• Following a suit filed by several unnamed Service members, the U.S. District Court of Washington, D.C. placed an injunction against the DoD's mandatory anthrax vaccination program on 27 October 2004.
• DoD immediately issued orders to comply with the court decision, stopping anthrax vaccinations for all personnel on 27 October 2004, pending resolution of all legal issues.
• Following the procedure established by law, the Deputy Secretary of Defense (under authority assigned by the Secretary) determined that a significant potential for a military emergency exists that involves a heightened risk of U.S. military forces of attack with anthrax spores. To avoid the harm to the Armed Forces associated with stopping the vaccination program for high-risk personnel, DoD sought an Emergency Use Authorization.
• The Assistant Secretary of Defense for Health Affairs (ASD (HA)) submitted to the FDA a detailed summary of the evidence for safety and effectiveness that form the scientific foundation for the current FDA license for anthrax vaccine. • The ASD (HA) asked the Commissioner of FDA to approve the EUA.
• The Commissioner of FDA considered the evidence regarding the safety and effectiveness of anthrax vaccine for protection against anthrax disease via inhalation exposure, consulted with the Centers of Disease Control and Prevention and National Institutes of Health, and then issued the Emergency Use Authorization on 27 January 2005.
• On April 6, 2005, the District Court modified it's injunction to allow program resumption under EUA.
• On December 15, 2005, the FDA issued a Final Rule and Final Order on the license status of anthrax vaccine adsorbed (AVA). After reviewing extensive scientific evidence and carefully considering comments from the public, the FDA again determined that AVA is licensed for the prevention of anthrax infection regardless of route of exposure.
• On 12 October 2006 Deputy Secretary of Defense approved resumption of a mandatory AVIP program for military and civilian personnel in higher risk areas or with special mission roles. The policy allows voluntary vaccinations for other groups.
• The Under Secretary of Defense for Personnel and Readiness released DoD implementation guidance for the AVIP on 6 December 2006
• Service implementation plans were approved by the Assistant Secretary of Defense for Health Affairs on 08 February 2007
• On December 11, 2008, the Food and Drug Administration (FDA) approved a change in route of administration and the dosing schedule for the anthrax vaccine.
There is some evidence that the Japanese used anthrax as a biological weapon (BW) in China during World War II (Christopher GW, et al. Biological warfare: A historical perspective. JAMA 1997; 278 (Aug 6): 412-17).
Since then, several countries are believed to have incorporated anthrax spores into biological weapons. Intelligence analysts believe that at least seven potential adversaries have an offensive BW capability to deliver anthrax -- twice the number of countries when the 1972 Biological and Toxin Weapons Convention (BTWC) took effect. The BTWC was designed to prohibit such activity.
Iraq admitted to the United Nations in 1995 that it loaded anthrax spores into warheads during the Gulf War. In the post-cold war era, the former Soviet Union admitted to having enough anthrax on hand to kill every person on the planet several times over. The accidental aerosolized release of anthrax spores from a military microbiology facility in the former Soviet Union city of Sverdlovsk in 1979 resulted in at least 79 cases of anthrax infection and 68 human deaths and demonstrated the lethal potential of anthrax aerosols. Members of Aum Shinrikyo, the group responsible for the 1995 Tokyo sarin attack, reportedly experimented with biological agents in Japan before resorting to chemical agents. A lengthy article in the May 26, 1998, edition of the New York Times reported that members of Aum Shinrikyo released anthrax spores and botulinum toxin in Tokyo, Yokohama, and Yokosuka in 1990, targeting Japanese government and U.S. Navy facilities. Fortunately, no one was injured in these events.
Anthrax spores have also been used as a weapon inside the United States by unknown terrorists in the Fall of 2001. The attack killed 5 people and infected at least 17 others.
Anthrax is a rapidly progressing acute infection caused by spore-forming bacteria called Bacillus anthracis. Anthrax most commonly occurs in warm-blooded animals, especially goats, cattle, and sheep, but it can also infect humans. Anthrax spores can be easily produced in a dry form for biological weapons. Spores can survive many years in adverse conditions and still remain capable of causing disease. When inhaled by humans, these spores cause respiratory failure that can lead to death within a week.
Anthrax can make an excellent weapon of mass destruction. The spores may be used as a weapon in a variety of delivery systems. They can be produced in large quantities without sophisticated equipment. All it takes is a single breath of aerosolized anthrax to inhale enough spores to cause the disease. Then, if serious symptoms occur, it kills 99% of unprotected people. Even if a person with symptoms receives antibiotics, the death rate is still about 50%. Anthrax spores are odorless, colorless, and tasteless.
A nasal swab involves placing a swab inside the nostrils and taking a culture. The CDC and the U.S. Department of Health and Human Services do not recommend the use of nasal swab testing by clinicians to determine whether a person has been exposed to Bacillus anthracis, the bacteria responsible for anthrax, or as a means of diagnosing anthrax. At best, a positive result may be interpreted only to indicate exposure; a negative result does not exclude the possibility of exposure. Also, the presence of spores in the nose does not mean that the person has inhalational anthrax. The nose naturally filters out many things that a person breathes, including bacterial spores. To have inhalational anthrax, a person must have the bacteria deep in the lungs, and also have symptoms of the disease.
Another reason not to use nasal swabs is that most hospital laboratories cannot fully identify anthrax spores from nasal swabs. They are only able to tell that bacteria that resemble anthrax bacteria are present.
Yes, since 1978, seven independent civilian panels affirmed the safety and efficacy of anthrax vaccine. These include (each discussed in detail below):
The IOM committee reached two major conclusions: that anthrax vaccine works and that anthrax vaccine is as safe as other vaccines. Regarding effectiveness:
"The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, shows that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by all known or plausible engineered strains of B. anthracis." [Pages 7 and 58].
The whole report is available at the website of the National Academy Press: Joellenbeck LM, Zwanziger L, Durch JS, Strom BL, editors. The Anthrax Vaccine: Is it Safe? Does it Work? Washington, DC: National Academy Press, March 2002, 235 pages. http://www.nap.edu/catalog/10310.html
When responsibility for vaccine regulation shifted from the National Institutes of Health (NIH) to the Food & Drug Administration (FDA) in 1972, FDA convened a series of civilian advisory panels.
The FDA commissioned these panels to determine whether sufficient evidence of safety and effectiveness existed for vaccine licenses to be continued. These panels considered every vaccine used in America at that time, including such "old" vaccines as polio vaccine, tetanus toxoid, measles vaccine, and many others. The Panel on Review of Bacterial Vaccines & Toxoids met first in 1978 and published their report in 1985 in the Federal Register (1985; 50:51002-117).
The panel consisted of prominent infectious disease experts and other physicians and scientists with expertise in pharmaceutical manufacturing quality. The panel recommended that the federal licenses for each bacterial vaccine be continued, but the panel recommended that several other product licenses be terminated. In the case of anthrax vaccine, this civilian panel concluded: "The Panel recommends that this product be placed in Category I and that the appropriate license(s) be continued because there is substantial evidence of safety and effectiveness for this product." The FDA accepted this recommendation completely. FDA revoked the licenses for the other products, following the recommendations of the civilian panel.
The Defense Health Board (DHB), formerly known as Armed Forces Epidemiological Board (AFEB), has a proud 60-year heritage of protecting the health of America's Armed Forces. The DHB consists of civilian physicians and scientists selected to advise the Surgeons General of the Armed Services.
From its first reviews of anthrax vaccine under DoD Directive 6205.3, the DHB has affirmed the value of this vaccine. In August 1994, the DHB concluded: "The licensed anthrax vaccine is suitable for use in personnel assigned, pre-designated or scheduled for deployment to areas with a validated higher threat under its approved indications." In November 1996, the Defense Health Board reported that it "endorses the proposed DoD anthrax vaccine implementation plan under the current vaccine protocol [i.e., dosing schedule]."
The DHB reaffirmed its recommendations to use anthrax vaccine for bio-defense of military personnel in 1999 and 2000. A March 25, 1999, report states "The DHB continues to strongly endorse the current DoD Anthrax Vaccine Immunization Program."
On March 29, 2000, the DHB reported: "...we are (DHB) concerned and somewhat surprised at the criticism surrounding the program given the high level of professionalism that had characterized this effort... Anthrax vaccine is a fully licensed FDA vaccine.
The vaccine does cause local side effects, but has an excellent safety profile. The Anthrax Vaccine Immunization Program has carefully tabulated person-specific immunization data and has assiduously investigated reported complications associated with receipt of anthrax vaccine. These data have been regularly reviewed by the board and attest to the safety of the vaccine." http://www.anthrax.mil/resource/library/afeb.asp
The DHB continues to receive regular updates regarding implementation of the Anthrax Vaccine Immunization Program and the variety of safety surveillance methods used by the Department of Defense to monitor the vaccine's use.
The Advisory Committee on Immunization Practices (ACIP) consists of America's preeminent vaccine scientists, civilian physicians who advise the Centers for Disease Control & Prevention (CDC) (http://www.cdc.gov/nip/publications/ACIP-list.htm). The ACIP sets national standards for vaccine delivery. ACIP guidelines for the nation are published in the CDC's weekly journal, the Morbidity & Mortality Weekly Report (MMWR).
Between fall 1999 and June 2000, an ACIP working group reviewed published and unpublished information about anthrax vaccine adsorbed (AVA). In June 2000, the ACIP unanimously adopted a report finding anthrax vaccine effective and safe for the prevention of anthrax. The report notes that: "The efficacy of AVA is based on several studies in animals, one controlled vaccine trial in humans, and immunogenic data for both humans and lower mammalian species. ...Routine vaccination with AVA is indicated for persons engaged in work involving production quantities or concentrations of B. anthracis cultures and in activities with a high potential for aerosol production."
The ACIP recognizes that it is the role of the Defense Health Board (DHB) to advise the military Surgeons General on vaccination policies for military personnel. Nonetheless, the ACIP noted that "For the military and other select populations or for groups for which a calculable risk can be assessed, pre-exposure vaccination may be indicated." Advisory Committee on Immunization Practices. Use of anthrax vaccine in the United States MMWR-Morbidity & Mortality Weekly Report 2000; 49(RR-15):1-20. http://www.cdc.gov/mmwr/PDF/rr/rr4915.pdf
The Working Group on Civilian Bio-defense included 23 representatives from staff of major academic medical centers and research, government, military, public health, and emergency management institutions and agencies. The original consensus statement of 1999 resulted from a synthesis of published information and the revision of three drafts. Members of the working group reviewed anthrax literature again in January 2002, with special attention to articles following the anthrax attacks of 2001. Members commented on a revised document with proposed revisions being incorporated in the final product put out by The Center for Civilian Bio-defense Strategies (http://www.hopkins-biodefense.org/). The working group concurred with the findings of the March 2002 IOM report on the safety and efficacy of AVA, that AVA is effective against inhalational anthrax and concluded that if given with appropriate antibiotic therapy, it may help prevent the development of disease after exposure. The working group also found that: "Pre-exposure vaccination of some persons deemed to be in high-risk groups should be considered when substantial supplies of vaccine become available."
The working group also addressed the use of anthrax vaccine in children: "The U.S. anthrax vaccine is licensed for use only in persons aged 18 to 65 years because studies to date have been conducted exclusively in this group. No data exist for children, but based on experience with other inactivated vaccines, it is likely that the vaccine would be safe and effective." Inglesby TV, O'Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Gerberding J, Hauer J, Hughes J, McDade J, Osterholm MT, , Parker G, Perl TM, Russell PK, Tonat K, Working Group on Civilian Bio-defense. Anthrax as a biological weapon, 2002: Updated recommendations for management. Journal of the American Medical Association 2002; 287:2236- 52. http://jama.ama-assn.org/cgi/content/short/287/17/2236
The vaccine schedule should be followed as closely as possible. However, if a person is late for a dose, the next dose should simply be given as soon as possible. Then subsequent doses should be given according to the standard dosing intervals from the most recent dose. This applies to anthrax vaccine, as well as other vaccines, according to the Centers for Disease Control & Prevention. http://www.cdc.gov/mmwr/PDF/rr/rr4915.pdf
If an annual booster has not been administered on time, administer the booster dose at the earliest possible date, adjusting the subsequent booster schedule accordingly. Once the primary series of five doses is complete, the primary series is never repeated.
The current FDA-licensed schedule calls for doses to be administered intramuscularly in the deltoid according to the following schedule (the first dose is considered "week 0"): 0, 4 weeks; 6 months, 12 months, and 18 months.
Recipients receive the first shot, then the second shot four weeks later, and then the third shot five months after the second shot. Six months after the third shot, recipients receive the fourth shot. Six months after that, they receive the fifth shot. The entire primary series takes 18 months to complete. Annual booster doses of the vaccine are required for ongoing protection.
On 11 Dec 08, the Food and Drug Administration (FDA) approved two updates to the package insert for the anthrax vaccine. The route of administration was changed from a subcutaneous injection over the deltoid to an intramuscular injection in the deltoid. The FDA also approved a change in the vaccination series by removing the 2-week dose. The new schedule is now 0, 4 weeks, and 6 months, 12 months, 18 months, and annual boosters.
Brachman PS, Friedlander AM, Grabenstein JD. Anthrax. In: Plotkin SA, Orenstein WA, Vaccines, 4th ed. Philadelphia: W. B. Saunders, 2003.
Brachman PS, Gold H, Plotkin SA, Fekety FR, Werrin M, Ingraham NR. Field evaluation of a human anthrax vaccine. American Journal of Public Health 1962;52:432-45. http://www.anthrax.mil/documents/338field_eval.pdf
Advisory Committee on Immunization Practices. Use of anthrax vaccine in the United States. MMWR-Morbidity & Mortality Weekly Report 2000;49(RR-15):1-20. http://www.cdc.gov/mmwr/PDF/rr/rr4915.pdf
Food & Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review. Federal Register 1985;50:51002-117. http://www.anthrax.mil/documents/338field_eval.pdf
Franz DR, Jahrling PB, Friedlander AM, McClain DJ, Hoover DL, Bryne WR, Pavlin JA, Christopher GW, Eitzen EM Jr. Clinical recognition and management of patients exposed to biological warfare agents. Journal of the American Medical Association 1997;278(Aug 6):399-411. http://jama.ama-assn.org/cgi/content/short/278/5/399
Hambleton P, Carman JA, Melling J. Anthrax: The disease in relation to vaccines. Vaccine 1984;2:125-32.
Inglesby TV, O'Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Gerberding J, Hauer J, Hughes J, McDade J, Osterholm MT, , Parker G, Perl TM, Russell PK, Tonat K, Working Group on Civilian Biodefense. Anthrax as a biological weapon, 2002: Updated Recommendations for Management. Journal of the American Medical Association 2002;287:2236- 52. http://jama.ama-assn.org/cgi/content/short/287/17/2236
Ivins BE, Fellows PF, Pitt MLM, Estep JE, Welkos SL, Worsham PL, Friedlander AM. Efficacy of a standard human anthrax vaccine against Bacillus anthracis aerosol spore challenge in rhesus monkeys. Salisbury Medical Bulletin 1996;87(Suppl): 125-6.
Ivins BE, Pitt MLM, Fellows PF, Farchaus JW, Benner GE, Waag DM, Little SF, Anderson GW Jr., Gibbs PH, Friedlander AM. Comparative efficacy of experimental anthrax vaccine candidates against inhalation anthrax in rhesus macaques. Vaccine 1998;16:1141-8.
Pitt MLM, Ivins BE, Estep JE, et al. Comparison of the efficacy of purified protective antigen and MDPH to protect non-human primates from inhalation anthrax. Salisbury Medical Bulletin. 1996;87:130.
Sidell FR, Takafuji ET, Franz DR. Medical Aspects of Chemical & Biological Warfare. Washington, DC: Department of the Army, 1997.
Turnbull PCB. Guidelines for the Surveillance and Control of Anthrax in Humans and Animals, 3rd ed., WHO Report WHO/EMC/ZDI/98.6.
Food & Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review. Federal Register 1985;50:51002-117. http://www.anthrax.mil/documents/205Fed_Reg.pdf
Food & Drug Administration. Biological products; Bacterial vaccines and toxoids; Implementation of efficacy review. Federal Register 2004;29:78281-93. http://www.anthrax.mil/documents/library/bvactox.pdf
In nearly 30 years of licensed use, there is no evidence of any sterility or fertility impairment from anthrax vaccine. Regarding reproductive health, the Center for Disease Control and Prevention's Advisory Committee on Immunization Practices states, "there is no convincing risk from vaccinating pregnant women with inactivated virus or bacterial toxoids."
In the March 27, 2002, issue of the Journal of American Medical Association, 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, but the study may have been too small to detect small differences. [Wiesen AR, Littell CT. Relationship between pre-pregnancy anthrax vaccination and pregnancy and birth outcomes among U.S. Army women. Journal of the American Medical Association (JAMA) 2002; 287:1556-60. http://jama.ama-assn.org/content/vol287/issue12/index.dtl.
Preliminary data from the Naval Health Research Center raised a tentative signal that there may be an association with an increased rate of birth defects if vaccinated in the first trimester of pregnancy. This signal is being investigated thoroughly, to determine which of several explanations for the signal is most likely.
Long-standing Defense policy is to defer routine vaccinations in women until after pregnancy. This policy has always applied to anthrax vaccine. Women are asked if they are pregnant before vaccination. Women who are not sure are offered pregnancy tests.
Data about anthrax vaccination was obtained from men at time of oocyte and sperm retrieval. Researchers assessed characteristics of male gametes, including 254 vaccinated men and 791 unvaccinated men. The two groups were comparable for semen concentration (million sperm per milliliter), sperm motility (movement), sperm morphology (shape), need for intracytoplasmic sperm injection, and rate of fertilization of mature oocytes, embryo transfer, and clinical pregnancy. A diagnosis of male-factor infertility was less common in anthrax-vaccinated men than in unvaccinated men. The researchers concluded that anthrax vaccination of men did not impair semen parameters, fertilization rate, embryo quality, or clinical pregnancy rates.
In addition to the Department of Defense, other agencies and groups advocate or support the use of the anthrax vaccine. The Food & Drug Administration licensed the anthrax vaccine in 1970. The Centers for Disease Control & Prevention, the World Health Organization, the Defense Health Board, and many other respected public health organizations support use for people at risk or exposed to Bacillus anthracis. Information about the AVIP is available on the Internet (a variety of DoD web sites as well as the Centers for Disease Control & Prevention (www.cdc.gov) and the Food & Drug Administration web sites), which includes facts about the anthrax vaccine, history, side effects, purpose for immunizations and more. [See the Q&A page on independent scientific reviews.] Evidence for the efficacy of the anthrax vaccine is sufficient for it to be included in standard medical reference books in the United States and around the world. These references include:
Advisory Committee on Immunization Practices. General recommendations on immunization. MMWR-Morbidity & Mortality Weekly Report 2002;51(RR-2):1-35. ftp://ftp.cdc.gov/pub/Publications/mmwr/rr/rr5102.pdf
American College of Obstetricians & Gynecologists, Committee Opinion, Immunization During Pregnancy, 2003;282:1-6. http://www.acog.org/from_home/publications/misc/bco282.pdf
Brachman PS, Friedlander AM, Grabenstein JD. Anthrax. In: Plotkin SA, Orenstein WA, ed. Vaccines, 3rd ed. Philadelphia: W. B. Saunders, 2003.
Catherino WH, Levi A, Leondires M, Segars JH, Alvero R, McKeeby J. Fertility & Sterility Abstracts Vol. 78, No. 3, Suppl. 1, September 2002, pages S108-S109. http://www.vaccines.mil/documents/library/Fertility&Sterility.pdf
Christopher GW, Cieslak TJ, Pavlin JA, Eitzen EM Jr. Biological warfare: A historical perspective. Journal of the American Medical Association 1997;278(Aug 6):412-17. http://jama.amaassn.org/cgi/content/short/278/5/412
Inglesby TV, O'Toole T, Henderson DA, Bartlett JG, Ascher MS, Eitzen E, Friedlander AM, Gerberding J, Hauer J, Hughes J, McDade J, Osterholm MT, , Parker G, Perl TM, Russell PK, Tonat K, Working Group on Civilian Biodefense. Anthrax as a biological weapon, 2002: Updated Recommendations for Management. Journal of the American Medical Association 2002;287:2236- 52. http://jama.ama-assn.org/cgi/reprint/287/17/2236.pdf
Peeler RN, Cluff LE, Trever RW. Hyper-immunization of man. Bulletin of the Johns Hopkins Hospital 1958;103:183-98. Peeler RN, Kadull PJ, Cluff LE. Intensive immunization of man: Evaluation of possible adverse consequences. Annals of Internal Medicine 1965;63:44-57.
Singleton JA, Lloyd JC, Mootrey GT, Salive ME, Chen RT, VAERS Working Group. An overview of the vaccine adverse event reported system (VAERS) as a surveillance system. Vaccine 1999;17:2908-17. Turnbull PCB. Guidelines for the Surveillance and Control of Anthrax in Humans and Animals, 3rd ed., WHO Report WHO/EMC/ZDI/98.6. http://www.who.int/emcdocuments/zoonoses/whoemczdi986c.html
White CS III, Adler WH, McGann VG. Repeated immunization: Possible adverse effects: Reevaluation of human subjects at 25 years. Annals of Internal Medicine 1974;81:594 600. http://www.vaccines.mil/documents/library/Repeated.pdf
At Fort Detrick, Maryland, 99 laboratory workers were evaluated 10 to 20 years after receiving anthrax vaccine. Most of these workers received 150 to 200 doses of various vaccines (including anthrax vaccine); some received more than 300 such injections during their tenure at Fort Detrick. This study "failed to produce evidence that development of neoplasms, amyloidosis, or autoimmune diseases was associated with the vaccine dosages and frequencies used at Fort Detrick. The authors concluded "These data and the accompanying evaluation of an intensively immunized population provide evidence that no obvious adverse effects result from repeated immunization." The first report of this group of vaccine recipients was published in the Bulletin of the Johns Hopkins Hospital in 1958. Two follow-up reports were published in the Annals of Internal Medicine in 1965 and 1974.
An extension of this long-term study is underway at the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) to determine, in even greater detail, whether people who received multiple vaccines, including anthrax vaccine, during their past employment at Fort Detrick demonstrated any adverse health effects over the long term. More than 1,500 employees have been followed annually there. In a case-control study begun in 1996, vaccinated and unvaccinated volunteers have been enrolled. All volunteers signed an informed-consent document. The study methods include a 9-page health history questionnaire, extensive blood tests and urinalysis. The questionnaire queries mental and physical conditions of the volunteers, as well as the health of their offspring. Study end points include symptoms, symptom complexes (including symptoms reported by veterans of the Persian Gulf War), diseases, and abnormal laboratory and urine tests. Study subjects will be compared to two to three race-, gender-, and age-matched control subjects to determine if any long-term medical effects exist among this unique group of study subjects. Analysis of the data from the extensive health history questionnaire and numerous laboratory tests are currently in progress. No unexplained symptoms due to repeated doses of anthrax or other vaccines have been found. From this and other monitoring, no patterns of delayed side effects to anthrax vaccine have been found. Monitoring continues. White CS III, Adler WH, McGann VG. Repeated immunization: Possible adverse effects: Reevaluation of human subjects at 25 years. Annals of Internal Medicine 1974; 81:594-600.
A recent study by the Department of Defense (DoD) Center for Deployment Health Research with the Naval Health Research Center and the National Center for Birth Defects and developmental Disabilities indicated that women who received anthrax vaccinations during their first trimester of pregnancy could have a slightly higher risk of birth defects than women receiving anthrax vaccine at other times before or after the first trimester. The study is still under review. Results are pending.
The Special Assistant for Gulf War Illnesses, Dr. Bernard Rosker, published an info paper entitled "Vaccine Use During the Gulf War" (http://www.gulflink.osd.mil/va/). When Persian Gulf War veterans returned and started reporting symptoms, some people asked if vaccines administered during the Gulf War might have caused the symptoms. Several independent expert panels addressed this and related questions head-on. These panels consisted of Veterans, civilian academic experts, scientists, health-care professionals, and policy specialists. Each of these panels included some of the nation's best scientists, who spent months or even years listening to veterans, reviewing the evidence, and deliberating the issues.
In each case, the independent expert panels found that there was no evidence of any link between any vaccine and any illness common to Gulf War veterans. These reports include:Presidential Advisory Committee on Gulf War Veterans' Illnesses: Final Report, December 1996. Pages of Interest: second page, Executive Summary, plus pages 112-114 of the original document (Chapter 4 in the web version). Institute of Medicine, Health Consequences of Service During the Persian Gulf War:Recommendations for Research & Information Systems, 1996. (http://books.nap.edu/books/0309055369/html/1.html)Pages of Interest: 49-52, 55, 100. National Institutes of Health, Technology Assessment Workshop: The Persian Gulf Experience and Health, 29 April 1994. Defense Science Board Task Force on Persian Gulf War Health Effects, June 1994. (http://www.gulflink.osd.mil/dsbrpt/index.html) See chapter VIII, section E.2. Three specific studies looking into the health of Gulf War veterans and their families were published in the New England Journal of Medicine. The postwar hospitalization experience of U.S. veterans of the Persian Gulf war. New England Journal of Medicine 1996; 335:1505-13. This study concluded that "During the two years after the Persian Gulf War, there was no excess of unexplained hospitalization among Americans who remained on active duty after serving in that conflict." The risk of birth defects among children of Persian Gulf war veterans. New England Journal of Medicine 1997; 336:1650-6. The authors concluded that "This analysis found no evidence of an increase in the risk of birth defects among the children of Gulf War veterans." Mortality among U.S. veterans of the Persian Gulf war. New England Journal of Medicine 1996; 335:1498-1504. The authors concluded: "Among veterans of the Persian Gulf War, there was a significantly higher mortality [death] rate than among veterans deployed elsewhere, but most of the increase was due to accidents rather than disease, a finding consistent with patterns of postwar mortality among veterans of previous wars." A DoD-funded British team at King's College, London, reported in the 20 May 00 issue of British Medical Journal that multiple vaccinations given in a theater of war, but not before deployment, were associated with multi-symptom illness, fatigue, psychological distress, health perception, and physical functioning. The analysis was limited to veterans who kept vaccination records.
Exposures other than vaccination were not controlled for, except pesticide use. Anthrax vaccine was not analyzed independently. The lead author was Matthew Hotopf; the research team included Catherine Unwin. The authors recommend that Armed Forces be vaccinated before deployment: "It would be folly to allow Service personnel to be committed to a modern battlefield without all necessary means of protection against endemic infection and biological weapons." The accompanying editorial calls Hotopf's evidence "inconclusive," citing design limitations and contradictory findings.
Despite treatment with highly active antibiotics there is still a significant mortality from inhalational anthrax. Because of this, the DHHS Biomedical Advanced Research and Development Authority (BARDA) Office, funded under Project Bioshield, is working to make a new kind of anthrax medication by collecting blood plasma from people who have been vaccinated against anthrax. Antibodies found in this plasma fight anthrax infections and will be used to create a medication which will be known as anthrax immune globulin or AIG.
Over 1.8 million people have received anthrax vaccine since 1998; most of which were U.S. service members. DHHS asked the U.S. Department of Defense (DoD) to assist with the AIG plasma program to improve the Nation's medical defenses against anthrax attack. The DoD agreed to distribute information about this voluntary DHHS BARDA office program to service members.
Per the brochure, eligible plasma donors who have received at least 4 or more doses of the anthrax vaccine, with the most recent dose within the past 21 days, are eligible for immediate donation without further vaccination.
In addition at some locations, individuals can also participate if they have ever received:
*Last dose of anthrax vaccine not within the last 21 days.
These additional AIG programs vary by location, so please contact your nearby plasma center for more details. A list of plasma centers can be found at www.cangeneplasma.com.
FDA standards allow plasma donation as often as twice a week.
However, USAMRIID and DoD laboratory workers are allowed to donate only once per week, if they are involved in duties that involve the risk of potential occupational exposure.
AIG is not yet licensed by the FDA; it is considered an investigational new drug, also called an IND. Products like AIG were commonly used before antibiotics became available in the 1930s and 1940s. Additional research is being done to understand the value of AIG better but animal studies suggest AIG will be useful.
AIG may also go unused if there is no emergency or if some other event arises that prevents its use.
The State of Michigan opened its first laboratory to manufacture vaccines and antibodies in Lansing in 1925, over 75 years ago, receiving license #99 to manufacture biological medications. On 7 July 1998, the State of Michigan approved the sale of the United States' only licensed manufacturer of anthrax vaccine to a for-profit company. The state-owned entity known as the Michigan Biologic Products Institute (MBPI) was sold effective 5 September 1998 to become BioPort Corporation. The facility's license is now listed as license #1260, with the sale of MBPI to Emergent BioSolutions Incorporated http://www.emergentbiosolutions.com.
Multiple shareholders own Emergent BioSolutions, whose headquarters remain in Lansing, Michigan. The two main companies that make up Emergent BioSolutions are Intervac, headed by William Crowe and Fuad El-Hibri, and Michigan Biologic Products Inc., which is made up of seven managers from the era when the State of Michigan owned the plant, headed by Robert Myers. The former state employees were specifically permitted by the Michigan State Legislature to bid on the sale. The legislators hoped that retaining local management as investors would help keep the plant and its 200 jobs in Michigan. Admiral William Crowe, Jr., is a former Chairman of the Joint Chiefs of Staff and the U.S. ambassador to Britain until 1997. Fuad El-Hibri, a U.S. citizen of Lebanese descent, transformed a British government plant for vaccine production into a successful private venture.
As Admiral Crowe testified to the U.S. Congress in October 1999, that the government's decision to vaccinate the Armed Forces was made after several years of internal analysis that culminated in a December 1997 decision. These events occurred well before the State of Michigan chose to sell its vaccine-production facilities to Emergent BioSolutions Incorporated.
The planning for renovations to the physical plant began in 1996. Construction began in early 1998 and was completed in May 1999. The Food and Drug Administration approved the renovations to Emergent BioSolutions' anthrax vaccine manufacturing facilities and processes January 31, 2002.
The FDA has steadily approved release of anthrax vaccine lots manufactured by Emergent BioSolutions ever since. Over the years, the State of Michigan appropriated money to upgrade and expand its existing facility in a staged fashion, as improvements in current Good Manufacturing Practices (cGMPs) were adopted by the U.S. pharmaceutical industry. In January 1993, FDA as part of a routine program inspected the anthrax vaccine manufacturing facility at Emergent BioSolutions. To improve its operations, a renovation to the Lansing facility was approved by the State of Michigan in July 1993 with funding coming in later years. The manufacturer closed the anthrax vaccine production line in January 1998 for planned renovation. Although the decision to close the facility for planned renovation was part of the manufacturer's facility improvement strategy, it was, in part, also based on a 1996 DoD assessment that concluded that the facility was inadequate to meet future production requirements. This renovation project cost $3.7 million and included upgrades of the anthrax vaccine manufacturing space along with the addition of a negative air pressure sink, a reach-in environmental chamber, and a state-of-the-art closed inoculation system.
In 1994, after Michigan authorities had approved the renovation schedule, the FDA conducted a rigorous inspection of Michigan's plasma-derivatives operation. Then, in 1995, the FDA issued a warning letter to Michigan concerning plasma operations and rabies vaccine manufacturing. After a November 1996 inspection, findings showed that corrections to the previous areas had not been completed. The FDA issued a "Notice of Intent to Revoke" (NOIR) letter in March 1997, threatening to begin a multi-step process to revoke Michigan's license to manufacture vaccines.
Michigan responded quickly to the NOIR letter, developing a strategic plan for compliance within 30 days. FDA later testified to Congress that Michigan "had made progress in achieving its compliance goals."
The FDA conducted a pre-approval inspection of the newly renovated production facility at Emergent BioSolutions in November 1999. The FDA inspection reported 30 observations to Emergent BioSolutions management that needed to be corrected as well as identified process validation steps that needed to be addressed for FDA to approve the new facility. FDA completed its approval of Emergent BioSolutions' physical renovations, as well as its extensive process-validation documentation in December 2001.
No. All lots of anthrax vaccine that have ever been released, including those used in the DoD's immunization program, met all FDA release criteria: general safety, purity, sterility, and potency. All stockpiled lots that have been used in the DoD immunization program have met DoD-mandated supplemental testing criteria and oversight of that testing has been provided by an independent DoD-contractor, Mitretek Systems, Inc.
Over the years the FDA acknowledged that the manufacturer was making progress in achieving compliance with FDA standards and regulations. FDA found no deficiencies serious enough to warrant recall of the anthrax vaccine, which is within FDA's authority. Link to FDA Enforcement Reports http://www.fda.gov/opacom/enforce.html.
Results of more recent FDA inspections of Emergent BioSolutions, both in Nov 1999 and Oct 2000, have indicated BioSolutions progress toward licensure in an environment of increasingly stringent FDA standards for process validation and for demonstrating consistency of manufacturing. FDA's actions in December 2001 and January 2002, approving all aspects of anthrax vaccine manufacture, reflect the FDA's satisfaction with Emergent BioSolutions' renovations and quality controls. FDA officials have visited Emergent BioSolutions several times since. FDA officials visit all vaccine manufacturers periodically.
Asa PB, Cao Y, Garry RF. Antibodies to squalene in Gulf War syndrome. Experimental & Molecular Pathology 2000;68(Feb):55-64.
Asa PB, Wilson RB, Garry RF. Antibodies to squalene in recipients of anthrax vaccine. Experimental & Molecular Pathology 2002;73(Aug):19-27.
Alving CR, Grabenstein JD. Letter to the editor. Experimental & Molecular Pathology 2000;68 (Jun):196-7 (letter).
Armed Forces Epidemiological Board. Recommendations regarding review of the paper "Antibodies to Squalene in Gulf War Syndrome" by P. B. Asa, Y. Cao and R. F. Garry. 11 Jul 2000. http://www.ha.osd.mil/afeb/reports/squalene.pdf
Asano KG, Bayne CK, Horsman KM, Buchanan MV. Chemical composition of fingerprints for gender determination. Journal of Forensic Science 2002;47(Jul):805-807.
Banzhoff A, Nacci P, Podda A. A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: Results from an immunogenicity meta-analysis. Gerontology. 2003;49(May-Jun):177-84.
Benisek Z, Suli J, Elias D, Lenhardt L, Ondrejkova A, Ondrejka R, Svrcek S, Bajova V. Experimental squalene adjuvant. II. Harmlessness and local reactogenity. Vaccine. 2004;22(Sep 3):3470-4.
Burdin N, Guy B, Moingeon P. Immunological foundations to the quest for new vaccine adjuvants. BioDrugs 2004;18(2):79-93.
Epstein JE, Charoenvit Y, Kester KE, Wang R, Newcomer R, Fitzpatrick S, Richie TL, Tornieporth N, Heppner DG, Ockenhouse C, Majam V, Holland C, Abot E, Ganeshan H, Berzins M, Jones T, Freydberg CN, Ng J, Norman J, Carucci DJ, Cohen J, Hoffman SL. Safety, tolerability, and antibody responses in humans after sequential immunization with a PfCSP DNA vaccine followed by the recombinant protein vaccine RTS,S/AS02A. Vaccine 2004;22(Apr 16):1592-603.
General Accounting Office. Questions about the presence of squalene antibodies in veterans can be resolved. GAO/NSIAD099-5, March 1999. http://www.gao.gov/archive/1999/ns99005.pdf
Hoffman SL, Edelman R, Bryan JP, Schneider I, Davis J, Sedegah M, Gordon D, Church P, Gross M, Silverman C. Safety, immunogenicity, and efficacy of a malaria sporozoite vaccine administered with monophosphoryl lipid A, cell wall skeleton of mycobacteria, and squalane as adjuvant. American Journal of Tropical Medicine & Hygiene 1994;51(Nov):603-12.
Institute of Medicine Committee on Health Effects Associated with Exposures During the Gulf War. Gulf War & Health: Volume I: Depleted Uranium, Sarin, Pyridostigmine Bromide, Vaccines. [Harold C. Sox, chair] Fulco CE, Liverman CT, Sox HC, editors. Washington, DC: National Academy of Sciences, September 2000. See http://stills.nap.edu/books/030907178X/html, pages 307-313 (especially 311-312).
Institute of Medicine Committee to Assess the Safety and Efficacy of the Anthrax Vaccine. The Anthrax Vaccine: Is it Safe? Does it Work? [Brian L. Strom, chair] Joellenbeck LM, Zwanziger L, Durch JS, Strom BL, editors. Washington, DC: National Academy of Sciences, March 2002. See http://www.nap.edu/catalog/10310.html, especially pages 96-97 and 147.
Kuroda Y, Nacionales DC, Akaogi J, Reeves WH, Satoh M. Autoimmunity induced by adjuvant hydrocarbon oil components of vaccine. Biomed Pharmacother 2004;58(Jun):325-37.
Lorentzen JC. Identification of arthritogenic adjuvants of self and foreign origin. Scandinavian Journal of Immunology 1999;49:45-50.
Matyas GR, Wassef NM, Rao M, Alving CR. Induction and detection of antibodies to squalene. Journal of Immunologic Methods 2000;245(Nov 1):1-14. http://www.vaccines.mil/documents/library/Squalene1.pdf
Matyas GR, Rao M, Alving CR. Detection of antibodies to squalene. II. Optimization of the assay for murine antibodies. Journal of Immunologic Methods 2001;267(Sep 15):119-129. http://www.vaccines.mil/documents/library/Squalene2.pdf
Matyas GR, Rao M, Pittman PR, Burge R, Robbins IE, Wassef NM, Thivierge B, Alving CR. Detection of antibodies to squalene. III. Naturally occurring antibodies to squalene in humans and mice. Journal of Immunologic Methods 2004;286(Mar):47-67. htthttp://www.vaccines.mil/documents/library/Squalene3.pdf
Miettinen TA. Diurnal variation of cholesterol precursors squalene and methyl sterols in human plasma lipoproteins. Journal of Lipid Research 1982;23:466-73. http://www.jlr.org/cgi/reprint/23/3/466
Nikkila K, Hockerstedt K, Miettinen TA. Serum and hepatic cholestanol, squalene and noncholesterol sterols in man: A study on liver transplantation. Hepatology 1992;15:863-70.
Nitayaphan S, Khamboonruang C, Sirisophana N, Morgan P, Chiu J, Duliege AM, Chuenchitra C, Supapongse T, Rungruengthanakit K, deSouza M, Mascola JR, Boggio K, Ratto-Kim S, Markowitz LE, Birx D, Suriyanon V, McNeil JG, Brown AE, Michael RA. A phase I/II trial of HIV SF2 gp120/MF59 vaccine in seronegative Thais: Armed Forces Research Institute of Medical Sciences--Research Institute for Health Sciences Vaccine Evaluation Group. Vaccine 2000;18(Feb 14):1448-55.
Pitisuttithum P, Nitayaphan S, Thongcharoen P, Khamboonruang C, Kim J, de Souza M, Chuenchitra T, Garner RP, Thapinta D, Polonis V, Ratto-Kim S, Chanbancherd P, Chiu J, Birx DL, Duliege AM, McNeil JG, Brown AE; Thai AIDS Vaccine Evaluation Group. Safety and immunogenicity of combinations of recombinant subtype E and B human immunodeficiency virus type 1 envelope glycoprotein 120 vaccines in healthy Thai adults. Journal of Infectious Diseases 2003;188(Jul 15):219-27.
Sesardic D, Dobbelaer R. European Union regulatory developments for new vaccine adjuvants and delivery systems. Vaccine 2004;22(Jun 23):2452-6.
Sever JL, Brenner AI, Gale AD, Lyle JM, Moulton LH, West DJ. Safety of anthrax vaccine: A review by the Anthrax Vaccine Expert Committee (AVEC) of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiology & Drug Safety 2002;11 (Apr-May):189-202. http://www.vaccines.mil/documents/library/AVEC_ms.pdf
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). Pharmacoepidemiology & Drug Safety 2004;13:in press. Epub version on Internet. http://www.vaccines.mil/documents/library/SeverArticle.pdf
Smith TJ. Squalene: Potential chemopreventive agent. Expert Opinion Investigational Drugs 2000;9(Aug):1841-8.
Spanggord RJ, Wu B, Sun M, Lim P, Ellis W. Enhancement of an analytical method for the determination of squalene in anthrax vaccine adsorbed formulations. Journal of Pharmaceutical and Biomedical Analysis 2002;29(Jun):183-193. http://www.vaccines.mil/documents/library/JPB42(2006)494-499.pdf
United States Senate, Committee on Veterans' Affairs, 105th Congress. Report of the Special Investigation Unit on Gulf War Illnesses. Chapter 3: Evaluation of Wartime Exposures, Gulf War Veteran Health Concerns and Related Research, and Unanswered Questions. Washington, DC: 1998, pages 123 and 303.
Vogel FR, Powell MF, Alving CR. A Compendium of Vaccine Adjuvants and Excipients, 2nd ed. Bethesda, MD: National Institute of Allergy & Infectious Diseases, 1998. http://www.niaid.nih.gov/daids/vaccine/pdf/compendium.pdf
Wang R, Epstein J, Charoenvit Y, Baraceros FM, Rahardjo N, Gay T, Banania JG, Chattopadhyay R, de la Vega P, Richie TL, Tornieporth N, Doolan DL, Kester KE, Heppner DG, Norman J, Carucci DJ, Cohen JD, Hoffman SL. Induction in humans of CD8+ and CD4+ T cell and antibody responses by sequential immunization with malaria DNA and recombinant protein. Journal of Immunology 2004;172(May 1):5561-9.
Yoshino S, Yoshino J. Recruitment of pathogenic T cells to synovial tissues of rats injected intraarticularly with nonspecific agents. Cellular Immunology 1994;158:305-313.
Related to Influenza and Other Vaccines with MF59 Adjuvant (which contains squalene as one component of the adjuvant):
In April 2000, the research project published its first peer-reviewed report, describing an enzyme-linked immunosorbent assay (ELISA) that could detect antibodies to squalene induced in mice. Use of squalene alone did not produce a significant amount of anti-squalene antibodies. A special chemical was needed to induce the antibodies against squalene in mice. After injecting mice with liposomes (fat globules) containing 71% squalene (710 million parts per billion), plus a second chemical called lipid A, antibodies to squalene were readily induced in mice. The validity of the method was established using positive and negative controls to preclude false positive and false-negative test results. The investigators concluded that squalene is a weak antigen (a weak inducer of antibodies). (Matyas et al., 2000).
By September 2001, researchers reported improving the assay and ensuring these tests were reproducible and sensitive enough to detect 80 ng/ml of anti-squalene antibody. The test was also reproducible from experiment to experiment (Matyas et al., 2001). The third study from this research effort, published in 2004, adapts the test described above so that it could detect anti-squalene antibodies if present in human serum. Serum from three groups of people were tested: retired employees of the U.S. Army Medical Research Institute of Infectious Diseases (average 68 years of age, 88% of whom received anthrax vaccine, mean = 26 doses per person) , civilian volunteers of similar age from Frederick, Maryland (none of whom received anthrax vaccine), and random blood donors from Fort Knox, Kentucky (vaccination status unknown), This next study indicates that anti-squalene antibodies are found in 7.5% of the vaccinated USAMRIID alumni, 15% of the unvaccinated Frederick civilians, and in 0% of the Fort Knox blood donors. The antibodies described in the previous sentence were a type of antibody called IgG. Researchers found another type of anti-squalene antibody called IgM in all three groups (37%, 32%, and 19%). The researchers found that anti-squalene antibodies are more common with increasing age (a characteristic also found in mice). The presence of anti-squalene antibodies was unrelated to anthrax vaccination status. They concluded that anti-squalene antibodies occur naturally in humans (Matyas et al., 2004).
The Joint Program Executive Office for Chemical and Biological Defense (JPEO-CBD) - http://www.jpeocbd.osd.mil is responsible to the Secretary of Defense for maintaining an adequate stockpile of biological warfare defensive vaccines and defined production capabilities, as determined by the Joint Staff and Services' demands. The JPEO-CBD has developed an anthrax vaccine production model to use as a tool to balance the total annual requirement for production with vaccination and inventory requirements to support total force vaccination.
Emergent BioSolutions recently received full FDA approval for the newly renovated manufacturing suite and its contract filler, Hollister-Stier LLC this will ensure production of the anthrax vaccine. To be used by DoD, each vial of anthrax vaccine must meet all FDA requirements. Additionally, a stockpile exists that could be used in an emergency situation.