The following anonymous
DOD document omits some relevant facts and misrepresents several studies
regarding anthrax vaccine safety.
I have provided additional information, comments and references. My remarks are in bold.
Meryl Nass, MD
March 20, 2007
Surveillance
Program for Short-term Health Effects of AVA.
To monitor rare or
unexpected adverse events associated in time to any vaccine, DoD health-care
providers have participated in the Vaccine Adverse Event Reporting System
(VAERS), since its inception in 1990.
Military medical providers have been loathe to
file anthrax vaccine adverse event reports due to perceived adverse effects on
their careers if they do so. This
probably stems from the instruction to medical providers NOT to report adverse
events unless the patient missed more than 24 hours of work, was hospitalized,
or contamination of an entire lot of vaccine was suspected.[1]
Therefore, after changing this guidance in
response to Congressional testimony about the failures to file,[2]
repeated instructions to file these reports by top military leaders have been
issued to providers in 1999,[3]
2000[4]
and 2004.[5] This would suggest that military
medical providers continued to fail to file the reports.
For anthrax vaccine, each
VAERS report involving anthrax vaccine between 1998 and 2001 was reviewed by an
independent panel of civilian physicians. This panel detected no patterns of
unexpected adverse events related to anthrax vaccination. Despite the extensive
body of knowledge regarding the safety of anthrax vaccine, safety monitoring
continues, as is prudent for all vaccines and medications.
The independent panel wrote two published papers
on their analysis. Contrary to the
claim that no patterns of unexpected adverse events were found, the second
paper,[6]
which reviewed more cases than the first, found several patterns of Gulf War
Illness-like reports to VAERS at 2 to 3 times the expected rate in anthrax
vaccine recipients.
As
directed by the 2001 National Defense Authorization Act, the DoD and the
Centers for Disease Control and Prevention have collaborated to establish a
Vaccine Healthcare Center Network, a system for enhancing the monitoring of
vaccine associated adverse events experienced by uniformed services members.
This monitoring assists in determining the need for immunization safety
assessments and possible alternative management strategies to preserve
deployability of those who experience adverse reactions.
The
network functions as an allergy-immunology clinical evaluation unit
specializing in vaccine-associated adverse events and is accessible to DoD
beneficiaries either directly or on a referral basis. The VHC maintains a
capability to support a comprehensive vaccine safety assessment program. The
scope of services is broad and ranges from surveillance through enhanced
vaccine adverse events reporting and case management of complex adverse events.
The Network assists in data collection and standardization in support of
improvement of the vaccine adverse events reporting system (VAERS) for all
required vaccines including the anthrax vaccine. Emphasis is placed on
standardization of clinical and educational programs that focus on healthcare
provider and beneficiary understanding of immunizations and vaccine
safety. Clinical research
partnerships have been developed to validate clinical guidelines and support
improvements in vaccine healthcare delivery.
The
discussion of the VHC network above is correct. However, several points should be added. First, many more clinics were initially
envisioned, but the number of clinics created stopped at four. Second, funding for this network has
been threatened during the past two funding cycles and remains in
question. Staff have resigned, and
there have been absent medical directors at some clinics, which are primarily
staffed by nurse practitioners.
Third, although the mission of the VHCs was, in part, to perform
research on vaccine reactions, there are no published papers or research
reports available from the VHC network.
No ongoing research projects have been announced to the public. Fourth, although at least 1,700
complete reviews of patients reporting illnesses related to anthrax vaccine
have been performed,[7]
the VHCs have failed to provide information on the types of reactions they have
evaluated, other contributing factors, their thoughts on causality and
treatment, which would greatly assist other medical providers.
Surveillance Program for
Long-term Health Effects of AVA.
There are no known
long-term patterns of side effects from the anthrax vaccine, based on an
ongoing series of studies at Fort Detrick, Maryland, and elsewhere. Reports in
this series were published in 1958, 1965, 1974, 2001, and 2004.
The reports from 1958, 1965 and 1974 were of
workers who received many vaccines at Fort Detrick, and were confounded by the
Òhealthy workerÓ effect and the inability to separate the effects of anthrax
vaccine from other vaccines. These
studies did show several abnormalities in blood tests of the multiply-vaccinated
cohort, but their clinical effect was uncertain.
Regarding the 2001 report by Pittman et al at Fort
Detrick:
Passive surveillance data on 1,583 Fort Detrick employees
who had received a total of 10,722 doses of anthrax vaccine between 1973 and
1999 were reviewed.[8] Two hundred seventy-three persons
received 10 or more doses. Other
vaccines were also given to this population. Employees visited the clinic after 3.6% of anthrax
inoculations for local reactions, and after 1% of inoculations for systemic
reactions. One female developed an
acute demyelinating disorder 8 days after the second anthrax vaccination. Reaction rates were significantly
affected by lot and gender, with women having more reported reactions than men. A first reaction increased the odds of
presenting with later reactions.
The authors concluded, ÒA prospective, randomized,
placebo-controlled study to actively examine reactogenicity is needed to more
completely define the extent and nature of reactions associated with receipt of
AVA in humans, as well as to confirm the gender and lot differences in local
reaction rates.Ó
Despite the extensive body
of knowledge regarding the safety of anthrax vaccine, safety monitoring
continues, as is prudent for all vaccines and medications.
Details of each study
appear below. The studies include:
1. Disability Study. The Department of
Defense (DoD) studied whether anthrax immunized Service members have higher
rates of evaluation for disability discharge from March 1998 to February 2002.
The study results were published in the Journal of Occupational and
Environmental Medicine in 2004.1
This study determined the rates of disability evaluation among 716,833 Service
members followed for 4.25 years 154,456 of whom received at least one dose of
anthrax vaccine. The study compared the risk of disability evaluation in
Service members (immunized vs. unimmunized) accounting for occupation and
sociodemographics (age, gender, race/ethnicity, marital status and education).
The results showed that anthrax immunization did not increase the risk of
either temporary or permanent disability among the Service members studied.
This study was performed by a contractor for the Anthrax Vaccine
Agency, which provided all the raw data.
There was no independent oversight or review to confirm validity of the
data provided to the contractor or the contractorÕs analysis. The second author was the Director of
the Anthrax Vaccine Agency.
2. Optic
Neuritis Study2 The optic neuritis study was a matched case-control
study among military personnel conducted from January 1998 through December
2003. The study determined whether
a statistical association exists between vaccine exposures and optic neuritis
within 6-, 12-, and 18-week study intervals. A total of 1131 cases of optic
neuritis and 3393 controls were matched by sex, military component, and
deployment status. No statistically significant associations between optic
neuritis and anthrax vaccine were observed for any of the three study
intervals. The same was true for the other vaccines evaluated (smallpox,
hepatitis B and influenza). The authors concluded that there is no association
between optic neuritis and receipt of anthrax, smallpox, hepatitis B, or
influenza vaccinations in the US military, whether administered alone or in
combination.
This
study[9]
employed a low power, case-control method to explore the role of vaccinations
in optic neuritis. Soldiers had to
be diagnosed with optic neuritis within 18 weeks post-vaccination to be
included as cases. Since 2003, soldiers have started the anthrax series just
before 6-12 month deployments to Afghanistan and Iraq. Thus CDCÕs inclusion criteria required
most cases to be diagnosed while on deployment. Since diagnosis requires an ophthalmologist evaluation, and
soldiers have limited access to these specialists in a war zone,[10] it is
likely that only the most severe cases met the inclusion criteria. Controls were not properly matched to
cases. The authors concluded that
optic neuritis is unrelated to anthrax vaccine. Although the DMSS provided the data, the studyÕs design
undercut this conclusion, as pointed out in a published Letter I submitted to
the editor.[11]
3. Military
Hospitalizations Study.3 This study included 170,723 active duty
anthrax-vaccinated service members deployed during the time period January 1,
1998 to December 21, 2001. This study evaluated hospitalizations for any-cause,
14 broad International Classification of Disease (ICD-9) diagnostic categories,
autoimmune organ specific and organ non-specific hospitalizations, and asthma.
The results of the study showed that anthrax vaccination was associated with
significantly fewer hospitalizations for any cause, diseases of the blood and
blood forming organs, and diseases of the respiratory system.
The fact
that anthrax vaccination was associated with significantly fewer hospitalizations
for any cause is a reflection of the well-known fact that deploying
servicemembers (who are vaccinated in preparation for deployment) are a
healthier group than nondeploying members. If they werenÕt, these results would imply that anthrax
vaccine prevents all sorts of diseases—and no one is claiming that. The better analysis is to compare the
same group pre and post vaccination, to avoid confounding by the Òhealthy
warriorÓ effect. When this was
done, hospitalizations for a number of illnesses (thyroid cancer, carcinoma in
situ of the breast and genitourinary system, diabetes, psychoses, depression,
other forms of ischemic heart disease, thrombophlebitis, asthma, other
disorders of intestine, noninflammatory disorders of the cervix, etc.)[12] were
greater in the vaccinated group.
Two Institute of Medicine committees have recommended since 2002 that
this be explored further[13] [14]—but
it has not happened.
4. Female
Reproductive Health Study4 This cohort study was designed to
determine whether receipt of anthrax vaccine by reproductive-aged women has an
effect on pregnancy rates. The study evaluated a total of 4092 women (ages
17-44) stationed at Fort Stewart, GA from January 1999 to March 2000. Results
showed there were 513 pregnancies in the women studied with 385 following at
least one dose of anthrax vaccine. After comparing pregnancy and birth rates
between vaccinated and unvaccinated women the authors concluded that anthrax
vaccination had no effect on pregnancy and birth rates.
The Naval Environmental Health Research
Center performed a study comparing birth defect rates in offspring of women who
inadvertently received anthrax vaccine during the first trimester, to birth
defect rates in women who got the vaccine at any other time.[15] The
results showed a "slight but significant increase" in birth defects
in the first trimester-vaccinated women. Ryan presented these results to
several groups in late 2001 and early 2002, including the FDA and Institute of
Medicine committee on the safety and efficacy of anthrax vaccine.
The research results, though unpublished, led
to several actions, according to the IOM report:[16]
1. December, 2001: The informed consent document for CDCÕs
IND trial of anthrax vaccine in those exposed to the anthrax letters added a
pregnancy warning.
2. Jan 16, 2002: The Assistant Secretary of Defense for Health Affairs issued
a memorandum[17] and
press release[18]
demanding the services check whether women were pregnant before vaccinating,
coordinate with the ArmyÕs Anthrax Program, and provide him Òwithin 14 days of
this memo, your ServiceÕs plan to strengthen the screening of females of
childbearing age with careful questioning or other positive efforts,
potentially including pregnancy testing when appropriate, to prevent the
administration of vaccine to pregnant women.Ó
3. January 31, 2002: FDA approved both the new anthrax
manufacturing facility and a new product label, and released stockpiled anthrax
vaccine. The vaccineÕs pregnancy
risk category was changed from category C (ÒRisk cannot be ruled outÓ) to D
(ÒPositive evidence of riskÓ).
However, on February 15, 2002 the Morbidity
and Mortality Weekly Report wrote that there were concerns regarding the
accuracy of computerized medical records used in the Navy study, and a paper
review, taking several months, would be performed for clarification.[19] The March 2002 IOM report stated,
ÒBecause of the importance of this issue, the study investigators are working
rapidly to validate both exposures and outcomes using primary data sources.Ó However, the Navy study of birth
defects remains unpublished, five years later.
An Army study of pregnancy rates following
anthrax vaccine was published in March 2002. [20] This
study used computerized records, but performed no verification with paper
records. This study excluded
high-risk pregnancies that were referred outside the military hospital.
Twenty-five pregnancies were lost to follow-up. In 385 pregnancies following any anthrax inoculations, of
which some were lost to follow-up, there were 15 known birth defects (a 3.9%
rate or greater) compared to a birth defect rate in the US overall of
approximately 3% and one military rate of 3.2%.[21] The pregnancy rate was the same in
immunized and unimmunized women. Although the authors said, ÒThis study did not
have sufficient power to detect adverse birth outcomes,Ó and ignored the
relatively high birth defect rate, the study is cited as evidence that anthrax
vaccine has no effect on reproductive health by the US military and by a
surrogate of the manufacturer.[22] [23]
5. Male
Fertility Study5 This study evaluated the impact of anthrax
vaccination on sperm and clinical pregnancy rates among couples in which the
man had or had not been exposed to anthrax vaccination. From October 1999 to
December 2003 254 males who had received anthrax vaccination and 791 unvaccinated
males enrolled in the Walter Reed Army Medical Center Assisted Reproductive
Technologies program were evaluated. To evaluate the impact of anthrax
vaccination on male fertility, the study compared characteristics of the men,
the couples, the fertilization, and the outcome of fertilization. The
investigators conclusion was that exposure to the anthrax vaccine by males
undergoing assisted reproduction did not negatively impact semen parameters,
fertilization rate, embryo quality, or clinical pregnancy rates.
They
compared anthrax-vaccinated males from infertile couples to unvaccinated males
from infertile couples. This fails
to answer the question of whether anthrax vaccine causes male fertility
problems.
6. Tripler
Army Medical Center Healthcare Worker Study6 This study evaluated a
broad range of health effects in a cohort of 601 healthcare workers immunized
with anthrax vaccine. The healthcare workers surveyed were a highly educated,
medically experienced population, familiar with adverse events, with easy
access to health care. The findings of this study showed that regardless of
gender, most adverse events after vaccination were mild and self-limited. There
was no evidence that anthrax vaccinated healthcare workers had higher rates of
either outpatient health visits, hospitalizations, or a change in self-reported
health and wellness when compared to unimmunized individuals.
According to the principal investigator, "The objectives
were to provide active surveillance of self-reported side effects and the
duration of symptoms." [24] Soldiers were asked to complete a
questionnaire about symptoms that developed after their last anthrax
vaccination when they presented for a subsequent inoculation or within two
weeks of an inoculation.
Three significant neurological events were described. One case of multiple sclerosis
developed early in the study. A
neonatologist developed upper extremity weakness and tremor associated with a
CPK level over 1000. A pediatric
cardiologist developed numbness and fasciculations, suggesting brachial
plexopathy, which was said to later resolve.
Despite the studyÕs original intention to actively follow adverse
events longitudinally, the exit questionnaire chosen was not designed to
capture specific information about vaccine-related adverse events and their
duration, and made no reference to anthrax vaccine. The published paper fails to provide the duration of
systemic reactions. It states that only local reactions could be linked to
vaccination, and dismisses vaccine causality for other reactions, without
providing a rationale. It fails to
explore why 0.5% of participants developed a serious neurologic condition in
close temporal relationship to vaccination, or why immunized women who
completed the trial were 4.4 times as likely to report poor or fair health as
an unvaccinated observational group of women at the same base.
Other problems with this study include the fact that although 603
persons were enrolled and originally reported on,[25] the
published paper mentions only 601 subjects. By the time the trial was completed, at eighteen months,
over half the participants had been lost to follow-up.
The abstract states that local reactions occurred more often in
women, but neglects to mention that systemic reactions did also, at 1.5 –
2 times the rate of men.
Although the published paper notes that one reason for enrollees to drop
out was pregnancy, it omits mention of eleven women who became pregnant after
starting the vaccine series, and does not report pregnancy outcomes.
7. Flight
Physicals Study (Forthcoming). This study retrospectively compared data from
periodic examinations of US Army aircrew members between 1998 and 2005. The
study included 6,820 immunized and 4,145 unimmunized personnel. For each
variable evaluated there was no association between anthrax immunization and
any clinically relevant change in a physiologic parameter.
Not
available for review.
8.
The Millennium Cohort Study (Ongoing).
The Millennium Cohort Study was designed to evaluate the long-term
health effects of military service, specifically deployments. The Department of
Defense realized after the 1991 Gulf War that there was a need to collect more
information about the long-term health of service members. The Millennium
Cohort Study was designed to address that critical need, and the study was
underway by 2001. Funded by the
Department of Defense, and supported by military, Department of Veterans
Affairs, and civilian researchers, almost 110,000 people have already
participated in this groundbreaking study. As force health protection continues
to be a priority for the future of the United States military, the Millennium
Cohort Study will be providing a crucial step towards enhancing the long-term
health of military service members. Additional information available from: www.millenniumcohort.org
Not
available for review.
References.
1. Sulsky
SI, Grabenstein JD, Deldos RG. Disability among U.S. Army personnel vaccinated
against anthrax. J Occup Environ Med 2004;46:1065-1075.
2. Payne DC, Rose CE, Kerrison J, Aranas
A, Duderstadt S, McNeil MM. Anthrax vaccination and risk of optic neuritis in
the United States military, 1998-2003. Arch Neurol 2006;63:871-5.
3. Wells TA, Sato PA, Smith TC, Wang LZ, Reed RJ, Ryan MAK. Military
hospitalizations among deployed US service members following anthrax
vaccination, 1998-2001. Huamn Vaccine 2006;2(2):54-59.
4. Weisen AR, Littell CT. Relationship between prepregnancy anthrax
vaccination and pregnancy and birth outcomes among US Army women. JAMA
2002;287(12):1556-60.
5. Catherino WH, Levi A, Kao TC, Leondires MP, McKeeby J, Segars JH.
Anthrax vaccine does not affect semen parameters, embryo quality, or pregnancy
outcomes in couples with a vaccinated male military service member. Fertil
Steril 2005;83:480-3.
6. Wasserman GM, Grabenstein JD, Pittman
PR, Rubertone MV, Gibbs PP, Wang LZ, Golder LG. Analysis of adverse
events after anthrax vaccination in US Army medical personnel. J of Occup
Environ Med 2003;45:222-33.
[1] Instructions from Secretary of the Navy: SECNAVINST 6230.4. April 29, 1998. ANNEX C TO ENCLOSURE (1). PAGE C-5. It stated, ÒReport all adverse vaccine reactions resulting in hospitalizations or time lost from duty (more than 24 hours), using the Health and Human Services Vaccine Adverse Events form. Other reactions will not be reported unless contamination of lots is suspected.Ó
[2] Hearing, Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations. Anthrax Vaccine Adverse Reactions. July 21, 1999.
[3] Bailey S. (Assistant secretary of defense for Health Affairs). Memorandum for Service Surgeons General. Subject: Policy for reporting adverse events associated with anthrax vaccine. October 15, 1999.
[4] Clinton JJ. (Acting Assistant Secretary of Defense). Memorandum for Service Surgeons General. Subject: Reactions to the anthrax vaccine. October 6, 2000.
[5] Peake JB.
(Lieutenant General Commanding). Memorandum for Commanders, regional Medical
Commands. Subject: Learning from adverse events after vaccination-ACTION
MEMORANDUM. FEBRUARY 10, 2004.
[6] Sever JL,
Brenner AI, Gale AD, Lyle JM, Moulton LH, Ward BJ, West DJ. Safety of anthrax
vaccine: an expanded review and evaluation of adverse events reported to the
Vaccine Adverse Event Reporting System (VAERS).Pharmacoepidemiol Drug Safety.
2004 Dec;13(12):825-40.
[7] Testimony of David Hrncir, MD, Director, Wilford Hall Vaccine Healthcare Center. Court martial trial transcript of Snr Airman Nathaniel Torquato, Travis Air Force Base. January 26, 2006. LTC Nancy J Paul, presiding.
[8] Pittman PR,
Gibbs PH, Cannon TL et al. Anthrax vaccine: Short-term safety experience in
humans. Vaccine 2001; 20: 972-8.
[9] Payne DC,
Rose CE Jr, Kerrison J, Aranas A, Duderstadt S, McNeil MM. Anthrax
vaccination and risk of optic neuritis in the United States military, 1998-2003.
Arch Neurol. 2006 Jun;63(6):871-5.
[10] Wells TS,
Sato P, Smith TC et al. Military Hospitalizations among deployed US service
members following anthrax vaccination, 1998-2001. Human Vaccines 2006; 2:
54-59.
[11] Nass M.
Data vs Conclusions in the Optic Neuritis Vaccination Investigation. Arch
Neurol 2006; 63: 1809-10.
[12] Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. Medical Follow Agency, Institute of Medicine. Anthrax Vaccine: Is it Safe? Does it Work? National Academy Press 2002; Washington, DC. Appendix G.
[13] Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. Medical Follow Agency, Institute of Medicine. Anthrax Vaccine: Is it Safe? Does it Work? National Academy Press 2002; Washington, DC.
[14] Committee to Review the CDC Anthrax Vaccine Safety and Efficacy Research Program. Assessment of the CDC Anthrax Vaccine Research Program. Institute of Medicine 2003: National Academies Press. Washington, DC.
[15] Johannes L.
Anthrax Vaccine May Increase Incidence Of Birth Defects For Pregnant Women.
Wall Street Journal. January 16, 2002.
[16]
Op cit. Committee to Assess the Safety and Efficacy of the Anthrax Vaccine.
Medical Follow Agency, Institute of Medicine. Anthrax Vaccine: Is it Safe? Does it Work? National Academy Press
2002; Washington, D.C. chapter 6. (http://www.nap.edu/openbook/0309083095/html/171.html and the following
page)
[17] http://www.fda.gov/ohrms/dockets/dockets/80n0208/80n-0208-c000019-03-vol142.pdf
[19] MMWR 127
vol 51 No. 6. Notice to Readers: Status of US Department of Defense preliminary
evaluation of the association of anthrax vaccination and congenital anomalies. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5106a5.htm
[20] Op. cit.
Wiesen AR, Littell CT. Relationship between prepregnancy anthrax vaccination
and pregnancy and birth outcomes among US Army women. JAMA. 2002 Mar
27;287(12):1556-60.
[21] Bush RA, Smith TC, Honner WK, Gray GC. Active
surveillance of birth defects among U.S. Department of Defense beneficiaries: a
feasibility study. Mil Med. 2001 Feb;166(2):179-83.
[22] http://www.anthrax.osd.mil/resource/qna/qaAll.asp?cID=312 ÒIn the March
27, 2002, issue of the Journal of American Medical Associations, two Army
physicians published their peer-reviewed findings that women get pregnant at
the same rate, whether anthrax-vaccinated or unvaccinated. These physicians
from Fort Stewart, Georgia, also showed that women deliver offspring at the
same rate, whether anthrax-vaccinated or unvaccinated. The Fort Stewart study
found no difference in birth defect rates, either, but the study may have been
too small to detect small differences. http://jama.amaassn.org/content/vol287/issue12/index.dtl
Ò
[23] Partnership
for Anthrax Vaccine Information. Muhiuddin Haider at George Washington
University is the principal, under contract to the vaccine manufacturer,
Bioport. www.gwu.edu/~cih/newsletter/CGHNewsletter11-2003.pdf http://www.gwu.edu/~cih/anthraxinfo/vaccine/vaccine_myths.htm#7
ÒMyth: The vaccine causes miscarriages and infertility
Fact: There is no scientific
information to support this statement. A recent study reported in the Journal
of the American Medical Association followed over 4,000 military women to look
at pregnancy rates and adverse birth outcomes between groups of women who had
been vaccinated and women who had not. Although the study was small, it found
that anthrax vaccination had no effect on pregnancy or adverse birth outcomes.Ó
[24] Wasserman G. Tripler Army Medical Center Survey. First
Annual Department of Defense Conference for Biological Warfare Defense
Immunizations. Fort Detrick, Maryland. May 26, 1999. transcript.
[25] GAO.
Medical Readiness: Issues Concerning the Anthrax Vaccine. July 21, 1999.
GAO/T-NSIAD-99-226