Concerns Regarding Announced Anthrax Vaccinations: Lack
of Demonstrated Safety and Efficacy Given the Pentagon proposal to
vaccinate 1.4 to 2.4 million U.S. troops with human MDPH anthrax vaccine
(produced by the Michigan Department of Public Health)(1), using a vaccine
for which there is only limited published data regarding both safety and
efficacy, it is worthwhile to review what is known and allow ProMED-mail
subscribers to add additional information and comments. The vaccine was
licensed by the F.D.A. in 1970, based on one published study by Brachman et
al. (2) and presumably on other unpublished data. Brachman's study, which
would be even more difficult to do today, involved vaccinating New England
millworkers exposed to anthrax in imported animal products in the 1950's,
when (generally cutaneous) anthrax was still a common disease among the
employees. During the four year study period there were 26 cases of
anthrax, of which twenty-one were cutaneous, and five were due to
inhalation. One case occurred in a recipient of the complete vaccine, and
two in recipients of the partial vaccine series. 35% of participants
completed the vaccine series. Although the study calculated vaccine
effectiveness as 92.5%, I believe that all that can be said is that there
is some efficacy, but the actual % efficacy cannot be calculated due to the
small number of cases. Furthermore, what we would really like to know is
the efficacy against inhalation anthrax, because of its resistance to
standard treatments and high (about 90%) mortality. Cutaneous anthrax is
amenable to standard therapy and fatal only when septicemia intervenes. The
small numbers -- five inhalation cases -- do not permit any conclusion
about vaccine efficacy with regard to inhaled organisms. Nor could any
estimate be made of the infectious dose. This is particularly important
because exposure to anthrax in wartime is likely to involve very high
concentrations of the organism, and any vaccine intended for such use must
demonstrate efficacy in this setting. Since there are currently no
populations identified as being at high risk of anthrax, another "gold
standard" study of the vaccine in humans is not possible. There is animal
data, however, which provides an indirect and incomplete, yet suggestive
idea of vaccine efficacy. P.C.B. Turnbull (3) collected data from five
studies in which the U.S. human vaccine was compared to other anthrax
vaccines in exposed guinea pigs. Various challenge strains of anthrax were
used, although the infectious doses and means by which the animals were
exposed were not specified. Per cent survival in the vaccinated animals
ranged from a high of 100% to a low of 4%. An abridged summary of his
table follows. It comprises data from animals immunized with three doses
of the MDPH vaccine 2-3 weeks apart: Challenge % Survival Anthrax Strains
Vaccinated Unvaccinated Vollum/Vollum 1B 100 16 9 Other Strains 28 3
Ames 75 0 Vollum 100 0 Ames/NH/Pen Res 4 0 Ames/NH/Pen Res 17
0 Vollum 1B 71 0 Vollum 1B 67 0 Vollum 1B 67 10 Clearly, these guinea
pig survival rates do not engender enthusiasm about how well the vaccine
may perform in soldiers facing an airborne anthrax challenge. Turnbull
stated, "The study of Brachman et al. remains the only one supplying hard
data on the effectiveness of the vaccines in humans. However, with all the
usual cautions that must be applied when extrapolating data from animals to
humans, tests in animals have indicated that the protective efficacies of
both the UK and US vaccines are less than ideal." He also wrote, "In
addition to the uncertain performance outlined above, the injection into
human beings of crude and undefined preparations is increasingly regarded
as unsatisfactory, particularly, as in the case of the anthrax vaccines,
when they are associated with frequent complaints of unpleasant
side-reactions." (4) A number of candidate vaccines were developed during
the 1980's and 1990's, some of which Turnbull discusses. Their performance
in animal tests surpassed that of the MDPH vaccine. I am unaware whether
any of them underwent human trials. However, given the inadequate supply
of the MDPH vaccine at the time of the Gulf War, as well as the FDA waiver
which allowed the Department of Defense to use unlicensed vaccines and
other therapeutics, one wonders whether other human anthrax vaccines were
given to troops in the Gulf. If so, information on their performance, such
as antibody titres post vaccination, may be available. Because the MDPH
vaccine, despite its 35-year history, had only been used on small numbers
of veterinarians and others with possible occupational exposures, there was
no large scale use from which to make judgments about safety until the Gulf
War. Then an estimated 150,000 troops were given a partial or full series
of injections. It is critical that whatever data exist regarding safety as
well as efficacy in these vaccinees be made available to the public before
the vaccine is used again on a large scale. Furthermore, since anthrax
vaccine in the future is likely to be used in concert with other
prophylactic measures against threat agents like _C. botulinum_ [toxin] and
acetylcholinesterase inhibitors, the Gulf vaccinees form a particularly
important group for study. Safety should be demonstrated both when the
vaccine is used alone, and also when it is used with other measures,
including use with other vaccines and chemical protective agents, such as
pyridostigmine, atropine, etc. The Rockefeller Report (of the Senate
Committee on Veterans' Affairs) (5) drew the following conclusion:
"Although anthrax vaccine had been considered approved prior to the Persian
Gulf War, it was rarely used. Therefore, its safety, particularly when
given to thousands of soldiers in conjunction with other vaccines, is not
well established. Anthrax vaccine should continue to be considered as a
potential cause for undiagnosed illnesses in Persian Gulf military
personnel because many of the support troops received anthrax vaccine, and
because the DOD believes that the incidence of undiagnosed illness in
support troops may be higher than in combat troops." My final concern
regarding the use of the MDPH anthrax vaccine in the prevention of
biological warfare-induced disease is theoretical. I presume that
genetically engineered strains may be used. It does not require much
sophistication to create antibiotic-resistant anthrax strains. It is
possible, perhaps likely, that "vaccine-resistant" strains may be used.
Such strains have been used by anthrax researchers in the US to test the
efficacy of candidate vaccines. Other innovations in anthrax virulence can
only be guessed at. Has the MDPH vaccine demonstrated efficacy against
strains engineered for extra virulence? Even if it has, it may well face
strains never before seen in our laboratories. Is it reasonable to assume
any vaccine efficacy in such unpredictable circumstances? Because these are
serious issues which the Army failed to consider in its environmental
assessment (6), the one opportunity that existed for public comment, I hope
ProMED-mail's experts will shed additional light on this subject.
References: 1. N.Y. Times articles, both 12/16/97. p.A1: "U.S. Armed
Forces to be Vaccinated Against Anthrax", Steven Lee Myers; and p.A22: "A
Vaccine That Experts Say Is Effective", Nicholas Wade. 2. Brachman PS,
Gold H, Plotkin SA et al."Field Evaluation of a Human Anthrax Vaccine".
American Journal of Public Health 1962; 52: 632-645. 3. Turnbull PCB.
"Anthrax Vaccines: Past, Present and Future." Vaccine 1991; 9: 533-539. 4.
ibid. 5. "Is Military Research Hazardous to Veterans' Health? Lessons
Spanning Half a Century." Staff Report for the Committee on Veterans'
Affairs. US Senate, 12/8/1994. 103d Congress. S. Prt.103-97. 6. Joint
Vaccine Acquisition Program. Final Programmatic Environmental Assessment.
Department of the Army, Joint Program Office for Biological Defence. 9/1997
-- Meryl Nass, M.D. Parkview Hospital Brunswick, Maine 04011 Home 207
865-0875 Work 207 729-1641, ext. 220
Pentagon slammed for testing Drugs on Troops
By: Deborah Funk, 10-23-1997
Navy Times Published: 10-27-97
PENTAGON SLAMMED FOR TESTING DRUGS ON TROOPS/
FDA: DOD STILL HASN'T LEARNED FROM GULF WAR MISTAKES
Despite assurances that it would not repeat the mistakes it made with
experimental drugs in the Gulf War, the Pentagon is not abiding by the
regulations designed to ensure the safe use of such drugs -- as
demonstrated most recently in Bosnia.
The Defense Department has been using an experimental vaccine to prevent
tick-borne encephalitis from striking U.S. service members in Bosnia.
But,according to the Food and Drug Administration, there have been
"significant deviations" from the federal regulations designed to ensure that the use
of the drug is safe.
"The deviations in Bosnia show that DoD has not corrected its procedures
to prevent the recurrence of problems in the use of investigational products
that arose during the Persian Gulf War," wrote the FDA's lead deputy
commissioner, Dr. Michael A. Friedman, in a July 22 letter to Dr. Edward
A. Martin, acting assistant secretary of defense for health affairs.
"The deviations . . . do not give us confidence that DoD is, at present,
capable of carrying out its obligations under investigational new drug
applications for drugs and biologics that are intended to provide
potential protection to deployed military personnel," Friedman wrote.
Biologics are immunizations against biological warfare agents.
"We have previously discussed most of these concerns with various DoD
personnel over the last several years," Friedman wrote. "We are concerned
that a number of the lessons that should have been learned from the Gulf
War have not led to corrections that should have been demonstrated in
Bosnia. Because of the recurrence of deviations from FDA regulations . .
FDA Warns Michigan Biologic Products Institute of Intention to Revoke
Licenses, Wed, 10 Dec 1997
FDA issued a letter to the Michigan Biologic Products Institute (MBPI),
Lansing, Michigan, on March 11, 1997, warning that the agency will
initiate steps to revoke MBPI's establishment and product licenses
unless immediate action is taken to correct deficiencies at the firm.
MBPI is currently licensed to manufacture Diphtheria Toxoid Adsorbed,
Tetanus Toxoid Adsorbed, Rabies Vaccine Adsorbed, Antihemophilic Factor
Human, Immune Globulin (Human), Albumin (Human), Anthrax Vaccine
Adsorbed, Pertussis Vaccine Adsorbed, Diphtheria & Tetanus Toxoids
Adsorbed, and Diphtheria & Tetanus Toxoids & Pertussis Vaccine Adsorbed.
MBPI can remain open while it attempts to address the deficiencies cited
by FDA.
An FDA inspection of MBPI conducted between November 18 and 27, 1996,
documented numerous violations in the following areas: 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. Some examples
include: failure of the quality control unit to approve or reject all
components, drug product containers, closures, in-process materials,
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, packing 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; failure
to record the performance of each step in the manufacture and
distribution of products.
Although similar deficiencies have been identified during past
inspections, MBPI has failed to make satisfactory corrections. FDA has
determined that continuing problems represent a failure to comply with
the regulations that safeguard the drug and pharmaceutical industry.
However, the agency is not aware of any injuries to recipients of these
products as a result of the noted deviations. In its letter, FDA
requires MBPI to submit a written commitment for achieving full
compliance within 10days. MBPI must also submit a comprehensive plan for
correcting all deficiencies within 30 days. The action plan must include
corrective actions to ensure that the firm's quality assurance unit
functions in an adequate, effective and timely manner, including
addressing all quality assurance oversight deficiencies,and to conduct a
thorough review of all standard operating procedures to achieve
compliance with good manufacturing practices as
specified in Subchapter C, Parts 210 and 211, Title 21, Code of Federal
Regulations.
If MBPI fails to correct these deficiencies, FDA may begin the process
for revoking the facility's licenses. Under FDA's procedures, MBPI can
request a public hearing before an administrative law judge on the
proposed revocation of its licenses. The revocation of the licenses
would prohibit MBPI from distributing any of its products in interstate
commerce.
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