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Clinical Policy Bulletin:
Anthrax Vaccine/Treatment
Number: 0483


Policy

Pre-exposure Vaccination:

Aetna considers anthrax immunization a medically necessary preventive service for indications recommended by the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP).  The ACIP recommends pre-exposure anthrax vaccination for the following groups:

  • Decontamination personnel and persons who work directly with the organism in the laboratory.*
  • Military personnel deployed to areas with high-risk for exposure to the organism (as when it is used as a biological warfare weapon).*
  • Persons who handle potentially infected animal products in high-incidence areas.  (Incidence is low in the United States, but veterinarians who travel to work in other countries where incidence is higher should consider being vaccinated.)*
  • Persons who work with imported animal hides or furs in areas where standards are insufficient to prevent exposure to anthrax spores.*
  • Environmental investigators and remediation workers who, as part of their occupation, might repeatedly enter areas contaminated with B. anthracis spores.*
  • Responder units engaged in response activities that might lead to exposure to aerosolized B. anthracis spores.*  (However, emergency and other responders are not recommended to receive routine pre-event anthrax vaccination because of the lack of a calculable risk assessment.)

The immunization consists of 2 intramuscular injections given 4 weeks apart followed by 3 additional subcutaneous injections given at 6, 12, and 18 months. The ACIP recommends annual booster injections of the vaccine thereafter.

*Note: In general, Aetna does not cover immunizations required solely for the purpose of employment, or because of incarceration.  In addition, HMO plans usually exclude coverage of immunizations solely for the purpose of travel.  Coverage of medically necessary preventive immunizations is available only to members with preventive service benefits.  Check contract language, limitations and exclusions for coverage details.

Post-exposure Vaccination:

Aetna considers post-exposure anthrax vaccination medically necessary according to the ACIP guidelines.  The ACIP guidelines recommend post-exposure anthrax vaccination for the following indications:

  • After aerosol exposure to Bacillus anthracis spores.
  • Following cutaneous or gastrointestinal exposure to Bacillus anthracis.

Note: Medically necessary post-exposure anthrax vaccinations are covered for medically necessary indications regardless of whether the member has preventive services benefits.

Anthrax vaccine is considered experimental and investigational for all other indications because of insufficient evidence of its safety and effectiveness for these indications.

Aetna considers raxibacumab injection medically necessary for the prevention and treatment of inhalational anthrax.



Background

The following discussion is based primarily on guidelines on use of anthrax vaccine from the Advisory Committee on Immunization Practices (ACIP) and information on anthrax from the Centers for Disease Control and Prevention (CDC).

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis.  Anthrax most commonly occurs in wild and domestic lower vertebrates (antelopes, camels, cattle, goats, sheep, and other herbivores), but it can also occur in humans when they are exposed to infected animals or tissue from infected animals.

Because anthrax is considered to be a potential agent for use in biological warfare, the Department of Defense (DOD) has begun mandatory vaccination of all active duty military personnel who might be involved in conflict.

Anthrax is most common in agricultural regions where it occurs in animals.  These include South and Central America, Southern and Eastern Europe, Asia, Africa, the Caribbean, and the Middle East.  When anthrax affects humans, it is usually due to an occupational exposure to infected animals or their products.  Workers who are exposed to dead animals and animal products from other countries where anthrax is more common may become infected with B. anthracis (industrial anthrax).  Anthrax in wild livestock has occurred in the United States.

Anthrax infection can occur in 3 forms: (i) cutaneous (skin), (ii) inhalation, and (iii) gastrointestinal.  B. anthracis spores can live in the soil for many years, and humans can become infected with anthrax by handling products from infected animals or by inhaling anthrax spores from contaminated animal products.  Anthrax can also be spread by eating under-cooked meat from infected animals.  It is rare to find infected animals in the United States.

Symptoms of disease vary depending on how the disease was contracted, but symptoms usually occur within 7 days.  Most (about 95 %) anthrax infections occur when the bacterium enters a cut or abrasion on the skin, such as when handling contaminated wool, hides, leather or hair products (especially goat hair) of infected animals.  Skin infection begins as a raised itchy bump that resembles an insect bite but within 1 to 2 days develops into a vesicle and then a painless ulcer, usually 1 to 3 cm in diameter, with a characteristic black necrotic (dying) area in the center.  Lymph glands in the adjacent area may swell.  About 20 % of untreated cases of cutaneous anthrax will result in death.  Deaths are rare with appropriate anti-microbial therapy.

Initial symptoms of anthrax inhalation may resemble a common cold.  After several days, the symptoms may progress to severe breathing problems and shock.  Inhalation anthrax is usually fatal.  The intestinal disease form of anthrax may follow the consumption of contaminated meat and is characterized by an acute inflammation of the intestinal tract.  Initial signs of nausea, loss of appetite, vomiting, and fever are followed by abdominal pain, vomiting of blood, and severe diarrhea.  Intestinal anthrax results in death in 25 % to 60 % of cases.

Anthrax is diagnosed by isolating B. anthracis from the blood, skin lesions, or respiratory secretions or by measuring specific antibodies in the blood of persons with suspected cases.

Anthrax can be found globally.  It is more common in developing countries or countries without veterinary public health programs.  Certain regions of the world (South and Central America, Southern and Eastern Europe, Asia, Africa, the Caribbean, and the Middle East) report more anthrax in animals than others.  Direct person-to-person spread of anthrax is extremely unlikely to occur. Communicability is not a concern in managing or visiting with patients with inhalational anthrax.

The World Health Organization and the CDC recommend that, in countries where anthrax is common and vaccination levels of animal herds are low, humans should avoid contact with livestock and animal products and avoid eating meat that has not been properly slaughtered and cooked.  Also, an anthrax vaccine has been licensed for use in humans.  The vaccine is reported to be 93 % effective in protecting against anthrax.

The anthrax vaccine is manufactured and distributed by BioPort, Corporation (Lansing, MI).  The vaccine is a cell-free filtrate vaccine, which means it contains no dead or live bacteria in the preparation.  According to the CDC, anthrax vaccines intended for animals should not be used in humans.

Anthrax pre-exposure prophylaxis consists of 2 intramuscular injections given 4 weeks apart followed by 3 additional subcutaneous injections given at 6, 12, and 18 months.  Annual booster injections of the vaccine are recommended thereafter.

Mild local reactions occur in 30 % of recipients and consist of slight tenderness and redness at the injection site.  Severe local reactions are infrequent and consist of extensive swelling of the forearm in addition to the local reaction.  Systemic reactions occur in fewer than 0.2 % of recipients.

Pre-exposure Vaccination

Occupational and Laboratory Exposures

According to the ACIP, routine vaccination with Anthrax Vaccine Adsorbed (AVA) is indicated for persons engaged in:

  • Activities with a high potential for aerosol production
  • Work involving production quantities or concentrations of Bacillus anthracis cultures.

The ACIP has concluded that laboratorians using standard Biosafety Level 2 practices in the routine processing of clinical samples are not at increased risk for exposure to Bacillus anthracis spores.

The CDC announced that decontamination personnel and state and private laboratory workers who are involved in analyzing possible anthrax exposures will be eligible for vaccination against anthrax.

The risk for persons who come in contact in the workplace with imported animal hides, furs, bone meal, wool, animal hair, or bristles has been reduced by changes in industry standards and import restrictions.  ACIP recommends routine pre-exposure vaccination only for persons in this group for whom these standards and restrictions are insufficient to prevent exposure to anthrax spores.

The ACIP does not recommend routine vaccination of veterinarians in the United States because of the low incidence of animal cases.  However, the ACIP guidelines note that vaccination might be indicated for veterinarians and other high-risk persons handling potentially infected animals in areas with a high incidence of anthrax cases.

Bioterrorism Preparedness

Although groups initially considered for pre-exposure vaccination for bioterrorism preparedness included emergency first responders, federal responders, medical practitioners, and private citizens, the ACIP does not recommend vaccination of these groups.  The ACIP guidelines note that recommendations regarding pre-exposure vaccination should be based on a calculable risk assessment.  The guidelines explain that, at present, the target population for a bioterrorist release of Bacillus anthracis can not be predetermined, and the risk of exposure can not be calculated.  In addition, studies suggest an extremely low-risk for exposure related to secondary aerosolization of previously settled Bacillus anthracis spores.  Because of these factors, the ACIP does not recommend pre-exposure vaccination for the above groups.  The ACIP does state that pre-exposure vaccination may be indicated for the military, decontamination personnel, and other select populations or for groups for which a calculable risk can be assessed.

Options other than pre-exposure vaccination are available to protect personnel working in an area of a known previous release of Bacillus anthracis.  According to the ACIP guidelines, if concern exists that persons entering an area of a previous release might be at risk for exposure from a re-release of a primary aerosol of the organism or exposure from a high concentration of settled spores in a specific area, initiation of prophylaxis should be considered with antibiotics alone or in combination with vaccine as is outlined in the section below on post-exposure prophylaxis.

Post-exposure Prophylaxis - Chemoprophylaxis and Vaccination

Penicillin and doxycycline are approved by Food and Drug Administration (FDA) for the treatment of anthrax and are considered the drugs of choice for the treatment of naturally occurring anthrax.  In addition, ciprofloxacin and ofloxacin have also demonstrated in- vitro activity against Bacillus anthracis.  On the basis of studies that demonstrated the effectiveness of ciprofloxacin in reducing the incidence and progression of inhalation anthrax in animal models, the FDA approved the use of ciprofloxacin following aerosol exposure to Bacillus anthracis spores to prevent development or progression of inhalation anthrax in humans.  Although naturally occurring Bacillus anthracis resistance to penicillin is rare, such resistance has been reported.

Antibiotics are effective against the germinated form of Bacillus anthracis but are not effective against the spore form of the organism.  Following inhalation exposure, spores can survive in tissues for months without germination in non-human primates.  This phenomenon of delayed vegetation of spores resulting in prolonged incubation periods has not been observed for routes of infection other than inhalation.

Currently, ciprofloxacin is the only antibiotic approved by the FDA for use in reducing the incidence or progression of disease after exposure to aerosolized Bacillus anthracis.  Although post-exposure chemoprophylaxis using antibiotics alone has been effective in animal models, the definitive length of treatment is unclear.  Several studies have demonstrated that short courses (5 to 10 days) of post-exposure antibiotic therapy are not effective at preventing disease when large numbers of spores are inhaled.  Longer courses of antibiotics may be effective.

Studies have demonstrated that antibiotics in combination with post-exposure vaccination are effective at preventing disease in nonhuman primates after exposure to Bacillus anthracis spores.  Vaccination alone after exposure was not protective.  Because the current vaccine is labeled for use in specifically defined pre-exposure situations only, no FDA-approved labeling addresses the optimal number of vaccinations for post-exposure prophylaxis use of the vaccine.  An estimated 83 % of human vaccines develop a vaccine-induced immune response after 2 doses of the vaccine and greater than 95 % develop a fourfold rise in antibody titer after 3 doses.  Although the precise correlation between antibody titer and protection against disease is not clear, these studies of post-exposure vaccine regimens used in combination with antibiotics in non-human primates have consistently documented that 2 to 3 doses of vaccine were sufficient to prevent development of disease once antibiotics were discontinued.

Only 1 study has directly compared antibiotics plus vaccine with a longer course of antibiotics following aerosol exposure.  This study documented no significant difference in survival for animals treated with doxycycline alone for 30 days or animals treated with 30 days of doxycycline plus two doses of anthrax vaccine post-exposure (9 of 10 versus 9 of 9, p = 0.4).  However, the study suggests a possible benefit of post-exposure combination of antibiotics with vaccination.

Following Inhalation Exposure

The ACIP recommends post-exposure prophylaxis against Bacillus anthracis following an aerosol exposure to Bacillus anthracis spores.  Such exposure might occur following an inadvertent exposure in the laboratory setting or a biological terrorist incident.  Aerosol exposure is unlikely in settings outside a laboratory working with large volumes of Bacillus anthracis, textile mills working with heavily contaminated animal products, or following a biological terrorism or warfare attack.  Following naturally occurring anthrax among livestock, cutaneous and rare gastrointestinal exposures among humans are possible, but inhalation anthrax has not been reported.  Because of the potential persistence of spores following a possible aerosol exposure, the ACIP recommends 60 days of anti-microbial prophylaxis in conjunction with 3 doses of anthrax vaccine for optimal protection of previously unvaccinated persons after exposure to aerosolized B. anthracis spores.  Because of concern about the possible antibiotic resistance of Bacillus anthracis used in a bioterrorist attack, the ACIP guidelines state that doxycycline or ciprofloxacin can be chosen initially for antibiotic chemoprophylaxis until organism susceptibilities are known.  The guidelines note that antibiotic chemoprophylaxis can be switched to penicillin VK or amoxicillin once antibiotic susceptibilities are known and the organism is found to be penicillin susceptible with minimum inhibitory concentrations (MICs) attainable with oral therapy.

Although the shortened vaccine regimen has been effective when used in a post-exposure regimen that includes antibiotics, the duration of protection from vaccination is not known.  Therefore, if subsequent exposures occur, additional vaccinations might be required.

Following Cutaneous or Gastrointestinal Exposure

No controlled studies have been conducted in animals or humans to evaluate the use of antibiotics alone or in combination with vaccination following cutaneous or gastrointestinal exposure to Bacillus anthracis.  Cutaneous and rare gastrointestinal exposures of humans are possible following outbreaks of anthrax in livestock.  In these situations, on the basis of pathophysiology, reported incubation periods, current expert clinical judgment, and lack of data, post-exposure prophylaxis might consist of antibiotic therapy for 7 to 14 days.

Vaccination during Pregnancy

No studies have been published regarding use of anthrax vaccine among pregnant women.  The ACIP guidelines recommend anthrax vaccine as a component of post-exposure prophylaxis in pregnant women exposed to aerosolized B. anthracis spores.  In a pre-event setting, in which the risk for exposure to aerosolized B. anthracis spores is presumably low, vaccination of pregnant women is not recommended and should be deferred until after pregnancy.

Vaccination during Lactation

No data suggest increased risk for side effects or temporally related adverse events associated with receipt of anthrax vaccine by breast-feeding women or breast-fed children.  According to the ACIP guidelines, breast-feeding is neither a precaution nor a contraindication to vaccination, and vaccination does not need to be deferred in a pre-event setting if the occupation of the breast-feeding mother poses a risk for exposure to B. anthracis.

Allergies

Although anaphylaxis following anthrax vaccination is extremely rare and no anaphylaxis deaths associated with Anthrax Vaccine Adsorbed (AVA) have been reported, this adverse event can be life-threatening.  The ACIP guidelines state that AVA is contraindicated for persons who have experienced an anaphylactic reaction following a previous dose of AVA or any of the vaccine components.

Previous History of Anthrax Infection

The ACIP guidelines note that anthrax vaccine is contraindicated in persons who have recovered from anthrax because of previous observations of more severe adverse events among recipients with a vaccine history of anthrax than among non-recipients.

Illness

According to the ACIP guidelines, in the context of the routine pre-exposure program, vaccination of persons with moderate or severe acute illness should be postponed until recovery.  This prevents super-imposing the adverse effects of the vaccine on the underlying illness or mistakenly attributing a manifestation of the underlying illness to the vaccine.  The ACIP guidelines state that vaccine can be administered to persons who have mild illnesses with or without low-grade fever.

Additional Information

The anthrax vaccine is made by BioPort Corp. (Lansing, MI), which is awaiting U.S. FDA approval to resume shipping the vaccine.  The FDA stopped production at BioPort in 1998 because of quality concerns.  Virtually all the U.S. stockpile of the vaccine is under the control of the Pentagon, which has long worried that its soldiers will face enemy use of anthrax on the battlefield.

For more information about anthrax vaccination, the anthrax Vaccine Immunization Program in the U.S. Army Surgeon General's Office can be reached at 1-877-GETVACC (1-877-438-8222), or at the following web address: http://www.anthrax.osd.mil.

Raxibacumab: Prevention and Treatment of Anthrax

Raxibacumab is a monoclonal antibody that neutralizes toxins produced by B. anthracis that can cause massive and irreversible tissue injury and death.  On December 14, 2012, FDA approved raxibacumab injection to treat inhalational anthrax.  Raxibacumab also is approved to prevent inhalational anthrax when alternative therapies are not available or not appropriate.  The FDA granted raxibacumab fast track designation, priority review, and orphan product designation.  The drug demonstrated the potential to fill an unmet medical need, has the potential to provide safe and effective treatment where no satisfactory alternative therapy exists, and is intended to treat a rare disease, respectively.

Raxibacumab is the first monoclonal antibody approved under the FDA’s Animal Efficacy Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct trials in humans.  In this case, because inhalational anthrax is a rare and lethal disease, it is not possible to conduct adequate efficacy trials in humans.  Raxibacumab’s effectiveness for inhalational anthrax was demonstrated in 1 study in monkeys and 3 studies in rabbits.  All animals were administered aerosolized B. anthracis spores, and efficacy was determined by survival at the end of the studies.  Animals received varying doses of raxibacumab, placebo or antibiotics normally used to treat anthrax.  More animals treated with raxibacumab lived compared to animals treated with placebo; 64 % of animals in the monkey study and 44 % of animals in 1 rabbit study receiving the 40 mg/kg dose of raxibacumab survived exposure to anthrax, compared with none in the placebo groups.  All surviving animals developed toxin-neutralizing antibodies.  Another study in rabbits showed that 82 % of animals treated with antibiotics and raxibacumab survived exposure to anthrax compared with 65 % of animals receiving antibiotic treatment alone.  The safety of raxibacumab was evaluated in 326 healthy human volunteers.  Common side effects included rash, extremity pain, itching and drowsiness.

 
HCPCS / CPT Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
90581
ICD-9 codes covered if selection criteria are met:
V01.81 Contact or exposure to anthrax
V03.89 Other specified vaccinations against single bacterial diseases
Other ICD-9 codes related to the CPB:
022.0 - 022.9 Anthrax


The above policy is based on the following references:
  1. Centers for Disease Control and Prevention (CDC), Advisory Committee on Immunization Practices. Use of anthrax vaccine in the United States. MMWR Recomm Rep. 2000;49(RR-15):1-20.
  2. Centers for Disease Control and Prevention (CDC), National Center for Infectious Diseases, Division of Bacterial and Mycotic Diseases. Anthrax. General Information. Atlanta, GA: CDC; October 1, 2001. Available at: http://www.cdc.gov/ncidod/dbmd/diseaseinfo/anthrax_g.htm. Accessed October 11, 2001.
  3. World Health Organization (WHO), Emerging and Other Communicable Diseases, Surveillance and Control. Guidelines for the Surveillance and Control of Anthrax in Humans and Animals. WHO Doc. No. WHO/EMC/ZDI/98.6. Geneva: WHO; 1998. Available at: http://www.who.int/emc-documents/zoonoses/docs/whoemczdi986.html. Accessed October 11, 2001.
  4. Centers for Disease Control and Prevention (CDC). Bioterrorism alleging use of anthrax and interim guidelines for management - United States, 1998. MMWR Morb Mortal Wkly Rep. 1999;48(4):69-74.
  5. U.S. Department of Defense (DoD). Anthrax Vaccine Immunization Program. Washington, DC: DoD; 2001. Available at: http://www.anthrax.osd.mil/. Accessed October 11, 2001.
  6. U.S. decides to issue anthrax vaccine. Reuters Medical News, October 29, 2001.
  7. Centers for Disease Control and Prevention (CDC). Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy, October 2001. MMWR Morb Mortal Wkly Rep. 2001;50(42):909-919.
  8. Swartz MN. Recognition and management of anthrax -- an update. N Engl J Med. 2001;345(22):1621-1626.
  9. Centers for Disease Control and Prevention (CDC). Use of anthrax vaccine in response to terrorism: Supplemental recommendations of the Advisory Committee on Immunization Practices. MMWR Morb Mortal Wkly Rep. 2002;51(45):1024-1026.
  10. Grabenstein JD. Anthrax vaccine: A review. Immunol Allergy Clin North Am. 2003;23(4):713-730.
  11. Ales NC, Katial RK. Vaccines against biologic agents: Uses and developments. Respir Care Clin N Am. 2004;10(1):123-146.
  12. Little SF. Anthrax vaccines: A development update. BioDrugs. 2005;19(4):233-245.
  13. Bravata D M, Wang E, Holty J-E, et al. Pediatric anthrax: Implications for bioterrorism preparedness. Evidence Report/Technology Assessment 141. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2006.
  14. Gorse GJ, Keitel W, Keyserling H, et al. Immunogenicity and tolerance of ascending doses of a recombinant protective antigen (rPA102) anthrax vaccine: A randomized, double-blinded, controlled, multicenter trial. Vaccine. 2006;24(33-34):5950-5959.
  15. Howdieshell TR, Heffernan D, Dipiro JT; Therapeutic Agents Committee of the Surgical Infection Society. Surgical infection society guidelines for vaccination after traumatic injury. Surg Infect (Larchmt). 2006;7(3):275-303.
  16. National Health Service, Department of Health. Anthrax. In: Immunisation Against Infectious Disease - 'The Green Book' - 2006 updated edition.  London, UK: Department of Health; 2007; Ch. 13, pp. 91-97.
  17. Jefferson T, Demicheli V, Deeks J, et al. Vaccines for preventing anthrax. Cochrane Database Syst Rev. 2007;(1):CD000975.
  18. Grabenstein JD. Vaccines: Countering anthrax: Vaccines and immunoglobulins. Clin Infect Dis. 2008;46(1):129-136.
  19. Stern EJ, Uhde KB, Shadomy SV, Messonnier N. Conference report on public health and clinical guidelines for anthrax. Emerg Infect Dis. 2008;14(4). pii: 07-0969.
  20. Marano N, Plikaytis BD, Martin SW, et al; Anthrax Vaccine Research Program Working Group. Effects of a reduced dose schedule and intramuscular administration of anthrax vaccine adsorbed on immunogenicity and safety at 7 months: A randomized trial. JAMA. 2008;300(13):1532-1543.
  21. Donegan S, Bellamy R, Gamble CL. Vaccines for preventing anthrax. Cochrane Database Syst Rev. 2009;(2):CD006403.
  22. Wright JG, Quinn CP, Shadomy S, Messonnier N; Centers for Disease Control and Prevention (CDC). Use of anthrax vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2010;59(RR-6):1-30.
  23. Bush LM, Perez MT. The anthrax attacks 10 years later. Ann Intern Med. 2012;156(1 Pt 1):41-44.
  24. Migone TS, Subramanian GM, Zhong J, et al. Raxibacumab for the treatment of inhalational anthrax. N Engl J Med. 2009;361(2):135-144.
  25. Antoniu SA. Raxibacumab for inhalational anthrax: An effective specific therapeutic approach? Expert Opin Investig Drugs. 2010;19(7):909-911.
  26. Corey A, Migone TS, Bolmer S. Bacillus anthracis protective antigen kinetics in inhalation spore-challenged untreated or levofloxacin/raxibacumab-treated New Zealand white rabbits. Toxins (Basel). 2013;5(1):120-138.
  27. Food and Drug Administration. FDA approves raxibacumab to treat inhalational anthrax. December 14, 2012. FDA: Silver Spring, MD. Available at: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm332341.htm?source=govdelivery. Accessed April 24, 2013.


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Copyright Aetna Inc. All rights reserved. Clinical Policy Bulletins are developed by Aetna to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. This Clinical Policy Bulletin contains only a partial, general description of plan or program benefits and does not constitute a contract. Aetna does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Aetna or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. This Clinical Policy Bulletin may be updated and therefore is subject to change.
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