact with animal products such as hides, hair, or bones which come from anthrax endemic areas and may be contaminated” as well as “high risk persons such as veterinarians and others handling potentially infected animals.”  It continues, “since the risk of exposure to anthrax infection in the general population is slight, routine immunization is not recommended.”  Furthermore, the product labeling and efficacy studies all explicitly state that effectiveness against inhalation anthrax is uncertain.  This language led the Subcommittee to characterize the AVIP’s use of this vaccine for “mass prophylaxis” for inhalation as “off-label.”
	The DoD and FDA have responded by maintaining that the AVIP uses the vaccine in a manner consistent with its labeling.  The FDA position appears to resolve the ambiguity in the labeling in favor of broad indication.  “The labeling for Anthrax Vaccine Adsorbed does not mention route of exposure (e.g., cutaneous), per se.  Use of the vaccine for protection against both cutaneous and inhalation anthrax exposure is not inconsistent with the labeling for Anthrax Vaccine Adsorbed.”  The DoD relies on the animal studies showing effectiveness against inhalation anthrax to support its use of the vaccine to prevent anthrax transmitted by that route.  The FDA has also cited these studies in affirming that the AVA labeling does not preclude its use against inhalation anthrax. 
	The indications for the anthrax vaccine are written in terms of industrial exposure to the disease, rather than defense against biological weapons.  Evaluating the risk of exposure to anthrax as a biological weapon requires intelligence, not medical, methods.  The FDA, which is normally in the business of balancing the risk and benefit of a vaccine, is hardly the appropriate agency to conduct military threat assessment.  It therefore appears that the FDA has deferred to the DoD on the issue of whether every service member, including those with remote prospects for deployment, risks exposure to anthrax.  The DoD, in turn, has done risk balancing of its own in choosing universal vaccination.  The theory underlying universal vaccination is that “[t]oday’s military force, including both active and reserve components, is highly mobile and deployable to high-threat areas on short notice.”  The DoD summarized its assessment of the anthrax threat, saying:
In at least two major theatres, thousands of troops go to work every day under the threat of weaponized anthrax.  Many others fly or sail in and out of these areas.  Many more are listed as first responders and as reinforcing units.  All of our force is subject to terrorist attack by anthrax.  At least two groups have it.  One has tried to use it.”.
This led DoD to conclude that “The risk-versus-risk balance clearly requires Total Force immunization.”
	The only counter-indication on the AVA package insert is for those with a history of a severe reaction to a previous dose.  There are also precautionary statements for pregnancy and pediatric use.  The vaccine is “pregnancy category C” which means that animal reproduction studies have not been performed and it is not known whether the vaccine can cause fetal harm when administered to pregnant women.  The general consensus among medical experts is that it is not likely to, but the DoD has adopted and publicized the policy that the vaccine be deferred for those members who are pregnant.  

E. Manufacturer’s Regulatory Problems
	In addition to considering the safety and efficacy of the anthrax vaccine as approved, a thorough treatment of the AVIP would be remiss if it did not also report and consider the manufacturing process, because, as GAO observed:
The quality of a vaccine is closely linked to its manufacturing process, which must be rigorously controlled to ensure that batches of vaccines produced on different occasions are of reproducible and consistent quality.  In general, quality is achieved by applying the current good manufacturing practice.  This process is not static but involves manufacturers and regulators in a continuing process of assessment and upgrades.
The only currently licensed manufacturer of the anthrax vaccine, BioPort Corporation (previously known as Michigan Department of Public Health or Michigan Biologics Products Institute) has recently encountered some difficulties in its interactions with FDA.  The February 17 Subcommittee Report referred to BiopPort as a “manufacturer, struggling to reopen a plant with a checkered regulatory history.”  Even the DoD’s own response to the Subcommittee Report, while characterizing it as “the normal process of FDA certification under a new Biologics License Application Supplement” acknowledged that the FDA has been critical of BioPort’s operation.  
	The “regulatory history” to which both the subcommittee and the DoD are referring includes an FDA warning, transmitted to Michigan Biologic Products Institute on March 11, 1997.  That warning recited a number of violations observed in the FDA inspections of MBPI’s facility between November 18 and 27, 1996.  This inspection uncovered violations in “organization and personnel, buildings and facilities, equipment, control of components, drug product containers and closures, production and process controls, laboratory controls, and records and reports.”  Examples of violations observed included:
•	failure of the quality control unit to approve or reject all components, drug product containers, closures, in-process material, packaging material, labeling, and drug products;
•	failure to have separate defined areas or other control systems for manufacturing and processing operations;
•	failure to assure that equipment used in the manufacture, processing, packaging or holding of a drug product is of appropriate design and of adequate size for its intended use and for its cleaning and maintenance;
•	failure to properly store and handle components and drug product containers and closures;
•	failure to calibrate instruments, apparatus, gauges and recording devices at suitable intervals; and
•	failure to record the performance of each step in the manufacture and distribution of products.
The FDA further asserted that similar deficiencies had been identified during past inspections but that MBPI had failed to make satisfactory corrections.  Although noting that no injuries resulted from the failure to comply with “good manufacturing practices,” the FDA threatened to revoke the MBPI license if the facility was not brought into compliance in a timely fashion.  MBPI responded to the FDA’s “notice of Intent to Revoke” (NOIR) letter with a “Strategic Plan for Compliance” in April 1997.  This plan provided for continued cooperation with FDA monitoring, towards the goal of achieving compliance with FDA regulations.  
	The FDA conducted a follow-up inspection in February 1998.  This inspection again discovered significant deviations from FDA regulations, and resulted in the quarantine of 11 lots of anthrax vaccine.  An October 1998 inspection found “continuing improvement,” but a November 1999 FDA document contains “a number of observations repeated from the February 1998 inspection.”
	In January 1998 production of the anthrax vaccine was halted as MBPI began a comprehensive renovation of the anthrax vaccine production facilities.  In September 1998 BioPort purchased the facility,  and Production of “consistency lots” at the renovated facility began in May 1999.  BioPort expects approval for new production by fall of 2000.  The FDA does not release the content of license applications under review, but the licensing process generally requires “that a product can be consistently manufactured under current good manufacturing practices to meet product specifications.” 
	In addition to the regulatory issues surrounding the general manufacturing practices at the BioPort facility, there have been at least two more specific problems.  Before the beginning of the AVIP, and therefore before the AVIP supplemental testing was implemented, the manufacturer detected gasket or stopper material in several vials during a routine visual quality-control check.  The manufacturer discarded all the vials containing this material, then obtained FDA approval to release the remainder of that lot.  During the February 1998 inspection of the manufacturing facility, the FDA requested further documentation on the destruction of the vials containing the particulate material.  The remaining vials from that lot were quarantined and must pass supplemental testing before they will be shipped to DoD for use.  No recall was instituted of the vials that had already been shipped.  
	Also, there is at least one documented incident when expired vaccine was administered to service members.  This incident occurred in April 1999, and resulted from a failure to verify the expiration date of every vial in a multi-lot shipment.  Most vials in the shipment were still current, expiring in August 1999, but 94 vials expired on March 16, 1999.  Fifty-nine Marines received these expired vaccinations before the error was detected.  In response to this incident, procedures now require recording the lot number and expiration date of every vial in a shipment upon receipt. 

III. History of the AVIP
	The Anthrax Vaccine Immunization Program was originally announced on December 15, 1997.  At that time, Secretary of Defense William S. Cohen listed four preconditions to implementation.  Those were supplemental testing to assure safety and potency of the vaccine; implementation of a personnel tracking system; approval of administration and communications plans; and independent expert review of the health and medical issues.

A. Motivation
	The decision to vaccinate the entire force was motivated by concerns about the proliferation of biological weapons in general and anthrax in particular.  The DoD has publicly asserted that several hostile countries possess or are pursuing biological weapons capabilities, including Iran, Iraq, Libya, and North Korea.  Anthrax is by far the easiest biological agent to produce and weaponize.  Anthrax is also extremely stable and can be stored almost indefinitely.  Exposure is 99% lethal to unprotected individuals, and antibiotics are only effective if administered within the first 24-48 hours.  Although protective masks and clothing are effective against anthrax, the DoD is concerned that an unexpected anthrax attack could infect service members at a time when they are not wearing protective gear.  The DoD currently has only a few detectors and early warning devices, described as “early state-of-the-art.”  DoD has concluded that vaccination is the “best and most effective” form of Bio-Protection.
	Having decided that vaccination is the most effective means of protection from the threat of biological warfare, the DoD further decided to make anthrax vaccination mandatory and universal.  The argument for making the vaccine mandatory is a familiar one.  Each member of a military unit depends on the others, if one service member becomes a casualty because he declined the anthrax vaccine, he jeopardizes the safety of his colleagues and the effectiveness of his unit.  Therefore, “to not use the vaccine constitutes a failure to protect our troops and a risk to carrying out military missions.”
	The decision to make the vaccine universal is somewhat more controversial.  According to DoD, it stems from the fact that the 6 shot regimen requires 18 months to complete.  It is therefore not feasible to inoculate service members as they deploy to high-risk areas, as is the practice with several other vaccines.  “In this age of no-notice, world-wide deployments, immunizing the total force is the only way to assure force protection against this biological warfare agent, which, in the form that it would be used against us, is as deadly as the Ebola virus.”
B. Implementation
1. Supplemental Testing
	Among Secretary Cohen’s four prerequisites for implementing the AVIP is supplemental testing of the stockpile of vaccine.  The purpose of this testing is to assure sterility, safety, potency, and purity.  An independent contractor oversees the supplemental testing conducted by the manufacturer.  The supplemental testing repeats tests that are already required by the FDA for lot release.  These include specific tests for general safety, potency, sterility, and purity:
•	General Safety: Follows Title 21 Code of Federal Regulations (CFR) section 610.11 guidelines. General safety is determined in the following manner: two animals each of two species (mouse and guinea pig) are given doses of the vaccine and observed for 7 days for adverse effects; and the passing result is that each animal survives the test period, gains weight, and does not show any adverse reaction. Twenty vials per lot are tested for general safety. 
•	Potency: Follows 21 CFR 610.10 guidelines. Potency is determined in the following manner: three serial dilutions of vaccine are used plus one control group (no vaccine) to vaccinate guinea pigs; 14 days after vaccination, all guinea pigs are injected with known amounts of virulent anthrax; average time to death is calculated for each group; and the passing result is that the test vaccine is no less potent than the reference vaccine. Two vials per lot are tested for potency. 
•	Sterility: Follows 21 CFR 610.12 guidelines. Sterility testing is performed on the final product to detect the presence of microorganisms. Twenty vials per lot are tested for sterility, using two separate culture media: fluid thioglycollate medium and soybean-casein digest medium. 
•	Purity: No formal 21 CFR requirements for individual testing of preservatives or additives. Only general requirements for calibration and controls. Purity testing consists of four individual tests for aluminum, benzethonium chloride, and formaldehyde. Five vials per each substance per lot are tested for purity.
	This supplemental testing began in 1998 and is ongoing.  According to DoD, “Only anthrax vacccine lots both released by the FDA and supplementally tested are used in the DoD AVIP."
	Supplemental testing will end, however, with lot 040.  On the AVIP web site, the DoD presents the results of supplemental testing by lot, and explains why supplemental testing is not being conducted on new production:
Supplemental tests are not performed on lots 040 or higher, because these lots have undergone (or will undergo) the same tests for sterility, purity, potency, and general safety in the last several months and the data have, or will be, independently reviewed by the FDA to determine whether the lots meet approval criteria for FDA release.
	Lot FAV038, the most recent lot for which the results of supplemental testing are available, was tested from 4 January 1998 through 18 September 1998, and BioPort reported the results on 24 September 1998.  While supplemental testing may have been a significant part of the DoD quality assurance program early in the AVIP, it appears that DoD will rely on BioPort’s own quality control testing, with FDA oversight, in the future.

2. Tracking System
	The experiences in the Persian Gulf War led Secretary Cohen to include “implementation of a system for fully tracking personnel who receive the anthrax vaccinations” as a prerequisite to implementing the AVIP.  AVA administrators now record each immunization on the patient’s AVA Immunization Record (MEDCOM Form 700-R).  This form includes a place for the patient to certify that s/he has been given an AVA information “tri-fold” and an opportunity to ask questions about the AVA prior to the immunization.  For each immunization, the provider records the date, site (left or right arm), lot number, and the provider’s name.  
	The FDA and CDC jointly administer the Vaccine Adverse Event Reporting System.  That system is one of the key mechanisms for identifying patterns of adverse effects from vaccines.  Properly completed, a MEDCOM Form 700 would provide most, but not all, of the information necessary to complete a Vaccine Adverse Event Reporting System report.  Missing are the time of vaccination and the name of the responsible physician (if different from the person administering the vaccine).  In light of the new requirement that the administrator check the expiration date of each vial of AVA, it would also seem sensible to record the expiration date along with the lot number on MEDCOM Form 700.
	The computer databases into which vaccinations are entered seem to be works in progress.  The DoD summarized the importance of a tracking system:
To ensure that servicemembers obtain the health care they need, especially if they experience short- or long-term adverse events associated with vaccinations, DoD must keep paper and electronic medical records accurate and current.  Also, because the anthrax immunization regimen requires several vaccinations over a short period and annual boosters, it is critical that commanders have timely information about servicemembers in their units who are scheduled for vaccinations.  
	Initially, vaccinations were entered into the Defense Enrollment Eligibility Reporting System (DEERS), an existing database of personal, service-related, benefits, and residence information.  DEERS proved not to be ideal, however, because of delays in updating records.  In particular, duty station information updates in DEERS have taken as long as 6 to 9 months, making AVIP implementation officials reluctant to rely on the system.  
	The GAO conducted an extensive evaluation of the immunization tracking systems, and concluded that:
DoD has a new recording and tracking system for vaccinations that is better than the one used during the Gulf War and in Bosnia, but DoD is not meeting its requirement to record vaccination data consistently in paper records and in its central database.
	The GAO reviewed records from one installation from each service.  At each installation, GAO selected 300 servicemembers who had received the vaccine and compared the paper records with the DEERS data for those members.  GAO found widespread discrepancies between the paper and electronic records.  The Army, Navy and Air Force records all agreed well on the number of inoculations administered to the member.  The Army and Air Force records did not agree as well on the specific dates of inoculation or the lot number of the vaccine.  The Navy records showed excellent agreement, with paper matching electronic data in better than 96% of sampled records for all three categories.  At Camp Lejeune, however, the Marine Corps record agreement was dismal.  Paper and electronic records showed the same number of inoculations in only 23% of cases.  The date of vaccination agreed in 17% of records, and the lot number only matched in 8%.
	The GAO observed that the delays and errors in the DEERS database limit its utility for commanders administering the vaccination program.  In light of the limitations of DEERS, service representatives rely on interim, service-specific tracking systems.  These service-specific systems are evidently more responsive to commanders’ reporting needs.  The GAO nonetheless concluded that:
Because the DoD-wide database, the Defense Enrollment Eligibility Reporting System, lacks current data on servicemembers’ duty stations, commanders do not find it useful for scheduling individual vaccinations or determining the status of vaccinations for their unit as a whole.  DoD’s plan to incorporate vaccine tracking in an upgrade to its Composite Health Care System program will be of limited use to commanders if it does not give them some of the capabilities of the service-level systems.
	The GAO recommended that the Secretary of Defense direct the Defense Manpower Data Center to take steps to detect and resolve time lags in the DEERS system.
3. Communication and Implementation Plans
	Secretary Cohen also required the approval of communications plans to inform military personnel about the AVIP.  The Subcommittee criticized these communications efforts as “[h]eavy handed, one-sided informational materials.”  Although the Subcommittee asserted that “Communications plans were approved centered around a ‘tri-fold’ brochure to be given to service personnel,” the DoD communications effort has been considerably more extensive:
The troops are begin clearly advised up front as to why the vaccination is needed, what vaccination they are receiving, the safety and efficacy of the vaccine, and what potential adverse effects could occur.  It is important that the troops understand the benefits as well as the risks, though very low, of Anthrax immunizations.  When the program starts in a particular unit, troops are given the opportunity to ask questions and the Commanders and medics work with troops who have concerns about the immunization.  Often this is done on an individual and personal basis.  In rolling out the program and in its ongoing operation, the Department [of Defense] has used a wide range of communications mechanisms to reach the troops and their families.  Briefings, newspapers and handouts have been used extensively.  The newest area of communications has been the Internet.  
	The AVIP website, located at www.anthrax.osd.mil, is extensive.  It includes the original Brachman Study from 1962, the DoD response to the Subcommittee’s report, the Bioport package insert, a detailed “infopaper” about the program, and links to several non-DoD sources of information about anthrax and the anthrax vaccine.  Other communications resources include:
•	a Toll-free information line (1-877-GET-VACC) in operation since 28 July 1999;
•	a Speakers Bureau that conducts AVIP open-house forums, staff assistance visits, briefings, press conferences, and training on immunization tracking systems; and
•	Online e-mail queries and responses (avip@otsg.amedd.army.mil)
In light of the extensive communications effort, especially the wealth of information available from the DoD website, I believe it is fair to characterize this as much more elaborate than distribution of a single “tri-fold.”
	While the DoD communications effort may be extensive, a GAO survey nonetheless found that service members want more information about some issues:
More than two-thirds of survey respondents reported that the information they received on reasons for the program, shot requirements and schedules, and consequences of refusals was at least moderately helpful.  However, over half said they either received no information on possible long-term side effects and procedures for reporting side effects or found the information less than moderately helpful.
	The GAO report observed, however, that DoD has little information to provide regarding long-term health effects, because no long-term studies have been carried out.  

4. Independent Review
	The final condition listed in Secretary Cohen’s announcement of the AVIP was independent expert review of the health and medical issues presented by the program.  For that review, the DoD secured the assistance of Dr. Gerard N. Burrow, who is the former Dean of Yale University Medical School, and is Special Advisor to the President (of Yale) for Health Affairs.  David Page Smith, Professor of Obstetrics and Gynecology, also participated in the expert review.  
	The DoD mandated independent review has been criticized as inadequate by the Subcommittee and certain AVIP opponents.  That criticism stems from the fact that the independent review was of a very general nature, and undertaken by someone who is not a specialist in immunology.  Dr. Burrow admitted as much himself in a letter to Representative Shays dated April 26, 1999:
Unfortunately I do not believe I can make a significant contribution to the work of your Committee.  … The Defense Department was looking for some [sic] to review the program in general and make suggestions, and I accepted out of patriotism.  I was very clear that I had no expertise in Anthrax and they were very clear that they were looking for a general oversight of the vaccination program.  … I had no access to classified information.
	Although Dr. Burrow’s review of the program was of a very general nature, many of his observations have been borne out by subsequent developments.
	Burrow and Smith transmitted their report to the Pentagon on February 19, 1998.  That report essentially repeats the DoD conclusions about the AVIP.  It asserts that there “have been no controlled clinical trials of the currently licensed US vaccine in humans” without mentioning the Brachman study. Burrow and Smith refer to a study entitled “Effectiveness of Medical Defense Interventions Against Predicted Battlefield Levels of Bacillus Anthracis” for its conclusion that unit effectiveness could best be preserved through vaccination.
	Burrow and Smith address the safety and efficacy of DoD’s stockpile by reporting the existence of supplemental testing.  They attribute the decision to perform supplemental testing to the March 11, 1997 FDA letter to MBPI and the manufacturing system issues it identified.  
The report correctly recites the 18 month immunization schedule for the AVA and suggests that Phase I of the program will serve to identify the logistical issues presented by the AVIP before it proceeds to total force inoculation.  It mentions DEERS but observes that “all conversations about immunization tracking ultimately devolved to the yellow immunization card as the ultimate record.”  They suggest that a tracking system should serve to remind commanders as vaccinations come due, a purpose that the GAO repeated in its report almost two years later.
	Regarding the communications effort, Burrow and Smith correctly predicted heightened concern about the health effects of the anthrax vaccine in light of Gulf War illness.  They made two recommendations that have not been prominently discussed elsewhere.  First, to use focus groups composed of military members to help ensure that the proper message is being conveyed to individuals receiving the vaccine.  Second, as adverse reactions to the vaccine are “inevitable” in such a widespread administration, DoD should prepare “contingency explanations” for release to the public.  The suggestion about focus groups resembles GAO’s later recommendation that DoD “continue improvements in educational efforts by regularly surveying vaccine recipients and addressing their educational needs.”  Since none of the “inevitable” severe adverse reactions have occurred, DoD has not faced a test of its “contingency explanations.”

C. Controversy 
	The studies summarized so leave a few gaps in our understanding of the anthrax vaccine, but they make a pretty compelling case that it is safe and effective.  The fact that many of the studies about vaccine-resistant strains or inhalation anthrax occurred in animals, or that there have been no published long-term safety studies would, by themselves, be unlikely to make the AVIP controversial.  But controversy has nonetheless occurred.  The breadth of the program—extending even to those members with remote prospects for deployment to high-risk areas, together with unanswered questions about Gulf War Illness, have led some members to refuse the vaccine.  DoD’s response to the alleged link to Gulf War illness has done little to alleviate the concerns of some members.  The courts-martial have not helped the matters, either, by excluding evidence which purports to show that the anthrax vaccine has been illegally adulterated.  

1. Squalene
	Although Representative Shays cited such diverse experiences as radiation testing and agent orange, the controversy over the anthrax vaccine largely revolves around the specific allegation that it contains a compound called squalene.  Some of those who have refused the vaccine believe that squalene in the anthrax vaccine is responsible for some of the “Gulf War Syndrome.”  In particular, many believe published allegations that during the Gulf War the DoD administered anthrax vaccine that used squalene rather than alum salts for its adjuvant.  They believe (correctly) that a vaccine containing squalene is experimental, and also that it is potentially unsafe.  Prior to May 1999 the squalene allegation was relatively obscure.  But in that month, the popular magazine Vanity Fair published a 9 page investigative report cataloging the support for the squalene hypothesis.  That one report brought the squalene allegation to the fore of the anthrax controversy.
	Since publication of the Vanity Fair article, the doctors who provided the squalene theory have published their research in a peer-reviewed medical journal.  The study reported in their article sought to determine whether the presence of antibodies to squalene correlates with symptoms of Gulf War Syndrome (GWS).  They used a test developed by one of the authors to measure antibodies to squalene in the blood of three groups of veterans.  Those were: veterans who deployed to the Persian gulf and are exhibiting symptoms of GWS (38); veterans who deployed but are well (12); and veterans who were immunized but did not deploy to the Gulf and are suffering GWS symptoms (8).  
	They found that 95% of the deployed, sick group tested positive for antibodies to squalene, none of the veterans who are well tested positive, and all of the GWS patients who were immunized for service but did not deploy to the gulf tested positive.  From these data, the authors conclude that:
Our results suggest that ASA [anti-squalene antibody] reactivity is a marker for the signs and symptoms of GWS.  Finding serum antibodies to squalene in Gulf War patients is unexpected, and the basis for the presense [sic] of these antibodies remains unclear. … Although not approved by the Food and Drug Administration for human use, squalene has been used as an adjuvant in experimental vaccines against a variety of pathogens, including Bacillus anthracis, … It is important to note that our laboratory-based investigations do not establish that squalene was added as adjuvant to any vaccine used in military or other personnel who served in the Persian Gulf War era.
	Although the article stopped short of concluding that adulterated anthrax vaccine caused gulf war syndrome, the article did prompt a response from LTC John D. Grabenstein, Deputy Director for Clinical Operations, Anthrax Vaccine Immunization Agency.  In a posting to the promed medical discussion group, LTC Grabenstein wrote:
The authors claim to create an assay that detects antibodies to squalene, but their test was not validated with proper positive controls (that assuredly contain such antibodies) nor proper negative controls (that assuredly do not).  Thus, the assay by Asa and colleagues remains unproven.  …  In other work, a DoD team is studying the feasibility of a validated test for antibodies to squalene.  This study should provide adequate scientific evidence to resolve whether squalene antibodies exist and can be detected in human serum.  Only if this kind of preliminary evidence indicates it is possible to create and measure anti-squalene antibodies can one contemplate further research.
Although LTC Grabenstein takes issue with the methodology of the Asa et al study, the DoD work to develop a validated test is actually an improvement over an earlier DoD response to the controversy.  In a report dated March 1999, GAO recommended that DoD conduct its own research to replicate or dispute the squalene antibody study results.  At that time the Asa article had not been published, and DoD dismissed the GAO recommendation by asserting that a study would be “scientifically and fiscally irresponsible” because there is no basis for believing that Gulf War-era veterans were exposed to squalene-containing vaccines.
	Where the Asa team avoided suggesting that anthrax vaccine containing squalene as an experimental adjuvant caused Gulf War illness, the Vanity Fair article was not so timid.  The Vanity Fair report begins by relating the story of Herbert Smith, a former Army Colonel and Gulf War veteran.  Smith now suffers from an illness that has left him barely able to walk.  The article then asserts that approximately 115,000 Gulf War veterans are suffering from some form of illness, and that “Vanity Fair uncovered military documents that show the Department of Defense made plans to run a clandestine trial of experimental vaccines and medical products during Desert Shield and Desert Storm.”
	The Vanity Fair article claims to link squalene to the anthrax vaccine.  The author claims that the DoD was motivated to improve on the licensed anthrax vaccine by making it effective in fewer doses against a more powerful “engineered” anthrax bacterium.  The article reports something called “Project Badger” by which the DoD allegedly contracted for the manufacture of anthrax vaccine at plants other than MBPI.  The plan allegedly called for shipping vaccine to MBPI for bottling, labeling, potency testing, and storage.  DoD, as the article reports, has unequivocally denied that this occurred.  
	The Vanity article admits that “[t]here are no documents available proving that the army used a squalene adjuvant in the unapproved vaccines, and the army has specifically denied it.”  Nonetheless, it suggests that the anthrax vaccine is indeed the culprit, by observing that Asa and Garry have “more than 100 sick veterans who had their shots and now test positive for antibodies to squalene.”  The implication, which requires a certain amount of credulity on the part of the reader, is that anthrax vaccine containing squalene was secretly and manufactured and illegally administered to unknowing troops.  It is reinforced by accounts from an Alabama National Guard Doctor, Dr. Gregory Dubay, who recounts administering vaccinations under secretive conditions.  
	The DoD dismisses any possible link between squalene and gulf war illness by asserting that military members were not given any vaccinations containing squalene.  To support their assertion, DoD contracted with Stanford Research International of Menlo Park, CA to test the vaccine stockpile for squalene.  The results of those tests, reported on the AVIP website, show that none of the fourteen lots tested contains squalene.  DoD concludes that these results confirm their assertions “that squalene is not, and has never been, an ingredient in human anthrax vaccines used in the United States.”
	If there is any support for the allegation that DoD added squalene to anthrax vaccine, it is the medical literature itself.  Squalene is among the adjuvants being evaluated for use in a second-generation anthrax vaccine.  Three different vaccines in the 1995 study by Ivins et al list squalene among their ingredients.  All of the authors of that study are affiliated with the U.S. Army Medical Research Institute of Infectious Diseases at Fort Detrick.  The Vanity article lists Detrick as one of the locations where “Project Badger” allegedly produced unlicensed anthrax vaccine.  
	Fort Detrick, specifically the National Cancer Institute’s Frederick Cancer Research and Development Center, is a location where the Vanity Fair article alleges anthrax vaccine was secretly produced during the Gulf War.  Furthermore, some recent literature lists squalene among the ingredients of cutting-edge adjuvants.  Although there is not a shred of evidence directly showing that any anthrax vaccine administered to servicemembers has contained squalene, some intriguing facts do indeed point to that inference.

2. Rate of Refusals
	The present controversy surrounding the AVIP centers on the cases presented by those service members who have refused to take the vaccine.  The AVIP administrators collected anecdotal data on refusals until January 1999.  The data collected included only 82 refusals after 172,000 servicemembers received one or more injection.  In light of this small number of refusals, and the demands of surveying individual commanders to collect the data, the program was determined not to be productive and halted.  The Air Force evidently has a database to track refusals, and intends to collect data on disciplinary actions taken against those who refuse, but as of October 1999 it had not yet begun to do so.  
	The most recent newspaper accounts of disciplinary proceedings put the total number of refusals at approximately 350.  Recent figures place the number of nonjudicial punishments of members who for refusing the vaccine at 120 in the Air Force alone.  One newspaper reported that on Thursday, February 17, 2000, the 37th service member court-martialed for disobeying an order to take the anthrax vaccine was convicted.  The same article reported that the Marine Corps has been the most aggressive branch in prosecuting those members who refuse, with 31 of those 37 members court-martialed being Marines.  Another report, published just two days later, placed the number of people court-martialed at “some 50.” 

3. Refusal Legal Issues
	The DoD position is that a refusal to take the anthrax vaccine constitutes disobedience of a lawful order.  There is no DoD-wide policy directing a specific disposition when a service member refuses the vaccine.  None of the military services has specified a particular response to apply service-wide.  The general practice is that servicemembers who refuse vaccination are initially counseled about their refusal and the AVIP generally.  This counseling presumably includes repetition of much of the information and assertions that appear in the AVIP quadfold “What Everyone Needs to Know About the Anthrax Vaccine.”  If the servicemember persists in refusing vaccination, s/he is given a direct order.  Disobedience of this order can lead to disciplinary action at the commander’s discretion. 
	In the military justice system, a commander has a wide range of remedies available with which to discipline a service member who disobeys a direct order.  These include, “formal page 13 counseling/warning, nonjudicial punishment, court-martial, and/or processing for administrative separation by reason of misconduct.”  Nonjudicial punishment refers to a procedure, authorized by Article 15 of UCMJ, whereby a commander may impose punishment without resort to a court-martial.  Article 15 punishment is usually limited to extra duties or restriction, forfeiture of pay, and reduction in grade.  Although the majority of refusal cases have been resolved without resort to a court-martial, the penalties available at a court-martial are considerably more severe.
	Disobeying a specific order to take the anthrax vaccine is a violation of Article 90(2) of the UCMJ.  There are 4 elements to this offense:
(a)	That the accused received a lawful command from a certain commissioned officer;
(b)	That this officer was the superior commissioned officer of the accused;
(c)	That the accused then knew that this officer was the accused’s superior commissioned officer; and
(d)	That the accused willfully disobeyed the lawful command.
The maximum punishment for a violation of Art. 90(2) is a dishonorable discharge, forfeiture of all pay and allowances, and confinement for 5 years, except that in time of war the maximum punishment is death. 
	There are two arguable defenses available to a servicemember accused of disobeying an order to take the anthrax vaccine.  Both defenses require the assertion that the order to take the vaccine can not legally form the basis for liability under the Uniform Code of Military Justice (UCMJ).  The first such argument is that the order is unlawful because the anthrax vaccine is an experimental drug.  The second argument is that the order can not give rise to criminal liability because it is not sufficiently related to the member’s military duty.

4. Experimental Drug Defense
	The “experimental drug defense” only applies if the service member is ordered to take a drug different from the approved anthrax vaccine, for example, one that contains squalene.  An order to take an experimental drug is permissible only under the narrow exceptions to the general requirement of informed consent.  The exception is the case where informed consent is not required because it is not feasible or contrary to the best interests of the recipients.  There is also a special statutory protection for military members, which provides that the requirements of § 505(i)(4) may only be waived by the President.  That statute limits Presidential waiver of informed consent to cases where obtaining consent is not feasible, is contrary to the best interests of the member, or is not in the interests of national security.  An interim FDA rule sets forth the procedures for meeting these statutory requirements and obtaining a waiver of informed consent.  
	The President has not waived the requirement of informed consent for the anthrax vaccine because it is already an approved drug, and informed consent does not apply.  If, however, the vaccine actually administered were actually an experimental drug, and not the drug already approved by FDA, the order to take the vaccine would be inconsistent with current statute and regulations.  An order that is inconsistent with federal statute and regulation can not form the basis for prosecution under either Article 90 or Article 92 of the UCMJ.  
	Article 90 first requires that the officer issuing the order have authority to do so.  Authority may be based on law, regulation, or custom of the service.  Since only the President can waive the informed consent requirement, it is at least arguable that for purposes of Article 90, any other officer lacks the authority to order a member to take an experimental drug.  Furthermore, even if the officer were somehow deemed to have authority to issue the order, an order that conflicts with the “statutory or constitutional rights of the person receiving the order” can not be punished under Article 90.  10 USC 1107 at least arguably creates a statutory right for a member to withhold consent to take any experimental drug except in the narrow circumstances that qualify for a waiver.  The case where a servicemember is ordered to take an experimental vaccine should therefore be an easy one to defend if that order is not pursuant to a lawful Presidential waiver of informed consent.

5. Defense that the Vaccine is Not Sufficiently Related to Military Duty

	The more difficult case to defend arises when a servicemember is ordered to take the approved anthrax vaccine.  The most likely defense in this situation is that the order to take the vaccine is not sufficiently related to the refusing member’s military duty.  This could be established under either of two theories.  First, that the order was given for the sole purpose of increasing the member’s punishment for an anticipated violation of Article 92.  Second, that the vaccine is not reasonably necessary to protect that member from anthrax.
	The first defense, that the order is for the sole purpose of increasing punishment, requires two elements.  First, that refusal to take an anthrax vaccine absent a specific, personal order be an offense under Article 92.  Second, that increasing the punishment above that provided by Article 92 is the sole purpose for which the commander issued the individual order.
	Refusal to take an anthrax vaccine absent a specific, personal order, is arguably a violation of Article 92.  Article 92(2), failure to obey a lawful order, is a lesser-included offense to Article 90.  It applies in situations where a servicemember violates or fails to obey a lawful general order or regulation, as distinct from orders directed specifically to the accused subordinate.  The various orders implementing the AVIP plausibly constitute an order or regulation in and of themselves.  If these orders create a duty for servicemembers to submit to anthrax shots regardless of the additional, personal order, then a refusal could be punished under Article 92.  The maximum penalty for a violation of Article 92 is 2 years confinement (in addition to a dishonorable discharge and forfeiture of all pay and allowances).
	If the servicemember violates Article 92 by refusing the vaccine even without an individual order, than the personal order, when it is issued, could serve to enhance that member’s punishment.  Liability under Article 90 requires disobedience of an individual, personal order as distinct from violation of a regulation or general order.  The punishment under Article 90 is more severe, 5 years confinement as opposed to 2.
	The Manual explanation of Article 90 describes the requirement of relationship to military duty as:
The order must relate to military duty, which includes all activities reasonably necessary to accomplish a military mission, or safeguard or promote the  morale, discipline, and usefulness of members of a command and directly connected with the maintenance of good order in the service.  The order may not, without such a valid military purpose, interfere with private rights or personal affairs.  However, the dictates of a person’s conscience, religion, or personal philosophy cannot justify or excuse the disobedience of an otherwise lawful order.  Disobedience of an order which has for its sole object the attainment of some private end, or which is given for the sole purpose of increasing the penalty for an offense which it is expected the accused may commit, is not punishable under this article. (emphasis added)
Under this formulation, an accused servicemember would need to establish not only that he could have been punished under Article 92 absent the order, but also that his/her commander had no other, legitimate, purposes in issuing the order besides increasing punishment.
	It is possible that the order might be given for parallel purposes.  Primarily, to increase punishment, but also in hopes the member will obey the order and be protected from infection. Vaccinating troops in order to prevent anthrax casualties obviously has the potential to enhance a unit’s ability to accomplish its mission and to safeguard the usefulness of its members.  Indeed, this language closely parallels the language used in DoD statements describing the motivation for the program.  
	There are, however, two legal issues.  First, consider a hypothetical commander whose subjective motivation for giving the order is spite.  S/he is seeking to increase the available punishment of a disfavored member as much as possible.  Yet the order may nonetheless be objectively relevant to a legitimate military duty.  Could a member be liable for disobeying this order?
	The Article 90 case law provides a framework for evaluating the legality of orders.  An order is presumed lawful except when “palpably illegal on its face.”  An order to take the anthrax vaccine is not unlawful on its face.  Therefore, the defense bears the burden of establishing that the order is unlawful by clear and convincing evidence.  Once the presumption is rebutted, the legality of the order is “at issue.”  In cases where legality of the order is at issue, the members must find that the order was lawful beyond a reasonable doubt.  In the hypothetical case of a vindictive commander, it would be nearly impossible for the defendant to show by clear and convincing evidence that the commander’s sole purpose was to increase the punishment.  
	The second legal issue is the standard by which the court-martial will evaluate an order’s relationship to military duty. The manual uses the “reasonable necessary” formulation to describe the legal standard.  In the case of a vaccine refusal, this language implies that the court must adjudicate whether the vaccine is reasonably necessary for the individual member charged with refusing it.  Yet this seems an unlikely approach for a court-martial.  
	The DoD has already taken over the traditional role of the FDA in performing the risk-benefit analysis of anthrax vaccination.  It seems unlikely that the court-martial would be sympathetic, for example, to a reservist whose unit has especially remote prospects for deployment to a high risk area, who argues that the vaccine is not reasonably necessary for him.  Instead, the most likely interpretation of “reasonable necessity” in the anthrax vaccine context is that the vaccination program overall must be reasonably necessary.  And the courts-martial are likely to defer to the command judgement on such a broad policy issue.

6. Refusal Case Histories
	To date, although there have evidently been as many as 50 members court-martialed, there have been no reported appellate cases arising out of the anthrax vaccine refusals.  Defense attorneys who have tried to challenge the safety of the vaccine and the validity of the AVIP have been rebuffed by the courts-martial.  Mark S. Zaid, Esq. is among the most outspoken opponents of the AVIP.  He is also the executive director of the James Madison Project and has been active in defending servicemembers who refuse the vaccine.  He first represented vaccine refusing members in April 1998 when several sailors onboard U.S.S. Independence refused the vaccinations.  
	Mr. Zaid’s experience defending Marine Lance Corporal Jared Schwartz, a Marine stationed at Twenty-Nine Palms, in June 1999 answers some of the questions presented by the legal analysis of Article 90.  Zaid sought to introduce evidence regarding the safety, efficacy, and necessity of the anthrax vaccine, but was rebuffed when this was ruled a “nonjusticiable policy issue.”  Likewise, he was not permitted to introduce “allegations regarding the illegal modification of the vaccine.”  Those allegations would have consisted of the testimony of none other than Dr. Robert Garry, the professor of Microbiology and Immunology at Tulane University School of Medicine who was among the authors of the squalene antibody study.  Mr. Zaid contends that Dr. Roberts would have testified about finding squalene antibodies in the blood of military personnel who have received the anthrax vaccine.  Mr. Zaid characterizes squalene as “a highly toxic adjuvant that does not have FDA approval” and contends that “[t]he presence of squalene in the anthrax vaccine would be in violation of U.S. domestic law and international laws that arose from the ashes of Nazi Germany and the Nuremberg trials.”
	Mr. Zaid is obviously presenting his case as an advocate.  In fact, as we have seen, the DoD has responded to the squalene allegation, both by testing some vaccine for the compound and by criticizing Dr. Garry’s study for its lack of sufficient controls.  Nonetheless, Mr. Zaid is correct to conclude that administration of a vaccine that contains squalene would be illegal.  It is puzzling that a court-martial would convict a servicemember for violating a lawful order yet refuse to hear evidence which, if true, would render the order patently unlawful.
	One possible explanation is that the court simply took judicial notice of the fact that there is no squalene in the anthrax vaccine.  Another possibility is that Dr. Garry’s testimony, even if true, would not suffice to rebut the presumption that the order was lawful.  To rebut the presumption of lawfulness, Garry’s testimony would have to establish that there is squalene in the vaccine that LCpl. Schwartz was ordered to take.  
	Of these two possible explanations, judicial notice seems the least likely.  Judicial notice of adjudicative facts is only permitted when:
the fact is not subject to reasonable dispute in that it is either (1) generally known universally, locally, or in the area pertinent to the event or (2) capable of accurate and ready determination by resort to sources whose accuracy cannot reasonably be questioned.
	Dr. Garry and his colleagues have compiled substantial evidence of squalene antibodies.  Some anthrax vaccines have used squalene to good effect in animal trials.  DoD’s enhancing a drug with squalene is not something that a military judge should be prepared to rule out by judicial notice.  
	The second possible ground for refusing to hear Dr. Garry’s testimony is that it would not establish that the vaccine Schwartz was ordered to take actually contains squalene.  At best it shows that some of the vaccine administered during the Gulf War contained squalene.  The legal issue presented is whether it is permissible to infer adulteration of the current vaccine from a past DoD practice of adding squalene to anthrax vaccine.  This amounts to an issue of evidence law.  If Dr. Garry could establish that DoD had a routine practice of adding squalene to anthrax vaccine, M.R.E. 406 would appear to permit the inference that it did so with the vaccine offered to LCPL Schwartz.
	Dr. Garry’s testimony, if believed, could create reasonable doubt as to whether the vaccine offered was the approved product it purported to be.  If he were able to successfully demonstrate that DoD had a routine practice of adding squalene to the anthrax vaccine, it could also meet the clear and convincing standard necessary to overcome the presumption of lawfulness.  Since there was no published opinion in this or any other anthrax refusal case, any theories about the legal basis on which this evidence was excluded is only speculation.  

IV. Current Status
A. Program Implementation Schedule
	When it originally announced the program, the DoD planned to implement the AVIP in three phases.  Phase I included the vaccination of service members assigned or deployed to “high-threat” areas: Southwest Asia (SWA) and Korea.  Phase I began in March 1998 in SWA and extended to Korea on August 16, 1998.  It continues today.  Phase II includes vaccination of “early deploying” forces supporting SWA and Korea, both Active and Reserve Component.  Phase II was slated to begin January of 2000 but was postponed due to Bioport’s delay in achieving FDA certification of its new plant.  DoD, in announcing the decision to postpone Phase II of the program, indicated that it expects a 6 to 12 month delay, depending on how long it takes Bioport to resolve FDA concerns about the new facility.  Phase III will extend vaccinations to all remaining service members.  Phase III inoculations were originally planned to begin in October 2002, and continue through September 2006.  

	B. Congressional Report
The Subcommittee on National Security, Veterans Affairs and International Relations, House Committee on Government Reform, issued a report about the AVIP on February 17, 2000.  That report was intensely critical of the program.  It included five major findings:
1.	The AVIP is a well intentioned but over broad response to the anthrax threat.  It represents a doctrinal departure overemphasizing the role of medical intervention in force protection.
2.	The AVIP is vulnerable to supply shortages and price increases.  The sole-source procurement of a vaccine that requires a dedicated production facility leaves DoD captive to old technology and a single, untested company.  Research and development on a second-generation, recombinant vaccine would allow others to compete.
3. 	The AVIP is logistically too complex to succeed.  Adherence to the rigid schedule of six inoculations over 18 months for 2.4 million members of a mobile force is unlikely, particularly in reserve components.  Using and artificial standard that counts only shots more than 30 days overdue, DoD tolerates serious deviations from the Food and Drug Administration approved schedule.
4. 	Safety of the vaccine is not being monitored adequately.  The program is predisposed to ignore or understate potential safety problems due to reliance on a passive adverse event surveillance system and DoD institutional resistance to associating health effects with the vaccine.  
5.	Efficacy of the vaccine against biological warfare is uncertain.  The vaccine was approved for protection against cutaneous (under the skin) infection in an occupational setting, not for use as a mass protection against weaponized, aerosolized anthrax.  
The Subcommittee Report continued with five recommendations:
1.	The force-wide, mandatory AVIP should be suspended until DoD obtains approval for use of an improved vaccine.  To accomplish this:
2.	DoD should accelerate research and testing on a second-generation, recombinant anthrax vaccine; and,
3.	DoD should pursue testing of the safety and efficacy of a shorter anthrax inoculation regimen; and,
4.	DoD should enroll all anthrax vaccine recipients in a comprehensive clinical evaluation and treatment program for long term study.
5.	While an improved vaccine is being developed, use of the current anthrax vaccine for force protection against biological warfare should be considered experimental and undertaken only pursuant to FDA regulations governing investigational testing for a new indication.  
	The full Government Reform Committee approved the anthrax report on March 9, 2000.  Just a few days prior, Chairman Dan Burton intervened in a vaccine refusal case.  In a letter to Secretary Cohen and Navy Secretary Richard Danzig, Burton accused the Navy of effectively denying legal counsel to a sailor accused of disobeying an order to take the vaccine:
It is my understanding that this sailor has requested and been denied access to legal counsel.  To whisk him out of the country to conduct a court-martial trial under the cloak of darkness where he will have great difficult retaining civilian counsel is outrageous.  … 
	As the Government Reform Committee prepares to approve a report later this week calling for the suspension of the mandatory anthrax vaccine immunization program, I find it hard to believe that the Defense Department continues to take such punitive measures against individuals who have legitimate concerns about the safety of the program.
	The majority members of the Committee on Government Reform are now apparently quite hostile to the continued administration of the anthrax vaccine.  It remains to be seen how this hostility will play out between now and the beginning of Phase II inoculations. 

C. 2nd Generation (recombinant) Vaccine 
	The one point on which the DoD and the Subcommittee agree is that a second generation anthrax vaccine would better serve the purposes of the AVIP.  The drawbacks of the current vaccine are the 6 dose, 18 month administration regimen, the requirement for a dedicated manufacturing facility, and the fact that the it is not highly purified and contains multiple extraneous proteins.  A vaccine based on purified protective factor made by recombinant technology has already been protective in animals.  Such a vaccine could be effective in as few as two doses.  The U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID) developed a second-generation recombinant vaccine against anthrax in 1995.  The DoD also appears eager to field a second generation anthrax vaccine, even while playing down that possibility during the current AVIP.  USAMRIID tested the new vaccine on animals but has not started clinical trials in humans.  The Department of Health and Human Services is funding research of a second-generation anthrax vaccine out of growing concerns over bioterrorism.
	One of the chief recommendations of the subcommittee’s report is that DoD aggressively pursue such a second generation vaccine.  The Subcommittee arrives at this recommendation for several reasons.  First, a second generation vaccine, because it would be highly purified, would likely produce fewer adverse reactions.  Second, the recombinant vaccine would not require a dedicated facility for its manufacture, making it likely that other pharmaceutical firms would be able to contribute to the supply.  Finally, the two dose regimen would ease the logistical challenge presented by the current six does regimen, which the Subcommittee described as “too complex to succeed.”
	The first issue presented by an effort to deploy a second-generation vaccine is whether, and to what extent, animal studies can ever constitute proof of effectiveness for a human drug.  Largely in response to the situation presented by military vaccines like the anthrax vaccine, the FDA has proposed a new rule titled “New Drug and Biological Drug Products; Evidence Needed to Demonstrate Efficacy of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted.”  This new rule would not apply directly to the AVA, because AVA is already approved on the basis of the Brachman study in humans.  But the guidance in the rule can inform analysis of subsequent animal studies that have tested AVA’s effectiveness against various strains of inhalation anthrax.  If a second-generation vaccine is ever approved, proof of its efficacy will likely rely heavily on animal results.
	The proposed rule first addresses whether and when it is ethical to expose volunteers to toxic chemicals or biological substances to test products that may protect against those substances.  The DoD comment on the proposed rule strongly opposed testing of such products in humans:
Because response to treatment of sublethal doses of chemical or biological agents (weapons) could not be extrapolated to predict response to higher doses, a lethal dose would be necessary to test the effectiveness of the protective drug or biologic.  If lethal doses were given to volunteers, a 100% effective rescue agent would need to be available, in case the protective agent failed and potentially fatal toxicity had to be reversed.  Antidotes to probable threat agents do not currently exist.
	The FDA concluded that it is unethical to expose volunteers to potentially lethal or permanently disabling doses of toxic biological, chemical, radiological, or nuclear substances to test the efficacy of protective products.  
	The alternative to exposing human volunteers to potentially lethal substances is to rely on animal studies, and the FDA proposed rule adopts this approach:
FDA would grant marketing approval for a new drug or biological product on the basis of “adequate and well-controlled animal trials when it is scientifically reasonable to expect that the effect of the drug or biological product in animals is reasonably likely to predict clinical benefits in humans.
This mode of approval is limited to new drug and biological products when clinical efficacy trial in human volunteers is not ethically possible and field trials are not feasible.  The safety of these new products would continue to be studied in human volunteers.
	Although products could be approved for “marketing” under the proposed rule, the FDA clearly intends to restrict their distribution more aggressively than with other prescription drugs.  For example, the agency may require that:
(1)	The product be stored at the control and direction of competent military and civilian emergency governmental personnel;
(2)	the product bbe used at the direction of, and as ordered by, competent military and civilian emergency governmental personnel; and
(3) applicants be obligated to followup on its usse and report to FDA in Phase 4 reports and descriptions of adverse reactions.  
In addition, the FDA would require provision of detailed information to the patients, and would supplement with an advisory committee in meetings open to the public when evaluating applications.
The rule would allow marketing approval for a new drug based on efficacy evidence from animal studies where:
(1)	There is a reasonably well-understood pathophysiological mechanism of the toxicity of the substance and its prevention by the product;
(2)	there is independent substantiation of the effect in multiple animal species, including species expected to react with a response predictive for humans;
(3)	the animal study endpoint is plainly related to the desired benefit in humans, which is generally the enhancement of survival or prevention of major morbidity; and
(4) 	the data or information on the kinetics and pharmacodynamics of the product or other relevant data or information n animals and humans allows selection of an effective dose in humans, and FDA therefore concludes that the effect of the product in animals is reasonably likely to predict clinical benefit in humans.
In addition, the rule requires that human experience be obtained to the extent possible, as by studying the effects of sublethal doses or by field results.  
	The first of the four requirements in the proposed rule is that there be a reasonable understanding of the mechanisms of infection and protection.  In general, anthrax and the anthrax vaccine appear to be well understood.  Modern theories of molecular biology, including our understanding of the three factors in anthrax toxin (PA, EF, and LF), explain why the vaccine works.  Blood titers for PA antibodies can measure the degree of protection that it affords.  It therefore seems likely that the medical profession believes that it understands both anthrax and the anthrax vaccine well enough to meet the first requirement of the proposed rule. 
	The second factor in the proposed rule is that there be data from multiple species, including species thought likely to react with a response predictive for humans.  Mice, rabbits, guinea pigs, monkeys and other species have all been used in anthrax vaccine trials.  Results have varied among species.  The AVA does not protect mice from virulent anthrax spores.  Most recent studies use guinea pigs.  They are partially protected by AVA, and some second-generation vaccines have provided them strong protection.  Rabbits were used in some early studies but have been replaced by guinea pigs in more recent studies.  A recent study involving both species, however, suggests that rabbits are more easily immunized than guinea pigs with AVA and some second-generation vaccines.  Finally, some of the recent studies at the US Army Medical Research Institute of Infectious diseases, Fort Dietrick, Frederick, MD, have used rhesus monkeys.  
	The Subcommittee Report asserts that various studies show “widely varied results within and between animal species” and “suggest variable modes of protection not necessarily correlated to antibody levels stimulated by the vaccine.”  DoD, on the other hand, has asserted that “reliance on animal data is necessary and appropriate” in this situation.  It is somewhat troubling that researchers seem to choose animal species for study based on how easy they are to vaccinate against anthrax.  Nonetheless, the current anthrax vaccine appears to be reasonably effective in several species, including non-human primates, and this may meet the requirement in the proposed rule for “substantiation of the effect in multiple animal species.”
	The animal studies of anthrax vaccines easily meet the third requirement of the proposed rule.  The endpoint of these studies is the prevention of death due to the anthrax exposure, which is exactly the desired benefit in humans.  The fourth requirement, however, is more troublesome.  It concerns the data for setting human dosing of the anthrax vaccine.  The current approved regiment of 6 shots originally appeared in the Brachman study.  Few if any of the subsequent animal studies have used a six shot regimen, however.  The Little and Knudson study used three doses at 2 week intervals.  The Ivins, Fellows, Nelson study used either one or two doses.  The DoD conducted a pilot study on humans to evaluate the effectiveness of a different regimen, and it appears that future modifications to the dosing schedule will be based on comparing the protective antigen antibody levels achieved in humans.  This approach seems likely to satisfy the fourth requirement of the proposed rule.
	Since it appears that the animal studies, combined with some human antibody data, likely meet the requirements of the proposed rule, it is appropriate to discuss the efficacy findings in those studies.
	The leading animal study on second-generation anthrax vaccines is Ivins, Pitt, Fellows, et al, “Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques.”  In that study, rhesus monkeys were immunized with AVA and a variety of second-generation vaccines, then challenged with inhalation of the Ames strain of anthrax.  All of the vaccines tested proved significantly effective.  They also had considerably less variability in their protein content than AVA.  The ultimate conclusion of the study is that “these studies have been a critical prerequisite to initial tests in humans of an anthrax vaccine candidate.  Indeed, the efficacy data specifically suggest that any of several potential new anthrax vaccines may be useful in humans as prophylaxis against anthrax.”
	The squalene controversy about the current, first-generation vaccine could ironically impede the implementation of a vaccination program using a second-generation vaccine.  It turns out that various squalene compounds are among the cutting-edge adjuvants being considered for a second-generation anthrax vaccine.  Recent results with squalene have been promising.  It has been administered to more than 6,000 humans as part of clinical trials of vaccines for herpes, HIV, and influenza.  It is generally well tolerated.  If not in an anthrax vaccine, it is likely to come up for FDA approval in some other vaccine in the near future.

V. Conclusion
	The limitations of the current anthrax vaccine create the chief difficulties in implementing anthrax vaccination for servicemembers.  Producing this first-generation vaccine consistently and in sufficient quantity has proven more difficult than expected.  Despite an enormous investment in the complete renovation of BioPort’s facility, the FDA continues to find fault with the manufacturing process.  
	The six dose, 18 month inoculation regimen presents an enormous logistical challenge.  DoD seeks to ensure that servicemembers complete necessary inoculations before any possible deployment to a high-threat area.  With most vaccines, that means a couple of shots immediately before deployment.  But with the 18 month lag in the anthrax vaccine, DoD concluded that the only way to achieve timely protection is to inoculate every servicemember, even those who presently have very remote prospects for deployment to a high-risk area.
	Refusals arise most common among those very members who have remote prospects for deployment to high-risk areas.  One Army Judge Advocate observed that almost nobody complains about anthrax vaccinations on the eve of deployment to Korea or the Gulf.  Although there is considerable evidence that the currently licensed vaccine is safe and effective, it is only indicated for those at high risk of exposure to anthrax.  The DoD has not publicly justified its conclusion that every last servicemember is in this category of high risk.  Instead it has made very general assertions that the U.S. military is deployable world-wide at a moment’s notice, and asserted that it would be irresponsible not to vaccinate everybody.
	Where members have refused the vaccine, the DoD has not handled the cases in a manner that helps its cause.  Everyone must realize that courts-martial are not a friendly forum for those who would decide national policy issues through litigation.  But when a court excludes evidence that purports to demonstrate a routine practice of administering unlicensed vaccines during the Gulf War, the courts-martial risk losing their credibility.  However remote the possibility that DoD may be secretly administering an unproven vaccine, a member who genuinely believes this to be the case will likely refuse.  A public trial of the issue, while potentially expensive and time-consuming, would give more credibility to the courts-martial and to the DoD’s denial that squalene was ever used in anthrax vaccine.  By refusing to address the squalene issue head-on with additional research, the DoD may only succeed in creating an unreasonable distrust of that promising adjuvant.  This could further delay the approval and implementation of an improved vaccine.
	The DoD has demonstrated remarkable foresight by recognizing the need to vaccinate every member.  It is indeed true, as the Gulf War showed, that it is not feasible to vaccinate a large force with the current vaccine in the interval between the outbreak of hostilities and deployment to the high-risk theater.  Only by starting early with vaccinations will the DoD achieve the desired protection.  But DoD seems to have put the cart before the horse.  Modern medical science can develop a better vaccine that is more highly purified and more suitable to the military application.  Such a vaccine could be limited to those members with immediate prospects for deployment to a high-risk area, and would therefore generate fewer refusals and less controversy.  Had DoD invested in a second-generation vaccine as eagerly as it has invested in adapting the old one to its purposes, the ultimate goal of Force Protection would likely have been better accomplished.