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 (2) and presumably on other unpublished data.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
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