Anthrax Vaccine Adsorbed (Monograph)

Drug class: Vaccines
ATC class: J07AC01
VA class: IM100

Medically reviewed by Drugs.com on Dec 23, 2024. Written by ASHP.

Introduction

Anthrax vaccine adsorbed (AVA) is a noninfectious, sterile suspension of a cell-free (no killed or live bacteria) filtrate that contains the 3 toxin components (PA, LF, and EF) of Bacillus anthracis. The vaccine stimulates active immunity to B. anthracis.

Uses for Anthrax Vaccine Adsorbed

Anthrax vaccine adsorbed is used to stimulate active immunity to Bacillus anthracis in selected adults 18–65 years of age who are at risk of infection from exposure to B. anthracis spores. The vaccine is used for both preexposure immunization against anthrax and in combination with appropriate anti-infectives (e.g., ciprofloxacin, doxycycline) for postexposure prophylaxis^{† [off-label]} following documented or suspected exposure to aerosolized anthrax spores. The infectious dose of B. anthracis in humans by any route is not precisely known; the estimated infectious dose for human inhalational anthrax is 2500–55,000 spores based on primate study data. The influence of B. anthracis strain or host factors on infectious dose has not been fully elucidated, although naturally occurring (endemic) B. anthracis is considered essentially monomorphic with only minor phenotypic variants. Although additional study is needed to determine if anthrax vaccine adsorbed would provide protection against infection from strains that might conceivably be bioengineered to contain additional virulence genes, including those conferring resistance to anti-infective therapy and vaccine protection, it is highly probable that the vaccine would be effective against bioengineered or naturally occurring strains since protective antigen (PA) is integral to anthrax pathogenesis and immunity.

The US Food and Drug Administration (FDA) has determined in conjunction with expert panels that anthrax vaccine adsorbed is safe and effective for the prevention of anthrax, regardless of the route of exposure. Similarly, the Institute of Medicine (IOM) of the National Academies concluded from its independent review of licensed anthrax vaccine adsorbed that it was safe and effective for preventing anthrax, including inhalational anthrax.

Types of Exposure

Anthrax is caused by infection with B. anthracis and is principally a disease affecting herbivores; however, most warm-blooded species are susceptible to infection with the bacterium. Anthrax in livestock generally occurs after spores are ingested during grazing; infection develops after the spores enter the submucosa through a GI lesion. Anthrax spores are found in contaminated soil, contaminated feedstuffs (e.g., meat and bone meals), and pastures that have been flooded with contaminated tannery wastewater. In addition, limited evidence suggests that certain species of biting flies may transmit anthrax under experimental conditions.

Naturally occurring (endemic) human anthrax develops from direct or indirect contact with infected animals or occupational exposure to infected or contaminated animal products (bones, hides, wool, and other animal products). The incidence of nonindustrial anthrax in humans prior to recent bioterrorist activities had reflected exposure to infected animals; analysis of historical global epidemiologic data indicate that one human cutaneous anthrax case occurs for each 10 anthrax livestock carcasses reported, one case of human GI anthrax occurs for each 30–60 anthrax-infected animals consumed by humans, and 100–200 human cutaneous cases occur for each human GI case. Anthrax in animals has been reported in every state; however, the infection rate in US animals is not known. Anthrax continues to be reported among domestic and wild herbivores, especially in Nebraska, Oklahoma, Texas, North Dakota, and South Dakota. The risk of industrial anthrax increases with the quantity of potentially contaminated materials handled and decreases with implementation of industrial hygiene measures (e.g, vaccination, ventilation). Person-to-person transmission of inhalational anthrax has not been reported and laboratory-acquired anthrax occurs rarely.

Anthrax also can develop as the result of intentional exposure in the context of biologic warfare or bioterrorism. (See Uses: Risks of Exposure and Infection.)

Risks of Exposure and Infection

Based on historical evidence, humans appear moderately resistant to anthrax; however, human outbreaks and epidemics do occur. The global incidence of human anthrax is not known, and estimates based on extrapolation of human and animal epidemiologic data are limited because of reporting inconsistencies. Globally, human anthrax infection rates are highest in agricultural regions of Africa, the Middle East, and central and southern Asia, where livestock anthrax control programs are inadequate. The largest recent human anthrax epidemic occurred in Zimbabwe during 1978–1980; 9445 individuals were infected and 141 (1.5%) cases were fatal.

Until recent deliberate acts of bioterrorism, human anthrax had not been reported in the US since 1992; the annual incidence had declined from approximately 130 cases per year in the early 1900s and most of these infections were cutaneous. During the 20th century, prior to these recent bioterrorist acts, inhalational anthrax had been reported in only 18 individuals in the US, with the last previous (prior to 2001) inhalational case being reported in 1976. Of the 18 cases of inhalational anthrax reported in the US since 1900 but before September 2001, 13 were reported in employees of livestock product processing facilities and 2 were reported in laboratory workers. The risk of inhalational anthrax generally is very low, except for industrial exposures or in the context of biologic warfare or bioterrorism. GI anthrax has not been reported in the US to date.

B. anthracis has been researched as an agent for use in biologic warfare and bioterrorist activities for approximately 80 years and has been produced by some countries and other groups for such use. Inhalational anthrax has a high mortality, and B. anthracis has long been considered a likely agent for use in biologic warfare or bioterrorist acts since B. anthracis spores can be transmitted by the respiratory route via aerosol and the spores are very stable in the environment. The World Health Organization (WHO) estimated that an aerosol of 50 kg of B. anthracis released upwind of a population center of 500,000 people could cause 95,000 fatalities and 125,000 hospitalizations. The US Congressional Office of Technology Assessment estimated that between 130,000 and 3 million deaths could follow aerosolized release of 100 kg of anthrax spores upwind of Washington, DC—a lethality matching or exceeding that of a hydrogen bomb.

B. anthracis spores mechanically released, initially form a primary aerosol, and secondary aerosols may occur when spores settled from the primary release are resuspended by disturbance of contaminated dust by wind, human or animal activities, or mechanical disturbances (e.g., automated mail sorting equipment). The aerobiologic factors that determine the time period spores are suspended in air include the size and hydrostatic properties of the particles and method of dispersal. It is generally believed that aerosol particles exceeding 5 µm in diameter quickly settle from the atmosphere, bind to surfaces, and generally require large amounts of energy to be resuspended and do not appear to represent a substantial threat of forming secondary aerosols. However, particles 1–5 µm in diameter appear to behave as a gas and do not settle in the environment; while no resuspension of these particles occurs, they are the most likely to cause infection by inspiration. The virulence of anthrax spores and the associated risk of inhalation also can be increased by finely milling and treating the spores with additives that prevent clumping and thus enhance their suspension and movement in air.

Management of Exposure

Strategies for Prevention and Control of Anthrax

Since cutaneous anthrax occurs after B. anthracis spores enter epidermal tissue through a cut or abrasion, the risk of infection should be reduced in high-risk industrial occupations by personal protection methods, including appropriate clothing and gloves, wound dressings, and other hygienic practices. In addition, import restrictions on raw livestock materials, disinfection methods, ventilation, and dust control have reduced potential spore exposure. The cycle of infection between livestock and humans can be interrupted by vigorous application of control measures including rapid diagnosis and isolation of infected animals, proper disposal of diseased carcasses, disinfection, decontamination, and disposal of contaminated materials, and vaccination of exposed susceptible animals and humans in high-risk occupations.

Protective clothing and appropriate respirators currently are recommended for firefighters and other first responders to a presumed biologic attack with anthrax. In addition, postal workers and the general public should be alert to potential anthrax exposure via the mail. Letters and packages should be evaluated and when they appear suspicious, appropriate protective steps should be taken to prevent anthrax exposure. The US Centers for Disease Control and Prevention (CDC) is working with the US Postal Service on strategies to reduce the risk of anthrax exposure during mail handling, including personal protective equipment and engineering, administrative, and housekeeping controls in mail facilities. Information to guide health-care providers and laboratory workers is available at [Web] and [Web]. Suspected cases of anthrax should be reported to CDC through corresponding state and local health departments.

Primary Vaccination

Preexposure Vaccination

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), others from CDC, the WHO, the manufacturer, and other experts (e.g., the US Working Group on Civilian Biodefense) do not recommend routine primary vaccination of the general population, since the risk of exposure to Bacillus anthracis spores currently is considered to be generally low. However, recent bioterrorist activities could increase the level of risk in certain US areas or populations. For the general population, the ACIP currently states that prevention of morbidity and mortality associated with anthrax will depend on public vigilance, early detection and diagnosis, appropriate treatment, and postexposure prophylaxis.

The ACIP and other experts from CDC state that the decision to employ preexposure vaccination with anthrax vaccine adsorbed as a component of a bioterrorism preparedness plan should be based on a calculable risk assessment. For the US military and other defined populations or groups who are at risk for repeated exposures to B. anthracis spores for whom calculable risk can be assessed, preexposure vaccination may be indicated. Priority for preexposure vaccination should be given to workers in settings in which repeated exposure to aerosolized B. anthracis spores may occur, including laboratory workers who are involved in testing potentially infected environmental specimens (especially powders) or those who perform confirmatory testing for B. anthracis in the US Laboratory Response Network (LRN) for Bioterrorism Level B laboratories or above, and workers who will repeatedly enter areas contaminated with B. anthracis spores. However, if the target population for a bioterrorist release of B. anthracis cannot be predetermined, the risk of exposure cannot be calculated. Although studies previously suggested that exposure from secondary aerosolization of previously settled B. anthracis spores was extremely unlikely, recent bioterrorism exposure to certain anthrax-contaminated mail suggests that fine milling and treatment of the spores with agents that enhance aerosolization and movement may have changed such risk estimates. In response to recent bioterrorist events in the US, a US Department of Health and Human Services (HHS) committee currently is considering other groups for whom vaccination would be appropriate, and CDC is working with appropriate government agencies to provide anthrax vaccine adsorbed for nonmilitary use. In addition, the US Working Group on Civilian Biodefense recommends consideration of preexposure vaccination of certain groups considered at high-risk of exposure as the vaccine becomes available. Clinicians should consult the CDC ([Web]) or HHS ([Web]) for ongoing developments on the nonmilitary use of anthrax vaccine adsorbed and possible expanded vaccine availability.

Individuals who plan to enter an area of a previous release may be at risk for exposure from a re-aerosolization of a primary aerosol of B. anthracis spores or exposure from a high concentration of settled spores in a specific area. As a result, the ACIP states that initiation of anti-infective chemoprophylaxis should be considered for such individuals, alone or in combination with anthrax vaccine adsorbed. (See Uses: Postexposure Prophylaxis.) Mechanical means of reducing inhalational exposure to personnel working in an area of a documented release of B. anthracis spores, including personal protective measures, also should be considered.

Laboratory and Occupational Exposures

The ACIP recommends routine vaccination with anthrax vaccine adsorbed for individuals who are employed in a laboratory position that involves production quantities or concentrations of B. anthracis cultures and in industrial settings with a high potential for B. anthracis spore aerosols. In addition, the ACIP and CDC recommend vaccination of laboratory workers in the US Laboratory Response Network (LRN) for bioterrorism level B laboratories or above who are involved in confirmatory testing for B. anthracis. At present, laboratory workers who adhere to biosafety level 2 practices in routine processing of clinical samples or environmental swabs (Level A laboratories) are not considered at increased risk for exposure to B. anthracis spores. CDC also recommends routine preexposure vaccination against anthrax for workers who involved in decontamination of sites where the organism is identified (e.g., secondary to bioterrorist activity). Extending preexposure vaccination to other groups at high risk also is being considered.

Routine preexposure vaccination with anthrax vaccine adsorbed also is recommended for certain individuals who are in contact with imported animal hides, bone meal, bristles, furs, hair, or wool only when such individuals are insufficiently protected from exposure to B. anthracis spores by industrial hygiene protective measures and import restrictions of raw materials.

Routine preexposure vaccination with anthrax vaccine adsorbed of veterinarians is not recommended because of the low incidence of anthrax in domestic animals in the US and the low risk of disease following animal exposure. However, the ACIP and WHO state that vaccination against anthrax might be indicated for certain veterinarians and other high-risk individuals who handle potentially infected animals in areas with high rates of endemic disease.

Postexposure Prophylaxis

Although the safety and efficacy of postexposure prophylaxis with anthrax vaccine adsorbed have not been established, the vaccine currently is available under an investigational new drug application (IND) from HHS. The ACIP states that appropriate postexposure use of the vaccine should minimize the risk of anthrax and provide data to support future recommendations to prevent anthrax. Although the benefit of postexposure anti-infective therapy in preventing inhalational anthrax has been demonstrated in a primate model of inhalational anthrax, the ACIP states that to develop public health recommendations for postexposure prophylaxis, further research is needed to determine the optimum chemoprophylactic regimen to prevent inhalational anthrax in humans, including the number of days of therapy, and to define better the additional benefit of combined postexposure prophylaxis^{† [off-label]} with anthrax vaccine adsorbed and anti-infective therapy. In addition, studies in rhesus monkeys have demonstrated that anti-infectives (e.g.,ciprofloxacin, doxycycline) in combination with postexposure vaccination with anthrax vaccine adsorbed are effective at preventing anthrax after inhalational exposure to B. anthracisspores while postexposure vaccination alone was not protective.

The ACIP, WHO, American Public Health Association (APHA), US military (e.g., US Army Medical Research Institute of Infectious Diseases, USAMRIID), and other experts (e.g., US Working Group on Civilian Biodefense) recommend postexposure prophylaxis against B. anthracis infection in individuals with known aerosol exposure to B. anthracis spores. Aerosol exposure to spores may occur after an inadvertent laboratory exposure or a biologic warfare or bioterrorist incident; however, inhalational exposure generally is considered unlikely except in laboratories that work with large volumes of B. anthracis, textile mills working with heavily contaminated animal products, or after an act of biologic terrorism or warfare. Following exposure to naturally occurring anthrax in livestock, cutaneous and GI exposures in humans are possible, but inhalational anthrax has not been reported. The principal strategy for postexposure prophylaxis against anthrax is chemoprophylaxis with appropriate anti-infectives (e.g., ciprofloxacin, doxycycline). However, if exposure is confirmed, postexposure vaccination with anthrax vaccine adsorbed (if available) may be indicated in conjunction with anti-infective prophylaxis, and US Working Group on Civilian Biodefense states that such combined postexposure prophylaxis appears to provide optimal protection. The ACIP states that combined postexposure prophylaxis with anthrax vaccine adsorbed and anti-infective therapy may have additional benefits, including reducing the duration of long-term chemoprophylaxis and the associated problems of such long-term therapy, including noncompliance and possible adverse events.

Anthrax vaccine adsorbed may be obtained from the CDC under an investigational new drug (IND) application for use in unvaccinated individuals at risk for inhalational anthrax and the ACIP and US Working Group on Civilian Biodefense states that patients with suspected or confirmed aerosol exposure should receive 3 doses of anthrax vaccine adsorbed, with the first dose administered as soon as possible after exposure followed by 2 more doses at 2-week intervals combined with anti-infective prophylaxis. The optimal duration of anti-infective therapy when used in conjunction with anthrax vaccine adsorbed for postexposure prophylaxis has not been determined. Since active immunity peaks 14 days after the third dose of anthrax vaccine adsorbed, ACIP states that it might be prudent to continue anti-infective therapy for 7–14 days after administering the third vaccine dose for postexposure prophylaxis. Based on limited data from unintentional human exposures and animal challenge studies , ACIP and the US Working Group on Civilian Biodefense recommend a 60-day anti-infective regimen when postexposure chemoprophylaxis alone is used in unvaccinated individuals. Data also are limited regarding the efficacy of postexposure anti-infective prophylaxis in individuals exposed to B. anthracis spores who have previously received a partial or complete series of anthrax vaccine adsorbed. In the single controlled field trial in humans that evaluated a previously available alum-precipitated protective-antigen (PA) vaccine, anthrax was reported in individuals who had received less than 4 doses of the vaccine prior to exposure. Because of the potential of an undefined benefit, ACIP recommends that individuals who have received all or part of the 6-dose vaccine regimen continue anti-infective prophylaxis for at least 30 days and receive any remaining scheduled vaccine doses. Anti-infective prophylaxis is not recommended for laboratory workers employed in biosafety level 3 laboratories that maintain recommended conditions or for workers in contaminated environments who wear appropriate personal protective equipment and who have received the complete vaccine series, unless a breech of respiratory protection occurs.

All individuals with suspected or confirmed exposure to inhalational anthrax should be closely monitored by their clinicians during and after postexposure prophylaxis, especially for signs of febrile illness. Information for health-care providers and patients regarding postexposure prophylaxis with anthrax vaccine adsorbed and/or extended anti-infective therapy can be obtained at [Web] and [Web] or by calling the CDC at 770-448-7100.

After the bioterrorist attacks involving US mail contaminated with anthrax spores in October 2001, the US Department of Health and Human Services (HHS) and ACIP initially recommended that individuals exposed to spores and considered at risk of developing inhalational anthrax receive a 60-day course of anti-infective therapy. While the risk of inhalational anthrax is not known in individuals with spore exposure who have received a 60-day postexposure regimen of anti-infectives, it is possible that the risk of inhalational anthrax continues beyond 60 days in these individuals and treatment with anthrax vaccine adsorbed and/or additional anti-infective therapy could reduce this risk. As many individuals exposed to spores through contaminated mail and at risk of inhalational anthrax began to complete the recommended 60-day postexposure anti-infective regimen in December 2001, the HHS offered 3 options for postexposure prophylaxis to these individuals: 1) no additional prophylaxis but continued careful monitoring for illness, 2) 40 additional days of anti-infective therapy (e.g., ciprofloxacin, doxycycline, amoxicillin), or 3) 40 additional days of anti-infective therapy combined with 3 doses of anthrax vaccine adsorbed^{† [off-label]} given at 2-week intervals over a 4-week period. The rationale for these latter 2 options is the fact that traces of live spores have been detected in animal lungs for up to 100 days following exposure, raising the theoretical risk that spores remaining in the lungs after the 60-day anti-infective regimen might still result in anthrax. The HHS and ACIP recommended that these patients consult with their clinicians to determine if treatment with anthrax vaccine adsorbed and/or additional anti-infective therapy is appropriate based on the perceived risks and benefits. To evaluate the efficacy of combined postexposure prophylaxis with anthrax vaccine adsorbed and/or additional anti-infective therapy, HHS provided anthrax vaccine adsorbed under an investigational new drug application (IND) to individuals exposed to inhalational anthrax who had concluded their anti-infective therapy and who elected to receive the vaccine and/or an additional course anti-infective therapy.

The HHS and ACIP acknowledge that data are limited regarding treatment and pathogenesis of inhalational anthrax. In addition, the extent and quantity of spore exposure in these recent anthrax incidents is not precisely known. Some laboratory animal studies indicate that inhalational anthrax is not likely to develop beyond 60 days after spore exposure; inhalational anthrax has not been reported in individuals with spore exposure who were prescribed a 60-day course of chemoprophylaxis, including those unable to comply with the full course of therapy. However, another animal study has shown that small numbers of spores can be detected in the lungs as long as 100 days after exposure. Although these animals did not develop anthrax, if spores can persist in the lungs of humans longer than 60 days after exposure and are present after completing recommended chemoprophylaxis, inhalational anthrax theoretically could develop. Individuals who develop such late infection may be successfully treated; however, the HHS, ACIP, and US Working Group on Civilian Biodefense state that individuals exposed to inhalational anthrax, especially those considered likely to have been exposed to very high concentrations of anthrax spores, may elect to receive postexposure treatment with anthrax vaccine adsorbed and/or an extended course of anti-infectives.

Although anthrax vaccine adsorbed currently is labeled by the US Food and Drug Administration (FDA) for use in specifically defined preexposure situations only and the optimal number of vaccine doses for postexposure prophylaxis is not addressed by labeling, current evidence from challenge studies in nonhuman primates indicates that such a combined anti-infective and partial vaccine regimen can be effective for postexposure prophylaxis. While a precise correlation between antibody titer and protection against anthrax is not clear, studies of postexposure vaccine regimens used in combination with chemoprophylaxis in nonhuman primates suggest that 2 or 3 doses of vaccine were sufficient to prevent development of disease once anti-infectives were discontinued. However, the degree and duration of protection of the partial vaccine regimen currently is not known, and additional doses of anthrax vaccine adsorbed should be considered if subsequent exposures are anticipated. The US military (USAMRIID) states that soldiers who have already received 3 vaccine doses within 6 months of initiating chemoprophylaxis should continue with the remaining 3 vaccine doses according to the currently recommended 6-dose schedule to complete primary immunization. (See Dosage and Administration: Preexposure Vaccination under Dosage.)

Anthrax vaccine adsorbed alone is not effective for postexposure prophylaxis.

For additional information on postexposure chemoprophylaxis following aerosol exposure to B. anthracis spores to prevent development or progression of inhalational anthrax, see Anthrax under Uses: in Ciprofloxacin 8:12.18.

Anthrax Vaccine Adsorbed Dosage and Administration

Administration

Anthrax vaccine adsorbed is administered by subcutaneous injection. The vaccine should not be administered IV, or intradermally; while IM administration currently also is not recommended, the immunogenicity and safety of administering anthrax vaccine adsorbed by IM injection is under evaluation. Anthrax vaccine adsorbed should be administered with a 25- or 27-gauge needle and a different site should be used for each injection; after the vaccine is administered, the site should be massaged briefly to promote dispersal.

Prior to administration of the vaccine dose, the plunger of the syringe should be drawn back to ensure that the needle is not in a blood vessel. If blood or any unusual discoloration is present in the syringe, the vaccine should not be injected; the needle should be withdrawn and the syringe discarded. A new dose of the vaccine should be administered at a different site using a new syringe and needle. Anthrax vaccine adsorbed should be inspected visually for particulate matter and discoloration prior to administration. Before withdrawing a dose of anthrax vaccine adsorbed, the vial should be shaken well to obtain a homogenous, milky-white suspension; the vaccine should be discarded if it appears otherwise. The vaccine is administered as supplied; no dilution or reconstitution is necessary, and the vaccine should not be admixed with other drugs or vaccines. To prevent transmission of blood-borne infectious agents from one vaccinee to another, a different sterile syringe and needle must be used for each individual who is receiving anthrax vaccine adsorbed. If another vaccine or immune globulin IM (IGIM) is administered concomitantly with anthrax vaccine adsorbed, each should be given with a different syringe and at a different injection site.

Dosage

Preexposure Vaccination

For preexposure primary vaccination, anthrax vaccine adsorbed is administered in a series of 6 doses. In adults 18–65 years of age, the usual dose of anthrax vaccine adsorbed is 0.5 mL containing a cell-free filtrate prepared from an avirulent culture of Bacillus anthracis adsorbed to an aluminum hydroxide adjuvant. The US Public Health Service Advisory Committee on Immunization Practices (ACIP), the World Health Organization (WHO), and US military recommend that the first dose of the primary vaccine series be followed by the second and third dose 2 and 4 weeks after the initial dose, respectively, and by 3 booster doses (i.e., the fourth, fifth, and sixth doses) 6, 12, and 18 months after the initial dose, respectively, to complete the series. To maintain immunity, annual booster doses are recommended. However, ACIP recognizes that the basis for this recommended 6-dose series and annual boosters currently is not well defined.

As with many vaccines, it does not appear that an increase in time interval between anthrax vaccine adsorbed doses has any deleterious effect on vaccine immunogenicity or safety. Therefore, the ACIP currently states that interruption of the vaccination schedule does not require restarting the entire series of anthrax vaccine adsorbed northe need for additional doses. The US military states, however, that the primary vaccination series should be restarted if more than 2 years elapse between the first and second doses. For all other missed doses, the US military states that the missed dose should be administered as soon as possible and the timeline for completion of the series be reset based on the most recent dose.

Human immunogenicity data are limited on the current 6-dose primary vaccination regimen with anthrax vaccine adsorbed and the complex regimen is associated with frequent injection-site reactions (see Cautions: Local Effects); therefore, the safety and efficacy of alternative schedules containing fewer vaccine doses and IM administration currently are under investigation. The ACIP states that while available preliminary data support some flexibility in the route of administration and time interval between doses under special circumstances, changes in the administration schedule of anthrax vaccine adsorbed currently are not generally recommended because of the preliminary nature of this information. Although studies in rhesus monkeys indicate that as few as 2 doses (0.5 mL/dose) administered 15 days apart may afford good protection for up to 2 years, such protection may be inadequate to protect against an extremely high spore challenge, and completing the currently recommended 6-dose primary series should be emphasized for all vaccinees.

Postexposure Prophylaxis and Treatment

Because of the current limited availability of anthrax vaccine adsorbed in the US and the lack of data regarding combined postexposure prophylaxis with anthrax vaccine adsorbed and anti-infective therapy, the US Centers for Disease Control and Prevention (CDC) initially recommended after the anthrax attacks of 2001 that 60 days of appropriate anti-infective therapy alone be used for postexposure prophylaxis and treatment regimens. As many individuals with spore exposure and at risk of inhalational anthrax began to complete the recommended 60-day postexposure anti-infective regimen, the US Department of Health and Human Services (HHS) offered 2 additional options for postexposure prophylaxis—40 additional days of anti-infective therapy (e.g., ciprofloxacin, doxycycline, amoxicillin) or 40 additional days of anti-infective therapy combined with 3 doses of anthrax vaccine adsorbed^{† [off-label]} given at 2-week intervals over a 4-week period. In addition the ACIP, the American Public Health Association (APHA), and the US military state that if postexposure prophylaxis or treatment regimens against B. anthracis infection include anthrax vaccine adsorbed, individuals with suspected or confirmed aerosol exposure to B. anthracis spores should receive chemoprophylaxis with an appropriate anti-infective regimen and 3 doses of anthrax vaccine adsorbed, with the first vaccine dose administered as soon as possible after exposure and 2 more vaccine doses at 2-week intervals; when the vaccine is administered soon after exposure, the ACIP states that continuing anti-infective therapy for 7–14 days after administering the third vaccine dose might be prudent. However, the US Working Group on Civilian Biodefense recommends that the vaccinees complete a 60-day course of chemoprophylaxis. In addition, if subsequent anthrax exposure is anticipated, additional doses of anthrax vaccine adsorbed should be considered since the duration of protection of the partial vaccine regimen is not known. (See Postexposure Prophylaxis: Primary Vaccination under Uses.)

Vaccination alone is not effective for postexposure prophylaxis against anthrax, although appropriate anti-infective therapy alone can be.

For information on postexposure chemoprophylaxis following aerosol exposure to B. anthracis spores to prevent development or progression of inhalational anthrax, see Anthrax under Uses: in Ciprofloxacin 8:12.18.

Duration of Immunity

The duration of immunity of anthrax vaccine adsorbed has not been determined. Data from animal studies suggest that the duration of immunity after 2 doses might be 1–2 years. Annual booster doses currently are recommended. Additional study is needed to define the level of vaccine-induced antibodies required to provide immunity to anthrax, including animal-challenge studies and the relationship of such animal data to human immunity.

Cautions for Anthrax Vaccine Adsorbed

Vaccine Safety

Anthrax vaccine adsorbed is noninfectious and cell-free (i.e., no killed or live bacteria) and generally appears to be well tolerated. While adverse reactions to the vaccine reported to date generally have been mild to moderate and transient, it is possible that increased clinical use of the vaccine may reveal rare, previously unreported adverse effects. Additional data from clinical studies and postmarketing surveillance of the vaccine are needed to define more precisely the incidence of adverse effects and frequencies of uncommon reactions.

The most common adverse effects of anthrax vaccine adsorbed are local effects at the site of injection (erythema, edema, pain), headache, arthralgia, asthenia, and pruritus. The rates of adverse reactions have been higher in women than in men. The manufacturer states that the severity of adverse local effects reported after each of the second through the fifth doses of anthrax vaccine adsorbed are higher than those reported after first doses of the vaccine and that the sixth and subsequent booster doses may be associated with a relative decreased severity in adverse effects.

Published studies evaluating the safety and efficacy of anthrax vaccine adsorbed in humans are limited and information on adverse events associated with use of anthrax vaccine adsorbed has been obtained principally from prelicensure investigational data, passive surveillance data regarding adverse events associated with postlicensure use of the vaccine, and a single published field trial of a similar protective-antigen vaccine. Additional data and experience are needed to define more precisely the frequencies of adverse reactions.

Anthrax vaccine adsorbed was licensed by the US Food and Drug Administration (FDA) in November 1970. The safety and efficacy of anthrax vaccine adsorbed was affirmed by an independent advisory panel of the FDA in 1985. Although the exact number of adults who have received the vaccine is not known, approximately 68,000 vaccine doses were distributed from 1974–1989; 268,000 doses in 1990; and 1.2 million doses from 1991–1999. Adverse events associated with anthrax vaccine adsorbed should be reported to the Vaccine Adverse Event Reporting System (VAERS) at 800-822-7967or Bioport at 517-327-1675 or 517-327-7200. The ACIP recommends that, if feasible, anthrax vaccine adsorbed be evaluated in long-term safety studies to define the nature and frequency of adverse events associated with use of the vaccine. (See Precautions and Contraindications: Adverse Event Management and Prophylaxis.) In addition, the ACIP recommends that several areas of research in humans be conducted to address safety and efficacy issues associated with the use of anthrax vaccine adsorbed, including the effects of route and method of vaccine administration (IM versus subcutaneous, jet-injector device versus syringe and needle) on the frequency and severity of adverse events, antigen content variation of vaccine lots (especially the effect of changes in manufacturing processes on concentrations of edema factor and protective antigen), prevaccination treatment strategies aimed at reducing reactogenicity, adverse event risk factors of the vaccinee (e.g., gender, positive Bacillus anthracis serology), and route of exposure to anthrax spores after vaccination.

The Institute of Medicine (IOM) states that the relative safety of anthrax vaccine adsorbed should be evaluated further through active long-term monitoring studies of large populations, since data from currently published studies are inadequate and/or insufficient to evaluate the association, if any, between the use of anthrax vaccine adsorbed and long-term adverse health effects. Such studies currently are being conducted by the US Department of Defense.

Postlicensure Surveillance

In the US, approximately 2 million doses of anthrax vaccine adsorbed were distributed from January 1, 1990 through October 2001 and 1544 postmarketing adverse event reports were received by VAERS; of the adverse events reported through August 31, 2000, approximately 75% were reported in individuals younger than 40 years of age, 25% in females, and 89% in adults who had received anthrax vaccine adsorbed alone. Since the military population contains a disproportionate number of individuals who are younger than 40 years of age, the increased incidence of adverse effects in this age group is likely to be an artifact. Women vaccinees experienced a rate of adverse effects 2–3 times that of men. During this period, the most frequently reported adverse events included local hypersensitivity, edema, erythema, and pain/tenderness at the injection site, headache, arthralgia, asthenia, fever, peripheral swelling, pruritus, nausea, and dizziness; however, 6% of the adverse events were considered serious (i.e., fatal or life-threatening events or those resulting in hospitalization or permanent disability).

The most frequently reported body systems affected by serious adverse events with anthrax vaccine adsorbed included general disorders and injection site conditions, nervous system disorders, skin and subcutaneous tissue disorders, and musculoskeletal, connective tissue and bone disorders. Less frequently reported serious adverse events included cellulitis, cysts, pemphigus vulgaris, endocarditis, sepsis, angioedema and other hypersensitivity reactions, asthma, aplastic anemia, neutropenia, idiopathic thrombocytopenia purpura, lymphoma, leukemia, collagen vascular disease, systemic lupus erythematosus, multiple sclerosis, polyarteritis nodosa, inflammatory arthritis, transverse myelitis, Guillain-Barré syndrome, immune deficiency, seizure, mental status changes, psychiatric disorders, tremors, cerebrovascular accident (CVA), facial palsy, hearing and visual disorders, aseptic meningitis, encephalitis, myocarditis, cardiomyopathy, atrial fibrillation, syncope, glomerulonephritis, renal failure, spontaneous abortion, and liver abscess. Multisystem disorders have been reported infrequently; these disorders manifest as chronic symptoms that involved at least 2 out of 3 of fatigue, mood-cognition, and/or musculoskeletal system. Fatalities attributed to sudden cardiac arrest (2), myocardial infarction with polyarteritis nodosa (1), aplastic anemia (1), suicide, (1) and central nervous system lymphoma (1) have been reported.

US Military Surveillance

Adverse events associated with anthrax vaccine adsorbed also have been evaluated by US Department of Defense surveys of military personnel who received the vaccine as part of a mandatory vaccine program that began in 1998. Overall, injection site reactions, muscle or joint aches, headache, and fatigue were the most frequently reported adverse events. Systemic reactions were reported in 5–35% of vaccinees and included malaise, chills, rashes, headaches, and low-grade fever. Sleep problems, nausea/abdominal pain, short-term memory loss, and mental concentration also have been reported in vaccinees. In questionnaires completed after the first or second dose of anthrax vaccine adsorbed by 4348 personnel stationed at US Forces, Korea, 1.9% of vaccinees reported limitations in work performance or being placed on limited duty, 0.5% sought medical attention, 0.3% were absent from work one or more days, and one individual (0.02%) was hospitalized for an injection-site reaction. Adverse events were reported more commonly in female than in male vaccinees.

In another survey of 603 military health-care personnel stationed at Tripler Army Medical Center, 7.9% of vaccinees sought medical attention or missed work because of adverse events after the first dose; 5.1% after the second dose, 3% after the third dose, and 3.1% after the fourth dose. Outpatient visits (13.8 versus 2% after the second dose) and local reactions (46.9 versus 20.4% reported moderate to severe redness after the second dose) were reported more commonly by female versus male vaccinees.

Although adverse events reported in these surveys of recipients of anthrax vaccine adsorbed generally were localized, minor, and self-limited, the ability of these surveys of recipients of anthrax vaccine adsorbed to detect adverse events is limited by methodologic limitations, including sample size, the lack of unvaccinated control groups, observational bias, exclusion of vaccinees who experienced an adverse event with a previous vaccine dose, and limited follow-up. In addition, these data currently are from summary results or congressional testimony and have not been published in peer-reviewed medical literature to date.

Clinical Experience

To date, a single published longitudinal clinical study series has evaluated the potential long-term adverse effects of an intense long-term vaccination program of multiple vaccines including a previously available alum-precipitated protective-antigen anthrax vaccine during a 25-year period; however, interpretation of study data is limited by the lack of a comparison cohort and randomization. During the period 1956–1957, male laboratory workers 28–65 years of age employed at Fort Detrick, MD received initial comprehensive medical examinations including laboratory, diagnostic, and medical history evaluations after 10 years of participation in an intensive vaccination program; approximately 75 adult vaccinees were reexamined after 16 and 25 years of follow-up. Before the initial evaluation, 99 vaccinees received complete vaccination regimens and boosters for botulism, psittacosis, plague, Q fever, Rocky Mountain spotted fever, tularemia, typhus, and Eastern, Western, and Venezuelan equine encephalitis; in addition, 95 adults were vaccinated for smallpox, 37 for brucellosis, 28 for anthrax, and 25 for diphtheria. Before the second evaluation, 72 of the 76 vaccinees had received a previously available alum-precipitated protective-antigen anthrax vaccine.

Serum increases in hexosamine, an acute-phase reactant, and polyclonal gamma globulins were observed in vaccinees; although these elevations could be evidence of a chronic inflammatory response, they also could have been secondary to occupational exposure to virulent microbes. There were no reports of any chronic vaccine-associated adverse effects, such as neoplasia, amyloidosis, or autoimmune diseases. Vaccinees did not report any sick leave secondary to any adverse effects of vaccination. However, since vaccinees who left employment were excluded, a selection bias for the most resilient vaccinees confounds interpretation of the data (i.e., vaccinees were selected by the intensity and length of their vaccination history [e.g., healthy worker effect]). In addition, since vaccinees received numerous vaccines, observed adverse effects cannot be attributed to a specific vaccine.

CDC Research Priorities

To assess the safe use of anthrax vaccine adsorbed in humans, the ACIP recommends several areas of research. ACIP recommends that adverse event surveillance through VAERS be enhanced, which could include development of electronic reporting capability and implementation of strategies to facilitate reporting. In addition, ACIP recommends that the influence of lot-to-lot variations in the vaccine on rates of adverse events be evaluated. Other safety issues related to use of anthrax vaccine adsorbed that ACIP recommends to be addressed include development and evaluation of pretreatment strategies to decrease short-term adverse events; assessment of risk factors for adverse events, including gender and preexisting antibody levels; and analysis of variation in rates of occurrence of adverse events by method of vaccine administration (IM, subcutaneous, or jet injector) and route of exposure to anthrax. The ACIP also recommends that the safety and efficacy of the vaccine be evaluated in children and pregnant women and that reproductive toxicology studies be conducted in animals. Because the role of multiple-dose vaccine regimens has not been defined in the occurrence of local and systemic reactions, further research also is needed in this area. Studies should also be conducted to evaluate chronic and systemic adverse events associated with anthrax vaccine adsorbed and the impact on vaccine safety and efficacy secondary to increases in concentrations of edema factor and protective antigen resulting from changes in manufacturing processes. In addition, the ACIP recommends that additional research be conducted to develop a safer and more effective anthrax vaccine and new strategies for treating the disease, including use of antitoxins (e.g., hyperimmune globulin).

Local Effects

In CDC prelicensure studies of anthrax vaccine adsorbed, 6985 individuals received 16,435 doses of vaccine, 9893 were primary series doses, and 6542 were annual boosters. Local reactions considered severe (defined as edema or induration exceeding 120 mm), moderate (edema and induration of 30–120 mm), or mild (erythema, edema, and induration less than 30 mm) were observed after 1, 3, or 20% of vaccinations, respectively. More severe local reactions that include extensive forearm edema combined with a local inflammatory reaction have been reported less frequently. Currently available anthrax vaccine adsorbed appears to be better tolerated locally than the previously available alum-precipitated protective-antigen vaccine.

In a field trial of the previously available alum-precipitated protective-antigen anthrax vaccine, mild or moderate local reactions were observed in 30 or 4% of vaccinees, respectively. Mild local injection site reactions were described as a 1- to 2-cm diameter ring of erythema with local tenderness that resolved in 24–48 hours and moderate reactions were described as a ring of erythema exceeding 5 cm in diameter with more extensive edema, erythema, pruritus, induration, and/or small painless subcutaneous nodules at the injection site that generally resolved after several weeks.

The rate of local vaccine reactions was compared in a small immunogenicity study of military personnel randomized to receive the initial portion of the approved regimen of anthrax vaccine adsorbed (3 subcutaneous doses at 2-week intervals) or an alternate regimen (either 2 subcutaneous or IM injections at a 4-week interval). Local reactions (i.e., tenderness, erythema, warmth, induration, and subcutaneous nodules) were observed more frequently after subcutaneous vaccination. Vaccinees who received one of the subcutaneous regimens experienced similar local reaction rates, but those vaccinated by IM injection reported fewer subcutaneous nodules and less erythema. In a survey of military health-care personnel stationed at Tripler Army Medical Center, data from self-administered questionnaires indicated that transient local injection reactions including subcutaneous nodules and muscle soreness occurred in 65–70% of vaccinees receiving anthrax vaccine adsorbed; however, methodologic limitations complicate interpretation of these reports.

Systemic Effects

In CDC prelicensure studies of anthrax vaccine adsorbed, systemic reactions including fever, chills, body aches, and/or nausea were reported in less than 0.06% of vaccinees (4 of approximately 7000). Anorexia and tiredness has been reported in individuals who received anthrax vaccine adsorbed. In a study of the previously available alum-precipitated protective-antigen anthrax vaccine, systemic reactions were reported in 0.2% of vaccinees.

While the risk of sensitivity reactions to anthrax vaccine adsorbed appears to be low, anaphylaxis and anaphylactoid manifestations have been reported rarely in patients receiving the vaccine; to date, 2 vaccinees have reported anaphylaxis during postmarketing surveillance. Two fatalities have been reported after vaccination with anthrax vaccine adsorbed; these deaths were attributed to coronary arteritis and aplastic anemia but a causal relationship to the vaccine was not established.

In a small immunogenicity study that compared IM or subcutaneous injection of anthrax vaccine adsorbed, adverse systemic effects were uncommon, and the rate of adverse systemic effects was similar in military personnel who received the vaccine by either route of administration.

Of 1544 postmarketing adverse events reports on anthrax vaccine adsorbed submitted to VAERS, those events considered serious included cellulitis, pneumonia, Guillain-Barré syndrome, seizures, cardiomyopathy, systemic lupus erythematosus, multiple sclerosis, collagen vascular disease, sepsis, angioedema, and transverse myelitis. To date, VAERS data analysis has not revealed a pattern of serious adverse events clearly associated with anthrax vaccine adsorbed.

In a survey of military health-care personnel stationed at Tripler Army Medical Center, myalgias were reported in 15% of vaccinees receiving anthrax vaccine adsorbed and other commonly reported adverse systemic events included joint aches, headache, and fatigue; however, methodologic limitations complicate interpretation of these reports.

Chronic Illness in Gulf War Veterans

The possible association of chronic illnesses of Persian Gulf War veterans and several potential risk factors has been evaluated by CDC epidemiologic surveys of military personnel. The chronic multisymptom illness associated with deployment to the Persian Gulf War included manifestations of fatigue, cognitive disturbances, changes in affect, sleep difficulties, muscle pain, and joint pain and stiffness of at least 6 months’ duration. The self-reported prevalence of medical and psychiatric conditions also was higher among deployed Persian Gulf War veterans compared with nondeployed veterans. However, there was no association between these illnesses and a specific Persian Gulf War exposure; in addition, nondeployed veterans also reported these manifestations. To date, the etiology or risk factors for illnesses associated with deployment to the Persian Gulf War have not been determined, and current scientific evidence does not support an association between anthrax vaccine adsorbed and such illness.

Precautions and Contraindications

Sensitivity Reactions

Anthrax vaccine adsorbed is contraindicated in individuals who have experienced an anaphylactic or anaphylactoid reaction to a previous dose of the vaccine or are hypersensitive to any ingredient in the formulation. Anthrax vaccine adsorbed should be administered with caution to individuals with latex sensitivity since some of the packaging components of the vaccine contain natural rubber latex which may cause sensitivity reactions in susceptible individuals. Patients experiencing hypersensitivity reactions after an anthrax vaccine adsorbed dose should not receive further doses of the vaccine. Immunization with anthrax vaccine adsorbed should be discontinued in individuals who experience a severe reaction after receiving a dose of the vaccine, including systemic reactions characterized by malaise, lassitude, chills, and/or fever .

Although anaphylaxis following anthrax vaccination has been extremely rare (see Cautions: Systemic Effects) and no anaphylaxis-associated deaths have been reported to date with the currently available anthrax vaccine adsorbed, the possibility of potentially life-threatening sensitivity reactions to the vaccine should be considered. Prior to administration of anthrax vaccine adsorbed, all known precautions should be taken to prevent adverse reactions, including a review of the patient’s history with respect to possible hypersensitivity to the vaccine or to similar vaccines; epinephrine should be readily available for immediate treatment of an anaphylactic or anaphylactoid reaction if such a reaction should occur.

Febrile Illness

As with any vaccine, administration of anthrax vaccine adsorbed should be delayed, if possible, in individuals with moderate or severe febrile illness. Delaying administration of the vaccine can avoid superimposing adverse effects of the vaccine on the underlying illness or mistakenly concluding that a manifestation of the underlying illness resulted from vaccination. However, anthrax vaccine adsorbed may be given to individuals with minor illness such as mild upper respiratory infection (with or without low-grade fever) if withholding the vaccine poses greater risk to the patient.

Individuals with Prior Bacillus Anthracis Infection

The ACIP states that anthrax vaccine adsorbed is contraindicated in individuals who have recovered from anthrax. More severe adverse events have been reported in vaccinees with a history of anthrax compared with vaccinees without such a history.

Individuals with Prior Guillain-Barre Syndrome

Anthrax vaccine adsorbed is contraindicated in individuals with a history of Guillain-Barre Syndrome unless the benefit of vaccination outweighs the risk of recurrence.

Adverse Effect Management and Prophylaxis

Adverse events may occur in individuals who, because of high risk of exposure or employment requirements, must still complete the anthrax vaccination series. Several therapeutic regimens have been developed to ameliorate or manage specific adverse local and systemic effects (see: [Web]); however, these regimens have not been evaluated in randomized trials to date.

The ACIP states that any adverse event that occurs after a dose of anthrax vaccine adsorbed, especially those considered serious, clinically important, or unusual, should be reported to the Vaccine Adverse Event Reporting System (VAERS) by calling 800-822-7967 or electronically at: [Web], [Web], or [Web].

Pediatric Precautions

Because safety and efficacy of anthrax vaccine adsorbed in children younger than 18 years of age have not been established, the manufacturer currently does not recommend use in this age group. However, based on experience with other inactivated vaccines in this age group, the US Working Group on Civilian Biodefense states that anthrax vaccine adsorbed is likely to be safe and effective in children.

Geriatric Precautions

Because safety and efficacy of anthrax vaccine adsorbed in geriatric adults older than 65 years of age have not been established, the manufacturer currently does not recommend use in this age group.

Mutagenicity and Carcinogenicity

Anthrax vaccine adsorbed has not been evaluated for carcinogenic or mutagenic potential.

Pregnancy, Fertility, and Lactation

Pregnancy

It is not known whether anthrax vaccine adsorbed can cause fetal harm when administered to pregnant women or can affect reproductive capacity. Preliminary data from an unpublished study of women in the military suggest that anthrax vaccine adsorbed administered during pregnancy may be associated with an increased rate of birth defects. Although these data remain to be confirmed, pregnant women should be vaccinated against anthrax only if the potential benefits of vaccination outweigh the risks to the fetus. Because the vaccine is produced from a sterile cellular filtrate of Bacillus anthracis, the theoretical risk to the fetus is expected to be low. However, the ACIP recommends that regulatory toxicology studies be performed in pregnant animals since the findings of such studies could provide baseline data for further studies of the safety of anthrax vaccine adsorbed in pregnant women.

Fertility

Animal reproduction studies have not been performed with anthrax vaccine adsorbed. The pregnancy rate was similar in women who had received at least one prepregnancy dose of anthrax vaccine adsorbed compared to those who had not received the vaccine in a cohort study of 4092 women (17–44 years of age) enrolled in the military.

Lactation

The ACIP states that administration of inactivated vaccines, including anthrax vaccine adsorbed, in nursing women is not medically contraindicated. There currently are no data to suggest that nursing women who receive the vaccine or their breast-fed children are at increased risk for adverse events.

Drug Interactions

Immunosuppressive Agents

Although specific studies are not available, individuals receiving immunosuppressive therapy (e.g., corticotropin, corticosteroids, alkylating agents, antimetabolites, radiation therapy) may have a diminished antibody response to anthrax vaccine adsorbed. Therefore, the manufacturer states that administration of the vaccine series should be deferred 3 months after patients complete short-term immunosuppressive therapy; those receiving long-term immunosuppressive therapy should receive the vaccine series during therapy and an additional dose of vaccine after completion of such therapy.

Vaccines

Since anthrax vaccine adsorbed is a noninfectious preparation, concomitant administration of anthrax vaccine adsorbed and other killed vaccines is not likely to cause interference with the immune response to these vaccines. Limited data suggest that the immunogenicity and adverse effects of either vaccine are not affected in adults vaccinated with anthrax vaccine adsorbed and other vaccines (e.g., influenza, poliovirus, yellow fever, plague, typhus, tetanus).

Pharmacology

Anthrax vaccine adsorbed stimulates active immunity to Bacillus anthracisinfection by inducing specific antibodies against the bacterium. Anthrax vaccine adsorbed induces both humoral and cell-mediated responses in vaccinees, although the role and relative contribution of each type of response to immunity against anthrax have not been fully determined. The virulence factors and immunogenic proteins of B. anthracis include capsular proteins and exotoxins (i.e., protective antigen [PA], lethal factor [LF], and edema factor [EF]); however, only PA appears to be essential for inducing antibodies required for protective immunity in vaccinees.

Anthrax vaccine adsorbed currently available for use in the US contains higher concentrations of PA (produced under microaerophilic conditions), a different adjuvant (aluminum hydroxide) and preservative (benzethonium chloride), and is prepared from a different strain of B. anthracis than the previously available US alum-precipitated anthrax vaccine. Unlike the previously available vaccine, the current anthrax vaccine adsorbed is produced in a protein-free medium.

Bacillus anthracis and Infection

Overview

B. anthracis, a gram-positive spore-forming bacillus, is the etiologic agent of anthrax, a zoonotic disease that occurs most commonly in wild and domestic herbivores (e.g., cattle, sheep, goats, camels, antelope). The influence of strain variation or host factors on infectious dose has not been fully determined. Anthrax spores germinate into the vegetative form of B. anthracis in the presence of amino acids, nucleosides, and glucose such as in infected animal and human tissues; conversely, rapidly multiplying vegetative anthrax bacilli will sporulate when local nutrients are exhausted, such as following exposure of anthrax-infected body fluids or tissues to air, resulting in the formation of extremely resistant infectious spores. The vegetative form exhibits poor survival outside of an animal or human host, whereas spores can survive in the environment for decades.

Humans develop anthrax after exposure to B. anthracis spores through infected animals or contaminated animal products or by direct contact with spores. Depending on the mode of spore exposure, anthrax may present as either a cutaneous, GI/oropharyngeal (ingestional), or respiratory (inhalational) disease. More than 95% of endemic anthrax is cutaneous. There currently is no evidence of person-to-person transmission of inhalational anthrax, and reinfection does not appear to occur.

Dormant B. anthracis spores are resistant for varying periods to drying, heat, UV light (e.g., sunlight), gamma radiation, and many disinfectants; infectivity of the spores is maintained for many years, even decades. For decontamination, a sporicidal agent is required for disinfection; although iodine can be sporicidal at disinfectant strengths, antiseptic-strength iodophors usually are not sporicidal. Chlorine (as sodium or calcium hypochlorite 0.05%; a 1:10 dilution of household “bleach”) also can be used for decontamination, but it may be corrosive to some surfaces and its activity may be reduced greatly in the presence of organic material.

Soil is the principal reservoir for anthrax infection; after a vegetative stage, spore density increases in soil and grazing ruminants may become infected. Human anthrax results from exposure through skin contact, ingestion, or inhalation of B. anthracis spores via infected animals or contaminated animal products (e.g., hair, wool, fur, hides, flesh, blood, excreta, ivory, manufactured products such as bone meal) or through contact with contaminated fomites (e.g., intentional exposure to spore-contaminated mail as a result of bioterrorist activities) or environments. Although the infectious dose of B. anthracis in humans has not been determined for any route of exposure, data from primate studies indicate an estimated human infectious dose by inhalation of 8000–55,000 spores. However, a human LD₅₀ (lethal dose sufficient to kill 50% of exposed individuals) as low as 2500 spores and infection from as few as 1–3 spores has been estimated from some primate data; The 1- to 2-µm diameter spores form aerosols that easily reach the alveoli when inspired. Inhaled spores do not germinate immediately in the alveolar recesses but reside there for up to several weeks before being taken up by macrophages. It appears that following alveolar deposition, macrophages ingest the spores, some of which undergo lysis and destruction; surviving spores are transported via lymphatics to the mediastinal lymph nodes where germination occurs up to 60 days later. Anti-infectives can prolong the incubation period for developing disease. Anti-infectives are effective against germinating or vegetativeB. anthracis but are ineffective against the dormant or spore form of the bacterium. As a result, anti-infectives are effective only as long as therapeutic concentrations of the drugs are maintained to kill germinated B. anthracis; if remaining dormant spores are sufficiently numerous after anti-infective discontinuance to evade or overwhelm the immune system when they germinate, disease will then develop. This delayed disease onset has been described only for inhalational anthrax and because of the high risk of concomitant spore inhalation following a bioterrorism exposure, prolonged anti-infective therapy (e.g., for 60 days) currently is recommended for inhalational and cutaneous anthrax associated with such exposure.

Direct skin contact (especially exposed areas of the arms, hands, face, and neck that are cut or abraded) with animal products contaminated with B. anthracis spores can result in cutaneous anthrax, and ingestion of infected and undercooked or raw meat by-products can result in oropharyngeal or GI forms of the disease. Inhalation of aerosolized spores associated with industrial processing of contaminated wool (woolsorters’ disease), hair, or hides can result in inhalational anthrax as can intentional exposure to aerosols from contaminated fomites (e.g., mail, mail-processing equipment).

Anthrax develops after B. anthracis endospores enter the body through abraded skin, ingestion, or inhalation. After the spores are phagocytized by macrophages, they germinate into vegetative bacteria that are released into the lymphatic system and multiply, resulting in bacteremia and toxemia. Vegetative B. anthracis produces a polyglutamyl capsule and toxins that inhibit phagocytosis and the immune response; full virulence requires the presence of both the antiphagocytic capsule and the toxins.

B. anthracis secretes 3 protein factors—protective antigen (PA), lethal factor (LF), and edema factor (EF)—that combine to form 2 binary toxins; PA and LF form lethal toxin and PA and EF form edema toxin. Lethal toxin and edema toxin cause lethality and extensive edema, respectively. Lethal toxin stimulates the release from macrophages of tumor necrosis factor α and interleukin-1, which appears to contribute to toxic effects associated with high degrees of bacteremia and terminally high levels of lethal toxin. PA, an 82-kD protein, is the major virulence factor for B. anthracis. After binding host cell receptors, PA is cleaved to a 63-kD fragment that permits translocation of LF and EF into the cell. Once toxin production reaches a critical level, death occurs even if systemic sterility is achieved with anti-infectives; therefore, corticosteroids have been suggested as an adjunct to anti-infective therapy for inhalational anthrax with extensive edema, respiratory compromise, or meningitis or as an adjunct for cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions of the head and neck.

Incubation Period

The incubation period and manifestations of human anthrax depend on the route of exposure to B. anthracis spores, but manifestations generally are evident within 1–7 days of exposure; the onset of inhalational anthrax may be delayed for weeks or months secondary to delayed spore germination. Cutaneous anthrax had been the most common form reported in the US, developing 3–5 days (range: 0.5–12 days) after exposure, and GI anthrax is rare, developing 2–5 days (range: 1–7 days) after ingestion of meat from infected livestock. Current human data indicate that inhalational anthrax develops about 1–10 days after spore exposure; however, incubation periods of up to 43 days have been reported in humans (range: 1–43 days) and viable spores have been detected in mediastinal lymph nodes of primates for at least 100 days after exposure.

Cutaneous Anthrax

Cutaneous anthrax is the most common form of B. anthracis infection, and 95% of anthrax cases in the US had been cutaneous prior to 2001. In recent (September and October 2001) intentional (bioterrorist) exposures to spore-contaminated fomites (e.g., mail, mail-processing equipment) and/or environments in the US, approximately half of reported cases were cutaneous with the remainder being inhalational. Cutaneous infection results when spores enter a break in the integument (usually on the arms, face, or neck) during contact with contaminated meat, wool, hides, leather, or hair products from infected animals or from other contaminated fomites (e.g., mail intentionally contaminated with spores as an act of bioterrorism). The primary lesion at the site of infection is a small, painless, tingling, pruritic papule that appears 1–17 days after introduction of the endospore and that forms a vesicle within 1–2 days; the vesicle dries and erodes into the pathognomonic coal-black necrotic central scab (eschar) surrounded by edema (secondary to toxin production) and purplish secondary vesicles. Edema may be massive, particularly when lesions are on the face or neck. Some patients may develop regional lymphadenopathy, lymphangitis, low-grade fever, malaise, and headache, and the local infection occasionally may disseminate systemically and be potentially fatal.

Although appropriate anti-infective therapy can render cutaneous anthrax lesions culture negative within 24 hours, progression to eschar formation still occurs; the eschar then dries, loosens, and falls off within 1–2 weeks of formation, usually leaving little or no permanent scar. In patients who receive appropriate anti-infective therapy, the case-fatality rate of cutaneous anthrax is less than 1%; the fatality rate in untreated patients is 20%. In addition, although cutaneous infection may produce an effective immune response, the potential for reactivation of latent infection following a typical 7- to 10-day course of anti-infective therapy may exist, and patients whose cutaneous infection resulted from a bioterrorism exposure also appear to be at high risk for simultaneous aerosol exposure. Therefore, even cutaneous anthrax should be treated with appropriate systemic anti-infectives for 60 days when the disease develops from intentional spore exposure.

Gastrointestinal Anthrax

Gastrointestinal (GI) anthrax has not been reported in the US. GI anthrax can manifest as an abdominal (intestinal) and/or oropharyngeal (when spores deposit in the oropharynx) form.

The intestinal form of anthrax usually results from ingestion of raw or undercooked meat contaminated with anthrax spores and/or vegetatitive organisms from infected livestock and subsequent germination in the lower GI tract. It appears that spores or vegetative bacilli gain entry through a break in the mucosa, where they germinate and induce acute GI inflammation, including mesenteric lymphadenitis, and ulceration at the site of infection. The primary ulcerative intestinal lesions occur mainly in the terminal ileum or caecum. Early manifestations include abdominal pain, nausea, loss of appetite, emesis, diarrhea, constipation, and fever followed by ascites (which can be massive), hematemesis, melena, and hematochezia. Rapid progression to sepsis may occur.

Less commonly, GI anthrax infection may originate in the oropharynx following deposition and subsequent germination of anthrax spores in the upper GI tract. The oropharyngeal form of GI anthrax manifests as a milder disease, with lesions at the base of the tongue or tonsils, regional lymphadenopathy, cervical edema, dysphagia, sore throat, respiratory difficulties, and fever. Respiratory distress secondary to marked lymphadenitis and massive edema also can occur.

The case-fatality rate of GI anthrax is estimated to be 25–60%; death occurs after GI perforation and/or toxemia develops. The effect of early anti-infective therapy on case-fatality rate in GI anthrax is not established, although aggressive intervention similar to that employed for inhalational anthrax may reduce mortality. However, given the difficulty in early diagnosis, mortality inevitably may remain high.

Inhalational Anthrax

Until recently, inhalational anthrax (woolsorters’ disease) had been rare in the US; relatively few cases were reported in workers with known aerosol exposure to high concentrations of spores prior to institution of primary vaccination and industrial hygiene measures. Inhalational anthrax appears to require inspiration of 2500–55,000 B. anthracis spores, and primate studies indicate that the incubation period for inhalational anthrax may be inversely related to the quantity of inspired spores. However, recent primate data inidicates as few as 1–3 spores may cause infection. Spores germinate in alveolar macrophages after phagocytosis, and the vegetative bacilli then multiply in the mediastinal and peribronchial lymph nodes resulting in hemorrhagic mediastinitis and toxic bacteremia. Inhalational anthrax generally has been described clinically as a biphasic illness. A nonspecific initial prodrome of influenza-like manifestations includes minimal or nonproductive cough, sweating (possibly profuse), chills, sore throat, mild fever, chest discomfort or heaviness, pleuritic pain and/or myalgia. Severe fatigue or malaise also often are present; other manifestations include abdominal pain, nausea, vomiting, and headache. After 1–3 days, the disease progresses to a second phase, which begins abruptly and includes further fever, acute dyspnea, diaphoresis, cyanosis, and respiratory failure. Hemorrhagic meningitis may occur with concomitant meningismus, delerium, and obtundation. The second phase is rapidly progressive, with shock, associated hypothermia, and death occurring within 24–36 hours.

Chest radiographs in inhalational anthrax may show typical mediastinal widening, paratracheal fullness, and hilar fullness; and computerized tomography (CT) may show mediastinal and parenchymal lymphadenopathy and pleural effusions. Pleural effusions often are hemorrhagic, reaccumulate, and may require repeated thoracentesis or chest tube placement. Pulmonary infiltrates, including multilobar infiltrates, also may be present.

Very rarely, the primary lesion of inhalational anthrax may be in the nasal mucosa or accessory sinus. In such cases, marked facial edema and a thick gelatinous nasal discharge are prominent findings.

Estimates of inhalational anthrax case-fatality and attack rates are derived from limited data, especially with respect to the number of individuals considered at risk of infection from aerosol exposure and concentration of spores in the aerosol. A case-fatality rate of 86% was reported in a 1979 outbreak of inhalational anthrax in the former Soviet Union; cases were reported up to 43 days after initial spore exposure following an accidental airborne release of B. anthracis spores from a military microbiologic facility in Sverdlovsk. The incubation period was reported as approximately 10 days, although the date(s) of exposure in this outbreak are unconfirmed estimates. This modal incubation period is slightly longer than estimated incubation periods reported in limited outbreaks of inhalational anthrax in humans. In the US, a similar case-fatality rate of 80% was reported from an outbreak of inhalational anthrax among workers at a goat-hair processing plant. Inhalational anthrax often has been fatal even when treated with appropriate anti-infective therapy and intensive supportive care; fatality rates as high as 97% were reported before such treatment was available. However, there is some evidence that modern mortality rates may be lower in the setting of contemporary medical and supportive therapy, particularly when early therapy with 2 or more parenteral anti-infectives predicted to be effective is employed. The case-fatality rate was approximately 45% in 11 patients who developed inhalational anthrax after exposure to spores from intentionally contaminated mail in 2001. Prompt recognition of the early features of inhalational anthrax and initiation of appropriate therapy are critical in the settings of known or suspected exposure.

Prolonged incubation periods for inhalational anthrax have been reported in patients who received postexposure chemoprophylaxis during human outbreaks and in nonhuman primate studies of anthrax. Nonhuman primates generally are considered an acceptable animal model of human inhalational anthrax pathogenesis, and study data with animals indicate that B. anthracis spores may lay dormant in host pulmonary parenchyma for several weeks postinfection and that anti-infective therapy may increase the incubation period. It appears that after spores are inhaled and impinge within alveoli, they do not germinate immediately, but may lay dormant for weeks before phagocytosis by alveolar macrophages and subsequent germination and replication. Germinated or vegetative B. anthracis are susceptible to appropriate anti-infective agents; however, the nonvegetative spore form is not susceptible to such therapy. Thus, pathogenesis may be arrested during appropriate anti-infective therapy as germinating B. anthracis organisms are eliminated; however, after discontinuance of anti-infective therapy, residual nongerminated spores may cause disease. Delayed disease onset has been reported only in cases of inhalational exposure.

CNS Anthrax

Fatal hemorrhagic meningitis may occur as a sequela to inhalational or any other form of anthrax, occurring frequently with the inhalational form of the disease and less commonly with the other forms. Cerebrospinal fluid (CSF) usually is hemorrhagic with polymorphonuclear pleocytosis. Anthrax meningitis is almost always fatal, although patients treated with appropriate anti-infectives occasionally survive.

Response to Anthrax Vaccine Adsorbed

Following subcutaneous injection of anthrax vaccine adsorbed, B. anthracis protective antigen (PA) contained in the vaccine stimulates a primary antibody response in the vaccinee. Levels of immunoglobulin G (IgG) anti-PA antibodies in vaccinees have been evaluated in an attempt to quantitate the immunologic response to the vaccine; however, the antibody level necessary to provide protection against B. anthracis spore exposure is not known. Although PA generally is considered the most important immunogen contained in anthrax vaccine adsorbed, the specific antigenic epitopes responsible for stimulating protective immunity have not been determined and additional trace antigens are present in the vaccine (e.g., lethal factor, edema factor). In addition to humoral immunity, cellular immunity also appears to play a role in protection from anthrax. Although a correlation between antibody titer to PA and protection against anthrax has not been fully defined, limited data indicate that approximately 80% of human vaccinees develop a vaccine-induced immune response after 2 doses of anthrax vaccine adsorbed and greater than 95% develop a fourfold rise in antibody titer after 3 vaccine doses.

Limited human immunogenicity data are available on the serologic response to anthrax vaccine adsorbed. In one small study, military personnel who received 3 subcutaneous doses of anthrax vaccine adsorbed at 2-week intervals developed a mean IgG anti-PA antibody titer of 1:4096 as measured by ELISA 2 weeks after the third dose; 97% of vaccinees seroconverted as determined by indirect hemagglutination. Of laboratory personnel receiving 3 subcutaneous doses of anthrax vaccine adsorbed at 2-week intervals, 83% had IgG anti-PA antibody titers of 1:8 or greater as measured by indirect hemagglutination 2 weeks after the third dose.

There presently are limited data to support the use of the current vaccination regimen for anthrax vaccine adsorbed comprised of a total of 6 subcutaneous injections administered at 0, 2, and 4 weeks, followed by vaccinations at 6, 12, and 18 months and annual booster doses to maintain protective immunity. Because of the complexity of the 6-dose regimen and the associated reactogenicity, studies currently are under way to evaluate the immunogenicity of primary regimens with fewer doses administered by IM injection. The US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and the US Department of Defense (DOD) plan to conduct a randomized, placebo-controlled, multicenter study to evaluate the immunogenicty and safety of a reduced-dose regimen of anthrax vaccine adsorbed administered by IM injection. In addition, the ACIP recommends serologic testing of vaccinees who receive the vaccine for postexposure prophylaxis under the investigational new drug application (IND) conducted by the US Department of Health and Human Services (HHS) so that data regarding the immunogenicity of anthrax vaccine adsorbed in a postexposure setting may be obtained.

Alternate anthrax vaccine adsorbed regimens have been evaluated in a few small studies. Longer dosing intervals were associated with increases in serum titers of IgG anti-PA antibody in 2 retrospective serologic studies of US military personnel who were given the second dose of anthrax vaccine adsorbed either 2, 3, or 4 weeks after the first dose. Geometric mean titers (GMT) of IgG anti-PA antibodies were 81, 253, or 317 ELISA units/mL after a mean of 13 days following the second vaccine dose given at 2, 3, or 4 weeks, respectively. The GMT of IgG anti-PA antibodies in these vaccinees 48 days after the initial vaccine dose was 450, 1225, and 1666 ELISA units/mL after a second vaccine dose given at 2, 3, or 4 weeks, respectively. The immunogenicity of the initial portion of the approved regimen (3 subcutaneous doses at 2-week intervals) was compared with an alternate regimen (either 2 subcutaneous or IM injections at a 4-week interval) in military personnel receiving anthrax vaccine adsorbed in a small randomized study. Immunogenicity of the 2 regimens was similar when serum antibody concentrations were measured 8 weeks after the first vaccine dose; all vaccinees developed anti-PA IgG levels exceeding 25 mcg/mL, except for one vaccinee in the IM group. In another small study, similar serum titers of IgG anti-PA antibody were measured in vaccinees 6–24 weeks after receving 2 doses of anthrax vaccine adsorbed administered by IM injection separated by a 4–week interval and in those who received 3 doses of the vaccine administered by subcutaneous injection separated by a 2–week interval. Overall, less adverse reactions were observed after the vaccine was administered IM compared with subcutaneously. Although injection-site reactions occured more often in women than men, female vaccinees who received the initial 2 doses of vaccine by IM injection at a 4–week interval experienced less local adverse reactions compared with those who received the 2 vaccinations by subcutaneous injection at a 2-week interval.

Adults 18–65 Years of Age

Prevention of Anthrax

The protective efficacy of anthrax vaccine adsorbed is based on a single controlled field trial in humans that evaluated a previously available alum-precipitated protective-antigen (PA) vaccine and data from several animal challenge studies with the current vaccine formulation and other similar PA anthrax vaccines. In the single-blind adjuvant-controlled field trial, adult workers at 4 goat-hair processing mills that utilized raw materials contaminated by anthrax spores received a regimen of 0.5-mL subcutaneous injections of an earlier aluminum potassium sulfate-precipitated PA anthrax vaccine (previously produced by Merck) or placebo (0.1% alum). This alum-precipitated anthrax vaccine was similar to the anthrax vaccine adsorbed currently available for use in the US; however, the previously available vaccine contained less PA, was prepared from a filtrate of a different strain (Vollum R1-NP) of B. anthracis by a different manufacturing process, and contained different preservatives and stabilizers. Adults who did not have a history of anthrax and were employed in positions considered at risk of developing anthrax received a regimen of 3 injections at 2-week intervals, followed by 3 injections at 6-month intervals and annual booster doses thereafter; vaccinees and alum-placebo recipients were examined at 24 and 48 hours after each injection for adverse local and systemic effects. The complete injection series was administered in 480 adults; 230 received vaccine and 250 received alum-placebo injections. The efficacy of the earlier alum-precipitated PA anthrax vaccine in preventing anthrax was 92.5% based on person time of occupational exposure; during the 4-year follow-up, 26 cases of anthrax (21 cutaneous and 5 inhalational) occurred in workers. The small number of inhalational cases prohibits independent statistical analysis of the vaccine’s protective efficacy against inhalational anthrax; however, all cases of inhalational anthrax occurred in unvaccinated individuals, and the US Food and Drug Administration (FDA) Institute of Medicine (IOM) of the National Academies currently consider safety and efficacy of the vaccine established for prevention of anthrax regardless of route of exposure. In addition, 24 cases of anthrax were reported to CDC in US mill workers during the period from 1962–74; however, no anthrax cases occurred in adults at occupational risk who had received the entire regimen of a PA anthrax vaccine and only 3 cases were reported in such adults who had received one or 2 doses of vaccine.

The protective efficacy of PA anthrax vaccines, including the previously available alum-precipitated vaccine and the currently available anthrax vaccine adsorbed, has been demonstrated in several animal challenge studies of anthrax; ethical reasons prohibit controlled human challenge and protection studies with B. anthracis. Extrapolation of animal study data to humans is difficult since the studies involved various animal species, vaccine preparations, challenge strains, routes of administration, and vaccination protocols. However, the primate model (Macaca mulatta, rhesus monkeys) is a generally accepted model for the study of human inhalational anthrax, and anthrax vaccine adsorbed has been shown to be prevent inhalational anthrax in rhesus monkeys after pulmonary challenge with a limited number of B. anthracis strains. In one study, rhesus monkeys that received 2 doses of anthrax vaccine adsorbed (0.5 mL/dose) IM at 2 week intervals developed complete protection against aerosol challenge 6 and 36 weeks after vaccination and 88% protection against a similar challenge 98 weeks after vaccination.

Duration of Immunity

The duration of protective efficacy of anthrax vaccine adsorbed has not been determined; however, the ACIP states that animal study data suggest a possible duration of immunity following 2 vaccine doses of 1–2 years. The manufacturer currently recommends annual booster doses of anthrax vaccine adsorbed to maintain immunity, but the basis of the currently recommended vaccination schedule that includes a 6-dose primary series and annual booster doses is not well defined.

Chemistry and Stability

Chemistry

Anthrax vaccine adsorbed is a noninfectious, sterile suspension that contains a cell-free (no killed or live bacteria) filtrate prepared from a culture of Bacillus anthracis. An avirulent but toxigenic, nonencapsulated bovine strain of B. anthracis (V770-NP1-R) that expresses protective antigen is used to prepare the vaccine.

Commercially available anthrax vaccine adsorbed meets the standards of potency and safety established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration. The filtrate contains a mixture of cellular products including 3 toxin components of B. anthracis (protective antigen [PA], lethal factor [LF], and edema factor [EF]) adsorbed onto an aluminum hydroxide adjuvant. The specific concentrations of PA and other proteins contained in the vaccine currently are not known; however, all 3 toxin components (PA, LF, and EF) are known to be present in the vaccine and the amount of PA elaborated is increased under the anaerobic conditions in which the B. anthracis strain is cultured. Each 0.5-mL dose of the vaccine contains no more than 0.6 mg of aluminum, 12.5 mcg benzethonium chloride as a preservative, and 50 mcg formaldehyde. Following thorough agitation, anthrax vaccine adsorbed occurs as a uniform, milky-white suspension.

Stability

Anthrax vaccine adsorbed should be refrigerated at 2–8°C and should not be frozen; if freezing occurs, the vaccine should be discarded. The vaccine should be stored as recommended and should be discarded after the expiration date on the package.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Currently, anthrax vaccine adsorbed is not commercially available. At present, the vaccine is available for military use. A limited supply of the vaccine currently is available under an investigational new drug application (IND) through the US Department of Health and Human Services (HHS) for certain individuals exposed to inhalational anthrax for postexposure prophylaxis combined with anti-infective therapy.

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