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Clinical Policy Bulletin:
Smallpox Vaccine
Number: 0644


Policy

  1. Aetna considers pre-exposure immunization with smallpox vaccine a medically necessary preventive service in instances where public health authorities advise that such vaccination is necessary.  The Center for Disease Control and Prevention (CDC)'s Advisory Committee on Immunization Practices (ACIP) currently recommends pre-exposure smallpox vaccination for any of the following groups:

    1. Laboratory workers who directly handle non-highly attenuated smallpox virus cultures or materials and those who work with animals contaminated or infected with these viruses*; or
    2. Persons pre-designated by public health authorities to conduct investigational and follow-up of initial smallpox cases that would necessitate direct patient contact*; or
    3. Selected personnel in facilities pre-designated to serve as referral centers to provide care for the initial cases of smallpox*.

    The ACIP states that vaccination can be offered to other healthcare workers who are in contact with materials (e.g., dressings) contaminated with non-highly attenuated vaccinia virus*.  Re-vaccination may be medically necessary as frequently as every 3 years.

  2. Smallpox vaccination of the general population has no proven value.  Because the risk of smallpox due to intentional release of a biologic agent is currently considered low, the ACIP does not recommend vaccination of the general population, because the potential benefits of vaccination do not outweigh the risks of vaccine complications.

  3. Aetna considers smallpox vaccine medically necessary for treatment of persons who have or may have been exposed to smallpox or other non-highly attenuated vaccinia virus.  The ACIP recommends post-exposure vaccination for persons who have or may have been recently been exposed to smallpox.

* Note: Most plans exclude coverage of vaccinations required for work or travel.  Please check benefit plan descriptions for details.

Note: The CDC is the only source of vaccinia vaccine and vaccinia immunoglobulin for civilians.

Notes: Tuberculin skin test (TST) should not be performed until 4 weeks after smallpox vaccination.  Breast-feeding is a contraindication for smallpox vaccination of the mother because of the theoretical risk for contact transmission from mother to infant.  Individuals who have recently received smallpox vaccine should be deferred as donors of assisted reproductive technology.



Background

Smallpox is transmitted from an infected person once a rash appears.  Transmission does not occur during the prodromal period that precedes the rash.  Infection is transmitted by large droplet nuclei and only rarely has airborne transmission been documented.  Epidemiologic studies have shown that smallpox has a lower rate of transmission than diseases such as measles, pertussis, and influenza.  The greatest risk of infection occurs among household members and close contacts of persons with smallpox, especially those with prolonged face-to-face exposure.  Vaccination and isolation of contacts of cases at greatest risk of infection has been shown to interrupt transmission of smallpox.  However, poor infection control practices resulted in high rates of transmission in hospitals.

The primary strategy to control an outbreak of smallpox and interrupt disease transmission is surveillance and containment, which includes ring vaccination and isolation of persons at risk of contracting smallpox.  This strategy involves identification of infected persons through intensive surveillance, isolation of infected persons, vaccination of household contacts and other close contacts of infected persons (i.e., primary contacts), and vaccination of household contacts of the primary contacts (i.e., secondary contacts).  This strategy was instrumental in the ultimate eradication of smallpox as a naturally occurring disease even in areas that had low vaccination coverage.

Depending upon the size of the smallpox outbreak and the resources that were available for rapid and thorough contact tracing, surveillance and containment activities in areas with identified smallpox cases was sometimes supplemented with voluntary vaccination of other individuals.  This was done in order to expand the ring of immune individuals within an outbreak area and to further reduce the chance of secondary transmission from smallpox patients before they could be identified and isolated.  Regardless of the geographic distribution, number of cases, or number of concurrent outbreaks, surveillance and containment activities remained the primary disease control strategy.

In June 2001, the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommended smallpox vaccination for laboratory workers who directly handle cultures or animals contaminated or infected with, non-highly attenuated vaccinia virus, recombinant vaccinia viruses derived from non-highly attenuated vaccinia strains, or other Orthopoxviruses that infect humans (e.g., monkeypox, cowpox, vaccinia, and variola).  Other health-care workers (e.g., physicians and nurses) whose contact with non-highly attenuated vaccinia viruses is limited to contaminated materials (e.g., dressings) but who adhere to appropriate infection control measures are at lower risk for inadvertent infection than laboratory workers.  However, because a theoretical risk for infection exists, vaccination can be offered to this group.  Vaccination is not recommended for persons who do not directly handle non-highly attenuated virus cultures or materials or who do not work with animals contaminated or infected with these viruses.

In June 2002, the Center for Disease Control and Prevention (CDC)'s Advisory Committee on Immunization Practices (ACIP) also recommended smallpox vaccination for persons pre-designated by the appropriate bioterrorism and public health authorities to conduct investigation and follow-up of initial smallpox cases that would necessitate direct patient contact.

To enhance public health preparedness and response for smallpox control, specific teams at the federal, state and local level should be established to investigate and facilitate the diagnostic work-up of the initial suspect case(s) of smallpox and initiate control measures.  These Smallpox Response Teams might include persons designated as medical team leader, public health advisor, medical epidemiologists, disease investigators, diagnostic laboratory scientist, nurses, personnel who would administer smallpox vaccines, and security/law enforcement personnel.  Such teams may also include medical personnel who would assist in the evaluation of suspected smallpox cases.

The ACIP recommends that each state and territory establish and maintain at least 1 Smallpox Response Team.  Considerations for additional teams should take into account population and geographical considerations and should be developed in accordance with federal, state, and local bioterrorism plans.

The ACIP recommends smallpox vaccination for selected personnel in facilities pre-designated to serve as referral centers to provide care for the initial cases of smallpox.  These facilities would be pre-designated by the appropriate bioterrorism and public health authorities, and personnel within these facilities would be designated by the hospital.

As outlined in the CDC Interim Smallpox Response Plan and Guidelines, state bioterrorism response plans should designate initial smallpox isolation and care facilities (e.g., type C facilities).  In turn, these facilities should pre-designate individuals who would care for the initial smallpox cases.  To staff augmented medical response capabilities, additional personnel should be identified and trained to care for smallpox patients.

According to data regarding the persistence of neutralizing antibody after vaccination, persons working with non-highly attenuated vaccinia viruses, recombinant viruses developed from non-highly attenuated vaccinia viruses, or other non-variola Orthopoxviruses should be re-vaccinated at least every 10 years.  To ensure an increased level of protection against more virulent non-variola Orthopoxviruses (e.g., monkeypox), empiric re-vaccination every 3 years can be considered.

Although use of biological agents is an increasing threat, use of conventional weapons (e.g., explosives) is still considered more likely in terrorism scenarios.  Moreover, use of smallpox virus as a biological weapon might be less likely than other biological agents because of its restricted availability; however, its use would have substantial public health consequences.  Therefore, in support of current public health bioterrorism preparedness efforts, the ACIP has developed the following recommendations if this unlikely event occurs.

The risk for smallpox occurring as a result of a deliberate release by terrorists is considered low, and the population at risk for such an exposure can not be determined.  Therefore, pre-exposure vaccination is not recommended for any group other than laboratory or medical personnel working with non-highly attenuated Orthopoxviruses (see the section titled "Routine Non-emergency Vaccine Use").

Recommendations regarding pre-exposure vaccination should be on the basis of a calculable risk assessment that considers the risk for disease and the benefits and risks regarding vaccination.  Because the current risk for exposure is considered low, the ACIP has determined that the benefits of vaccination do not outweigh the risk regarding vaccine complications.  If the potential for an intentional release of smallpox virus increases later, pre-exposure vaccination might become indicated for selected groups (e.g., medical and public health personnel or laboratorians) who would have an identified higher risk for exposure because of work-related contact with smallpox patients or infectious materials.

If an intentional release of smallpox (variola) virus does occur, vaccinia vaccine will be recommended for certain groups.  According to the ACIP, groups for whom vaccination would be indicated include:

  • Laboratory personnel involved in the collection or processing of clinical specimens from confirmed or suspected smallpox patients.
  • Personnel involved in the direct medical or public health evaluation, care, or transportation of confirmed or suspected smallpox patients.
  • Persons who had face-to-face, household, or close-proximity contact (less than 6.5 feet or 2 meters) with a confirmed or suspected smallpox patient at any time from the onset of the patient's fever until all scabs have separated.
  • Persons who were exposed to the initial release of the virus.
  • Other persons who have an increased likelihood of contact with infectious materials from a smallpox patient (e.g., personnel responsible for medical waste disposal, linen disposal or disinfection, and room disinfection in a facility where smallpox patients are present).

Using recently vaccinated personnel (i.e., less than 3 years) for patient care activities would be the best practice.  However, because recommendations for routine smallpox vaccination in the United States were rescinded in 1971 and smallpox vaccination is currently recommended only for specific groups, having recently vaccinated personnel available in the early stages of a smallpox emergency would be unlikely.  Smallpox vaccine can prevent or decrease the severity of clinical disease, even when administered 3 to 4 days after exposure to the smallpox virus.  Preferably, healthy persons with no contraindications to vaccination, who can be vaccinated immediately before patient contact or very soon after patient contact (i.e., less than 3 days), should be selected for patient care activities or activities involving potentially infectious materials.  Persons who have received a previous vaccination (i.e., childhood vaccination or vaccination more than 3 years before) against smallpox might demonstrate a more accelerated immune response after re-vaccination than those receiving a primary vaccination.  If possible, these persons should be re-vaccinated and assigned to patient care activities in the early stages of a smallpox outbreak until additional personnel can be successfully vaccinated.

Children who have had a definite risk regarding exposure to smallpox (i.e., face-to-face, household, or close-proximity contact with a smallpox patient) should be vaccinated regardless of age.  Pregnant women who have had a definite exposure to smallpox virus (i.e., face-to-face, household, or close-proximity contact with a smallpox patient) and are, therefore, at high-risk for contracting the disease, should also be vaccinated.  Smallpox infection among pregnant women has been reported to result in a more severe infection than among non-pregnant women.  Therefore, the risks to the mother and fetus from experiencing clinical smallpox substantially outweigh any potential risks regarding vaccination.  In addition, vaccinia virus has not been documented to be teratogenic, and the incidence of fetal vaccinia is low.  When the level of exposure risk is undetermined, the decision to vaccinate should be made after assessment by the clinician and patient of the potential risks versus the benefits of smallpox vaccination.

In a post-release setting, vaccination might be initiated also for other groups whose unhindered function is deemed essential to the support of response activities (e.g., selected law enforcement, emergency response, or military personnel) and who are not otherwise engaged in patient care activities but who have a reasonable probability of contact with smallpox patients or infectious materials.  If vaccination of these groups is initiated by public health authorities, only personnel with no contraindications to vaccination should be vaccinated before initiating activities that could lead to contact with suspected smallpox patients or infectious materials.  Steps should be taken (e.g., re-assignment of duties) to prevent contact of any un-vaccinated personnel with infectious smallpox patients or materials.

Because of increased transmission rates that have been described in previous outbreaks of smallpox involving aerosol transmission in hospital settings, potential vaccination of non-direct hospital contacts should be evaluated by public health officials.  Because hospitalized patients might have other contraindications to vaccination (e.g., immunosuppression), vaccination of these non-direct hospital contacts should occur after prudent evaluation of the hospital setting with determination of the exposure potential through the less-common aerosol transmission route.

Vaccinia vaccine should not be used therapeutically for any reason.  No evidence exists that vaccinia vaccine has any value in treating or preventing recurrent herpes simplex infection, warts, or any disease other than those caused by human Orthopoxviruses.  Misuse of vaccinia vaccine to treat herpes infections has been associated with severe complications, including death.

The CDC is the only source of vaccinia vaccine and vaccinia immunoglobulin for civilians.  It will provide vaccinia vaccine to protect laboratory and other health-care personnel whose occupations place them at risk for exposure to vaccinia and other closely related Orthopoxviruses, including vaccinia recombinants.

The American Society for Reproductive Medicine (ASRM) and the Society for Assisted Reproductive Technology (SART) stated that although there is presently no definitive evidence linking vaccinia virus transmission through reproductive cells, they recommended that practitioners of assisted reproductive technology consider deferring donors who have recently received smallpox vaccine or contracted symptomatic vaccinia virus infection through close contact with a vaccine recipient (until after the vaccine or infectious scab has spontaneously separated).  ARSM/SART also stated that good donor practice further suggests that donors who are not in good health, including those with recent complications from smallpox vaccine, should be similarly deferred (2006).

On September 1, 2007, the U.S. Food and Drug Administration (FDA) stated that it has licensed ACAM2000, a new vaccine that can protect against smallpox.  Currently, no FDA-approved treatment for smallpox exists, and the only prevention for the disease is vaccination.  The new vaccine augments the only other licensed smallpox vaccine, Dryvax (approved in 1931), which is in limited supply because it is no longer made.  ACAM2000 is manufactured by means of a pox virus called vaccinia, which is related to but different from the virus that causes smallpox.  The vaccine contains live vaccinia virus and acts by causing a mild infection; thus stimulating an immune response that effectively protects against smallpox without actually causing the disease.  ACAM2000 was studied in 2 populations: (i) individuals who had never been vaccinated for smallpox, and (ii) individuals who had received smallpox vaccination many years earlier.  The percentage of un-vaccinated persons who developed a successful immunization reaction was similar to that of Dryvax.  ACAM2000 also was found to be acceptable as a booster in those previously vaccinated for smallpox.

The National Center for Immunization and Respiratory Diseases (2011) stated that "Because of similar concerns about smallpox vaccine and tuberculin skin test (TST) suppression, a TST should not be performed until 4 weeks after smallpox vaccination .... Breastfeeding is a contraindication for smallpox vaccination of the mother because of the theoretical risk for contact transmission from mother to infant".

The Practice Committees of American Society for Reproductive Medicine and Society for Reproductive Technology (2012) noted that although there is presently no definitive evidence linking vaccinia virus transmission through reproductive cells, SART/ASRM accordingly recommends that ART practitioners consider deferring donors who have recently received smallpox vaccine or contracted symptomatic vaccinia virus infection through close contact with a vaccine recipient (until after the vaccine or infectious scab has spontaneously separated).  Good donor practice further suggested that donors who are not in good health, including those with recent complications from smallpox vaccine, should be similarly deferred.

Elizaga et al (2013) stated that vaccinia-associated myo/pericarditis was observed during the U.S. smallpox vaccination (DryVax) campaign initiated in 2002.  A highly-attenuated vaccinia strain, modified vaccinia Ankara (MVA) has been evaluated in clinical trials as a safer alternative to DryVax and as a vector for recombinant vaccines.  Due to the lack of prospectively collected cardiac safety data, the Food and Drug Administration required cardiac screening and surveillance in all clinical trials of MVA since 2004.  These investigators reported cardiac safety surveillance from 6 phase I trials of MVA vaccines.  Four clinical research organizations contributed cardiac safety data using common surveillance methods in trials administering MVA or recombinant MVA vaccines to healthy participants. “Routine cardiac investigations” (ECGs and cardiac enzymes obtained 2 weeks after injections of MVA or MVA-HIV recombinants, or placebo-controls), and “Symptom-driven cardiac investigations” were reported.  The outcome measure was the number of participants who met the CDC-case definition for vaccinia-related myo/pericarditis or who experienced cardiac adverse events from an MVA vaccine.  A total of 425 study participants had post-vaccination safety data analyzed, 382 received at least 1 MVA-containing vaccine and 43 received placebo; 717 routine ECGs and 930 cardiac troponin assays were performed.  Forty-five MVA recipients (12 %) had additional cardiac testing performed; 22 for cardiac symptoms, 19 for ECG/laboratory changes, and 4 for cardiac symptoms with an ECG/laboratory change.  No participant had evidence of symptomatic or asymptomatic myo/pericarditis meeting the CDC-case definition and judged to be related to an MVA vaccine.  The authors concluded that prospective surveillance of MVA recipients for myo/pericarditis did not detect cardiac adverse reactions in 382 study participants.

 
CPT Codes / HCPCS Codes / ICD-9 Codes
There is no specific code for small pox vaccine:
Other CPT codes related to the CPB:
86580
90749
ICD-9 codes covered if selection criteria are met:
V01.3 Contact with or exposure to smallpox
V04.1 Need for prophylactic vaccination and inoculation against smallpox [pre-exposure - see criteria]
Other ICD-9 codes related to the CPB:
050.0 - 050.9 Smallpox
V24.1 Lactating mother


The above policy is based on the following references:
  1. Centers for Disease Control and Prevention. Vaccinia (smallpox) vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2001;50(RR-10):1-25, CE1-7.
  2. Centers for Disease Control and Prevention (CDC). Use of smallpox (vaccinia) vaccine, June 2002. Supplemental recommendation of the ACIP. Atlanta, GA: CDC; June 2002. Available at: http://www.cdc.gov/nip/smallpox/supp_recs.htm. Accessed June 24, 2002.
  3. Health Canada, National Advisory Committee on Immunization (NACI). Statement on smallpox vaccination. An Advisory Committee Statement (ACS). Can Communicable Dis Rep. 2002;28(ACS-1).
  4. World Health Organization (WHO). WHO Fact Sheet on Smallpox. Communicable Disease Surveillance and Response (CSR). Geneva, Switzerland: WHO, October 2001. Available at: http://www.who.int/emc/diseases/smallpox/factsheet.html. Accessed July 26, 2002.
  5. World Health Organization (WHO). World Health Organization announces updated guidance on smallpox vaccination. Statement to the press by the Director General of the World Health Organization, Dr. Gro Harland Brundtland [press release]. Statement WHO/16. Geneva, Switzerland: WHO; October 2, 2001.  Available at: http://www.who.int/inf-pr-2001/en/state2001-16.html. Accessed July 27, 2002.
  6. National Academy of Sciences, Institute of Medicine, Committee on Smallpox Vaccination Program. Review of the Centers for Disease Control and Prevention's Smallpox Vaccination Program Implementation -- Letter Report #1. Washington, DC: National Academy Press; January 17, 2003. Available at: http://www.nap.edu/catalog/10601.html?onpi_topnews_011703. Accessed February 13, 2003.
  7. Wharton M, Strikas RA, Harpaz R, et al. Recommendations for using smallpox vaccine in a pre-event vaccination program. Supplemental recommendations of the Advisory Committee on Immunization Practices (ACIP) and the Healthcare Infection Control Practices Advisory Committee (HICPAC). MMWR Recomm Rep. 2003;52(RR-7):1-16.
  8. Guharoy R, Panzik R, Noviasky JA, et al. Smallpox: Clinical features, prevention, and management. Ann Pharmacother. 2004;38(3):440-447.
  9. Ein D, Gruchalla R, Baker JR, et al. Pre-event smallpox vaccination and postevent exposure and disease: A report of the Joint Task Force on Smallpox Vaccination for Allergists. Ann Allergy Asthma Immunol. 2005;94(1):4-7.
  10. Aragon TJ, Ulrich S, Fernyak S, Rutherford GW. Risks of serious complications and death from smallpox vaccination: A systematic review of the United States experience, 1963 - 1968. BMC Public Health. 2003;3(26).
  11. Nafziger SD. Smallpox. Crit Care Clin. 2005;21(4):739-746, vii.
  12. Lau CY, Wahl B, Foo WK. Ring vaccination versus mass vaccination in event of a smallpox attack. Hawaii Med J. 2005;64(2):34-36, 53.
  13. Practice Committee of the American Society for Reproductive Medicine; Practice Committee of the Society for Assisted Reproductive Technology. Society for Assisted Reproductive Technology position statement on donor suitability of recipients of smallpox vaccine (vaccinia virus). Fertil Steril. 2006;86(5 Suppl):S73-S74.
  14. U.S. Food and Drug Administration. FDA approves second-generation smallpox vaccine. September 1, 2007. Available at: http://www.fda.gov/bbs/topics/NEWS/2007/NEW01693.html. Accessed September 7, 2007.
  15. Metzger W, Mordmueller BG. Vaccines for preventing smallpox. Cochrane Database Syst Rev. 2007;(3):CD004913.
  16. Greenberg RN, Kennedy JS. ACAM2000: A newly licensed cell culture-based live vaccinia smallpox vaccine. Expert Opin Investig Drugs. 2008;17(4):555-564.
  17. Practice Committee of American Society for Reproductive Medicine; Practice Committee of Society for Assisted Reproductive Technology. Society for Assisted Reproductive Technology position statement on donor suitability of recipients of smallpox vaccine (vaccinia virus). Fertil Steril. 2008;90(5 Suppl):S272-S273.
  18. Frey SE, Newman FK, Kennedy JS, et al. Comparison of the safety and immunogenicity of ACAM1000, ACAM2000 and Dryvax in healthy vaccinia-naive adults. Vaccine. 2009;27(10):1637-1644.
  19. Wilck MB, Seaman MS, Baden LR, et al. Safety and immunogenicity of modified vaccinia Ankara (ACAM3000): Effect of dose and route of administration. J Infect Dis. 2010;201(9):1361-1370.
  20. Wiser I, Orr N, Kaufman B, Segev S, et al. Immunosuppressive treatments reduce long-term immunity to smallpox among patients with breast cancer. J Infect Dis. 2010;201(10):1527-1534.
  21. Nalca A, Zumbrun EE. ACAM2000: The new smallpox vaccine for United States Strategic National Stockpile. Drug Des Devel Ther. 2010;4:71-79.
  22. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Surveill Summ 2011;60(2):1-64.
  23. American College of Emergency Physicians. Guidelines for smallpox vaccination for health care workers. Ann Emerg Med. 2012;59(3):240.
  24. Practice Committees of American Society for Reproductive Medicine and Society for Reproductive Technology. Position on donors and smallpox vaccine: A committee opinion. Fertil Steril. 2012;98(1):e1-e2.
  25. Elizaga ML, Vasan S, Marovich MA, et al. Prospective surveillance for cardiac adverse events in healthy adults receiving modified vaccinia Ankara vaccines: A systematic review. PLoS One. 2013;8(1):e54407.


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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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