Countering Anthrax: Vaccines and Immunoglobulins
Review & Commentary
By Michele Barry, MD, FACP
Professor of Medicine and Global Health, Yale School of Medicine, New Haven, CT.
Dr. Barry is a consultant for the Ford Foundation and receives grant funding from Johnson & Johnson.
Synopsis: J. Grabenstein, the senior director of Merck, was invited by CID to review all the evidence regarding anthrax vaccine efficacy and safety in addition to post-exposure treatment of actual disease.
Source: Grabenstein JD. Vaccines: countering anthrax: vaccines and immunoglobulins. Clin Inf Dis. 2008;46:129-36
Anthrax in the U.S. was primarily an occupational disease of the wool textile industry in the 19th century when inhalation of aerosolized spores or cutaneous exposure was associated with industrial wool processing. Today the disease occurs primarily in Asia and Africa via contact with domestic animals (herbivores) or their products (e.g. hair, wool, hides, bones and meat). The intelligence community and civilian experts consistently rank anthrax spores as a leading bioweapon threat, due to anthrax spore stability and ease of dispersion.
Anthrax manifests itself in humans in three forms: cutaneous, inhalational and gastrointestinal. Cutaneous anthrax results when spores that enter skin breach host defenses and progress to lymphadenitis, bacteremia and death. In inhalational anthrax spores that were inhaled germinate in mediastinal nodes which commonly results in mediastinal widening, hemorrhagic pulmonary effusions and rapidly progressive parenchymal disease. Gastrointestinal disease occurs 2-5 days after eating anthrax contaminated meat and presents with abdominal pain and diarrhea which can rapidly progress to sepsis and death.
Active immunization
The pathogenic determinants of B. anthracis are the bacterial capsule and distinct exotoxins which share the same binding protein, known as protective antigen (PA). PA combined with a protein referred to as lethal factor constitutes anthrax lethal toxin. The same PA molecule combined with a protein called edema factor constitutes the edema toxin. Both of these toxins cause local necrosis and extensive edema, which are major characteristics of the disease. The current acellular vaccine is composed of sterile filtrates of an attenuated anthrax strain adsorbed and predominately PA-based. It has a 6-dose intramuscular regimen and has been administered to 1.8 million predominately military personnel since 1998. (see Table 1) In an anthrax attack post-exposure vaccination, by itself, is unlikely to provide protection because the disease has a short incubation period and a rapid course. Combination treatment with antibiotics and active immunization will be needed. Passive immunization with polyclonal anthrax immunoglobulin (now stockpiled in U.S. Strategic National Stockpile), produced by fractionating the plasma of volunteers given anthrax vaccine, is postulated to also aid recovery and theoretically protect against antibiotic resistant anthrax. Definitive efficacy of passive immunization efficacy has not been demonstrated, although it has been used in the successful treatment of a 2006 case of inhalational anthrax. Future development of monoclonal antibodies is being conducted.
Commentary
B. anthracis spores remain viable and infective in soil for many years. During this time they are a potential source of infection for grazing livestock which can directly infect humans if eaten, or indirectly if animals are handled as manifested by the more common form of cutaneous anthrax (>95% cases).1 Livestock vaccines use a live unencapsulated avirulent variant of B. anthracis. The first human vaccine used was an alum-precipitated cell-free filtrate from culture developed in 1954 and improved upon in 1965 by the production of high levels of PA (protective antigen) and the use of aluminum hydroxide as adjuvant. PA is an 82kD protein that binds to receptors on mammalian cells and is critical to the ability of B. anthracis to cause disease.
Pre-exposure vaccination with Biothrax, the only adsorbed anthrax vaccine that is available in the USA, (see Table 1) should be based on occupational risk to anthrax spores either naturally or as bioweapons. To treat anthrax infection or exposure, which can be rapidly fatal, one should offer antibiotics (ciprofloxacin or doxycycline) to cover spore germination for a minimum 30 days, vaccine and potentially passive immunization if available. The efficacy of vaccine has been studied in macaque monkeys after inhalational challenge, and during one study of mill workers with the original alum-precipitated vaccine, the precursor to the currently licensed AVA. This latter study, documented an efficacy rate of 92.5% during an inhalational anthrax outbreak.1 Adverse events following vaccination with AVA vaccine are minor, localized and self-limited. Current research has not documented any association with anthrax vaccination and Persian Gulf War syndrome. An Institute of Medicine (IOM) report confirmed after review of all published peer-reviewed studies that there was no higher incidence of adverse events with anthrax vaccine than with other routine immunizations.2 Based on animal studies, passive immunization with an antibody product could provide short term prophylaxis as well as adjunctive therapy. Unfortunately, the current vaccine requires 6 cumbersome doses and annual yearly boosters for those with continued risk. We await an ongoing CDC clinical trial assessing simpler schedules as well as future better vaccines and monoclonal antibodies.
References:
- Use of Anthrax Vaccine in the United States MMWR. Dec 15, 2000 / 49 (RR15):1-20.
- Committee on Health Effects Associated with Exposures During the Gulf War, Institute of Medicine. In: Fulco CE, Liverman CT, Sox HC, eds. Gulf War and health. Volume I: Depleted uranium, sarin, pyridostigmine bromide, and vaccines. Washington DC: National Academy of Sciences, 2000. Available at http://www.nap.edu. Accessed October 23, 2000.
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