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Clinical Policy Bulletin:
Vaccines for Travel
Number: 0473


Policy

Notes: Most Aetna HMO plans exclude coverage of vaccines for travel.  Most Aetna traditional plans cover medically necessary travel vaccines for members of plans with preventive services benefits.  Please check benefit plan descriptions.

The following table lists vaccines that may be required for travel, and their medically necessary indications, standard administration schedule, and contraindications:

Vaccine Standard Schedule Indications Precautions and Contraindications
Cholera

Primary: 0.5 ml intramuscularly or subcutaneously, or 0.2 ml intradermally, 2 doses 1 week to 1 month apart at least 6 days before travel.

Booster: 0.5 ml intramuscularly or subcutaneously or 0.2 ml intradermally every 6 months.

Travel to endemic areas. No longer required under international health regulations. Safety in pregnancy unknown; previous severe local or systemic reaction.

Meningococcal polysaccharide (see CPB 0356 - Meningococcal Vaccine)

Primary: 1 dose (0.5 ml) subcutaneously or intramuscularly.

Booster: not recommended

Travel to areas with epidemic meningococcal disease. Safety in pregnancy unknown.
Typhoid, inactivated bacteria

Primary: 2 doses (0.5 ml) subcutaneously given 4 or more weeks apart.

Booster: 0.5 ml subcutaneously or 0.1 ml intradermally, every 3 years.

Risk of exposure to typhoid fever. Previous severe local or systemic reaction.
Typhoid, attenuated live bacteria Primary: 4 oral doses; re-immunize every 5 years. Risk of exposure to typhoid fever. Immuno-compromised host ; enteric illness; concurrent antimicrobial treatment.
Oral polio (see CPB 0402 - Polio Vaccine)

Childhood dose: injectable vaccine is preferred; 4 doses administered before school entry, at 2, 4 and 6 to 18 months and 4 to 6 years.

Adult dose: 1 oral dose.

One-time booster for previously immunized persons; complete the series in partially immunized adults; alternative to inactivated vaccine when there is less than 1 month before travel exposure; not used for primary immunization in persons 18 years old or older. Immuno-compromised host or immuno-compromised contacts or recipients.
Yellow fever

Primary: 1 dose (0.5 ml) subcutaneously, 10 days to 10 years before travel.

Booster: every 10 years.

As requested by individual countries. Avoid in pregnant women, unless engaged in high-risk travel; immuno-compromised host; hypersensitivity to eggs.
Hepatitis B (see CPB 0410 - Hepatitis B Vaccine)

Primary: 2 doses (10 mg/dose) intramuscularly in deltoid, 1 month apart; third dose 5 months after second.

Booster: not routinely recommended.

For health care workers* in contact with blood; persons residing for more than 6 months in areas of high endemnicity of hepatitis B surface antigen; others at risk. Safety to fetus is unknown; pregnancy not a contraindication in high-risk persons.
Hepatitis A (see CPB 0048 - Hepatitis A Vaccine)

Primary: 2 doses, 0 and 6 to 12 months.

Booster: The need for periodic booster doses has not been established.

Men who have sex with men; IV drug users; certain populations (e.g., Pacific Islander, Native Americans, and Alaska Native Populations); institutionalized persons and workers in these institutions*; travelers to endemic countries.  
Inactivated polio (see CPB 0402 - Polio Vaccine)

Childhood dose: 4 doses administered before school entry, at 2, 4 and 6 to 18 months and 4 to 6 years.

Adult primary dose: 2 doses (0.5 ml) subcutaneously, 4 to 8 weeks apart; third dose 6 to 12

Preferred for primary immunization; one-time booster dose for travelers. Safety in pregnancy unknown; anaphylactic reactions to streptomycin and neomycin.
Japanese B encephalitis Primary: 3 doses (1.0 ml) subcutaneously on days 0, 7, and 30 or at weekly intervals. Travel to areas of risk with rural exposure or prolonged residence. Pregnancy; allergy to mice or rodents; immuno-compromised host.
Rabies (human diploid-cell vaccine)

Pre-exposure: 1 ml intramuscularly in deltoid on days 0, 7, and 21 or 28; or 0.1 ml intradermally, on days 0, 7, and 21 or 28.

Booster: every 2 years or when antibody titer falls below acceptable level.

For persons at high-risk of rabies exposure including international travelers who are likely to come in contact with animals in areas where dog rabies is enzootic. Allergy to previous doses; may be given in pregnancy if indicated; intradermal route should be completed 30 days or more before travel; intradermal route should not be used with concurrent chloroquine administration.
Lyme vaccine (LYMErix)††

Primary: 3 doses, 30 mg/0.5 ml, with the second dose 1 month after the first, and the third dose given at 1 year.

Booster: The need for periodic booster doses has not been established.

Age 15 to 70 and live, work,* or travel or take part in regular recreational activities that make them likely to come into contact with infected deer ticks. Hypersensitivity to vaccine; safety in pregnancy unknown; not tested in pediatric patients less than 15 years of age.

Persons who are immunocompromised because of immune deficiency diseases, leukemia, lymphoma, generalized cancer, or the acquired immunodeficiency syndrome, or who are receiving immunosuppressive therapy with corticosteroids, alkylating agents, anti-metabolites, or radiation.

†† LYMErix was withdrawn from the U.S. market in February 2002.

* Most Aetna benefit plans exclude coverage of vaccines for work.  Please check benefit plan descriptions.

Note: Many of these vaccines may also be considered medically necessary for reasons other than travel, and may be covered when medically necessary in members with preventive benefits, regardless of whether the plan excludes coverage of travel vaccines.

Note: Malaria vaccine for travel is considered experimental and investigational because an effective malaria vaccine has yet to be developed.

Note: The Advisory Committee on Immunization Practices (1996) states that plague vaccination is not indicated for most travelers to countries in which cases of plague have been reported.

Note: Oral or skin-patch cholera vaccine for prevention of entero-toxigenic Escherichia coli diarrhea is considered experimental and investigational because their clinical value has not been established.


Background

The Centers for Disease Control and Prevention (CDC)'s recommended vaccinations for travelers can be found at the following website: http://wwwn.cdc.gov/travel/contentVaccinations.aspx.

In a Cochrane review on vaccines for preventing malaria, Graves and Gelband (2006a) concluded that there is no evidence for protection by SPf66 vaccines against P. falciparum in Africa.  There is a modest reduction in attacks of P. falciparum malaria following vaccination with SPf66 in South America.  There is no justification for further trials of SPf66 in its current formulation.  Further research with SPf66 vaccines in South America or with new formulations of SPf66 may be justified.

In another Cochrane review, Graves and Gelband (2006b) concluded that the MSP/RESA (Combination B) vaccine shows promise as a way to reduce the severity of malaria episodes, but the effect of the vaccine is MSP2 variant-specific.  Pre-treatment for malaria during a vaccine trial makes the results difficult to interpret, particularly with the relatively small sample sizes of early trials.  The results show that blood-stage vaccines may play a role and merit further development.

Vaughan et al (2009) presented a comprehensive meta-analysis of more than 500 references, describing nearly 5,000 unique B cell and T cell epitopes derived from the Plasmodium genus, and detailing thousands of immunological assays.  This was the first inventory of epitope data related to malaria-specific immunology, plasmodial pathogenesis, and vaccine performance.  The survey included host and pathogen species distribution of epitopes, the number of antibody versus CD4(+) and CD8(+) T cell epitopes, the genomic distribution of recognized epitopes, variance among epitopes from different parasite strains, and the characterization of protective epitopes and of epitopes associated with parasite evasion of the host immune response.  The results identified knowledge gaps and areas for further investigation.  This information has relevance to issues, such as the identification of epitopes and antigens associated with protective immunity, the design and development of candidate malaria vaccines, and characterization of immune response to strain polymorphisms.

Currently, there is an ongoing phase III clinical trial of a candidate vaccine for malaria, but the study has not been completed (Birkett, 2010).

The Advisory Committee on Immunization Practices (ACIP) of the CDC provided the following recommendations regarding the prevention of plague (1996):

  • Routine plague vaccination is not necessary for individuals living in areas in which plague is enzootic.
  • Plague vaccination is not indicated for hospital staff or other medical personnel in such areas.
  • Plague vaccination is not indicated for most travelers to countries in which cases of plague have been reported.

In a Cochrane review, Ahmed et al (2013) evaluated the safety, effectiveness, and immunogenicity of vaccines for preventing entero-toxigenic Escherichia coli (ETEC) diarrhea.  These investigators searched the Cochrane Infectious Disease Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, and http://clinicaltrials.gov up to December 2012.  Randomized controlled trials (RCTs) and quasi-RCTs comparing use of vaccines to prevent ETEC with use of no intervention, a control vaccine (either an inert vaccine or a vaccine normally given to prevent an unrelated infection), an alternative ETEC vaccine, or a different dose or schedule of the same ETEC vaccine in healthy adults and children living in endemic regions, intending to travel to endemic regions, or volunteering to receive an artificial challenge of ETEC bacteria were included for analysis.  Two authors independently assessed each trial for eligibility and risk of bias.  Two independent reviewers extracted data from the included studies and analyzed the data using Review Manager (RevMan) software.  They reported outcomes as risk ratios (RR) with 95 % confidence intervals (CI) and assessed the quality of the evidence using the GRADE approach.  A total of 24 RCTs, including 53,247 participants, met the inclusion criteria -- 4 studies assessed the protective efficacy of oral cholera vaccines when used to prevent diarrhea due to ETEC and 7 studies assessed the protective efficacy of ETEC-specific vaccines.  Of these 11 studies, 7 studies presented efficacy data from field trials and 4 studies presented efficacy data from artificial challenge studies.  An additional 13 trials contributed safety and immunological data only.  The currently available, oral cholera killed whole cell vaccine (Dukoral®) was evaluated for protection of people against “travelers' diarrhea” in a single RCT in people arriving in Mexico from the USA.  These researchers did not identify any statistically significant effects on ETEC diarrhea or all-cause diarrhea (1 trial, 502 participants; low-quality evidence).  Two earlier trials, one undertaken in an endemic population in Bangladesh and one undertaken in people travelling from Finland to Morocco, evaluated a precursor of this vaccine containing purified cholera toxin B subunit rather than the recombinant subunit in Dukoral®.  Short-term protective efficacy against ETEC diarrhea was demonstrated, lasting for around 3 months (RR 0.43, 95 % CI: 0.26 to 0.71; 2 trials, 50,227 participants).  This vaccine is no longer available.  An ETEC-specific, killed whole cell vaccine, which also contains the recombinant cholera toxin B-subunit, was evaluated in people traveling from the USA to Mexico or Guatemala, and from Austria to Latin America, Africa, or Asia.  These investigators did not identify any statistically significant differences in ETEC-specific diarrhea or all-cause diarrhea (2 trials, 799 participants), and the vaccine was associated with increased vomiting (RR 2.0, 95 % CI: 1.16 to 3.45; 9 trials, 1,528 participants).  The other ETEC-specific vaccines in development have not yet demonstrated clinically important benefits.  The authors concluded that there is currently insufficient evidence from RCTs to support the use of the oral cholera vaccine Dukoral® for protecting travelers against ETEC diarrhea.  Moreover, they stated that further research is needed to develop safe and effective vaccines to provide both short- and long-term protection against ETEC diarrhea.

Also, an UpToDate review on “Travelers' diarrhea” (Wanke, 2014) states that “Use of vaccines to protect against travelers’ diarrhea is hindered by the varied pathogens that can cause it.  Although enterotoxigenic E. coli (ETEC) predominates as an etiology of travelers’ diarrhea, vaccination strategies that have focused on this pathogen as a target have been suboptimal.  Although vaccination to protect against cholera is not routinely recommended for travelers, a number of trials suggest that the oral, killed whole-cell vaccine given with the nontoxic B subunit of cholera toxin (Dukoral) provides protection for travelers against ETEC infection.  The rationale for such protection is that the B subunit of cholera is antigenically similar to the heat-labile enterotoxin of ETEC.  In two randomized trials, the killed whole-cell vaccine combined with the B subunit of cholera toxin reduced the incidence of diarrhea caused by ETEC by 67 percent in a trial in Bangladesh and 52 percent among travelers to Morocco.  The Dukoral vaccine was approved in the United States in late 2006 for use as a travelers' diarrhea vaccine.  However, a conservative estimate that took into account the incidence of ETEC infection throughout the world and the efficacy of the vaccine suggested that it may prevent ≤7 percent of travelers' diarrhea cases.  The 2006 guidelines on travel medicine from the Infectious Diseases Society of America concluded that the decision to use the vaccine to prevent travelers' diarrhea must balance its cost, adverse effects, and limited utility against the known effectiveness and costs of self-treatment as described above.  A separate vaccination strategy for ETEC also appears to have limited utility.  Despite initial promising data on vaccination with heat-labile enterotoxin from ETEC via a skin patch, it was not effective in decreasing the incidence of moderate to severe diarrhea due to either ETEC or any cause in a randomized, placebo controlled trial that included 1,644 individuals who traveled to Mexico or Guatemala.  In a subgroup analysis, the vaccine provided modest protection against ETEC that produced only heat-labile enterotoxin (vaccine efficacy 61 percent [95 % CI, 7 to 84 percent]), but not ETEC that produced heat-stable toxin or both.  This highlights the limitations of a single-antigen vaccine for travelers’ diarrhea”.

 
CPT Codes/ HCPCS Codes / ICD-9 Codes
CPT codes covered if selection criteria are met:
90632
90633
90634
90636
90675
90676
90690
90691
90692
90712
90713
90717
90725
90733
90734
90735
90738
90740
90743
90744
90746
90747
90748
Other CPT codes related to the CPB:
90460
+90461
90471
+ 90472
90473
+ 90474
90644
90727
HCPCS codes covered if selection criteria are met:
G0010 Administration of hepatitis B vaccine
ICD-9 codes covered if selection criteria are met:
V03.0 Need for prophylactic vaccination and inoculation against cholera alone
V03.1 Need for prophylactic vaccination and inoculation against typhoid-paratyphoid alone [TAB]
V04.0 Need for prophylactic vaccination and inoculation against bacterial diseases, poliomyelitis
V04.4 Need for prophylactic vaccination and inoculation against yellow fever
V04.5 Need for prophylactic vaccination and inoculation against rabies
V04.89 Need for prophylactic vaccination and inoculation against other viral diseases
V05.0 Need for prophylactic vaccination and inoculation against arthropod-borne viral encephalitis
V05.3 Need for prophylactic vaccination and inoculation against viral hepatitis
V06.0 Need for prophylactic vaccination and inoculation against cholera with typhoid-paratyphoid [cholera+TAB]
V06.2 Need for prophylactic vaccination and inoculation against diphtheria-tetanus-pertussis, with typhoid-paratyphoid [DTP+TAB]
V06.3 Need for prophylactic vaccination and inoculation against combinations of diseases, diphtheria-tetanus-pertussis with poliomyelitis [DTP-polio]
Other ICD-9 codes related to the CPB:
001.0 - 001.9 Cholera
002.0 Typhoid and paratyphoid
008.02 Intestinal infection due to enterotoxigenic E. coli
042 Human immunodeficiency virus [HIV] disease
045.0 - 045.9 Acute poliomyelitis
060.0 - 060.9 Yellow fever
062.0 Japanese encephalitis
070.0 - 070.1 Viral hepatitis A
070.20 - 070.23, 070.30 - 070.33 Viral hepatitis B
071 Rabies
088.81 Lyme disease
140.0 - 208.91 Malignant neoplasm
279.00 - 279.09 Disorders involving the immune mechanism
V08 Asymptomatic human immunodeficiency virus [HIV] infection status
V58.0 Encounter for radiotherapy
V58.69 Long-term (current) use of other medications


The above policy is based on the following references:
  1. Centers for Disease Control and Prevention (CDC). Recommendations for the use of Lyme disease vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1999;48(RR-7):1-17, 21-25.
  2. Centers for Disease Control and Prevention (CDC). Update: Recommendations to prevent hepatitis B virus transmission -- United States. MMWR Morbid Mortal Wkly Rep. 1995:44(30):574-575.
  3. Centers for Disease Control and Prevention (CDC). Update: Recommendations to prevent hepatitis B virus transmission -- United States. MMWR Morbid Mortal Wkly Rep. 1999;48(2):33-34.
  4. Centers for Disease Control and Prevention (CDC). Prevention of hepatitis A through active or passive immunization: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep. 1999;48(RR-12):1-37.
  5. Centers for Disease Control and Prevention (CDC). Prevention and control of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep. 2000;49(RR-7):1-10.
  6. Centers for Disease Control and Prevention (CDC). Recommendations of the Advisory Committee on Immunization Practices: Revised recommendations for routine poliomyelitis vaccination. MMWR Morbid Mortal Wkly Rep. 1999;48(27):590.
  7. Centers for Disease Control (CDC). Rabies prevention -- United States, 1984. MMWR Morbid Mortal Wkly Rep. 1984;33(28):393-402, 407-408.
  8. No authors listed. Cholera vaccine. MMWR Morbid Mortal Wkly Rep. 1988;37(40):617-618, 623-624.
  9. Centers for Disease Control and Prevention (CDC). Typhoid immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morbid Mortal Wkly Rep. 1990;39(RR-10):1-5.
  10. Cetron MS, Marfin AA, Julian KG, et al. Yellow fever vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2002. MMWR Morbid Mortal Wkly Rep. 2002;51(RR-17):1-11.
  11. Centers for Disease Control and Prevention (CDC). Inactivated Japanese encephalitis virus vaccine. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1993;42(RR-1):1-15.
  12. Marfin AA, Eidex RS, Kozarsky PE, Cetron MS. Yellow fever and Japanese encephalitis vaccines: Indications and complications. Infect Dis Clin North Am. 2005;19(1):151-168, ix.
  13. Wilder-Smith A. Meningococcal disease in international travel: Vaccine strategies. J Travel Med. 2005;12 Suppl 1:S22-S29.
  14. Arguin PM, Kozarsky PE, Reed C, eds. CDC Health Information for International Travel, 2008. St. Louis, MO: Mosby; 2007. Available at: http://wwwn.cdc.gov/travel/contentYellowBook.aspx. Accessed July 16, 2007.
  15. Graves PM, Deeks JJ, Demicheli V, Jefferson T. Vaccines for preventing cholera: Killed whole cell or other subunit vaccines (injected). Cochrane Database Syst Rev. 2001;(1):CD000974.
  16. Fraser A, Goldberg E, Acosta CJ, et al. Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. 2007;(3):CD001261.
  17. Schiøler KL, Samuel M, Wai KL Vaccines for preventing Japanese encephalitis. Cochrane Database Syst Rev. 2007;(3):CD004263.
  18. Carroll ID, Williams DC. Pre-travel vaccination and medical prophylaxis in the pregnant traveler. Travel Med Infect Dis. 2008;6(5):259-275.
  19. Ritz N, Connell TG, Curtis N. To BCG or not to BCG? Preventing travel-associated tuberculosis in children. Vaccine. 2008;26(47):5905-5910.
  20. Graves P, Gelband H. Vaccines for preventing malaria (SPf66). Cochrane Database Syst Rev. 2006a;(2):CD005966.
  21. Graves P, Gelband H. Vaccines for preventing malaria (blood-state). Cochrane Database Syst Rev. 2006b;(4):CD006199.
  22. Vaughan K, Blythe M, Greenbaum J, et al. Meta-analysis of immune epitope data for all Plasmodia: Overview and applications for malarial immunobiology and vaccine-related issues. Parasite Immunol. 2009;31(2):78-97.
  23. Jelinek T. Ixiaro: A new vaccine against Japanese encephalitis. Expert Rev Vaccines. 2009;8(11):1501-1511.
  24. Fischer M, Lindsey N, Staples JE, Hills S; Centers for Disease Control and Prevention (CDC). Japanese encephalitis vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-1):1-27.
  25. Birkett A. MVI discusses what's on the horizon for malaria vaccine development. Bethesda, MD: The PATH Malaria Vaccine Initiative; 2010. Available at: http://www.malariavaccine.org/RD_Strategy_QA.php. Accessed April 30, 2010.
  26. Gautret P, Wilder-Smith A. Vaccination against tetanus, diphtheria, pertussis and poliomyelitis in adult travellers. Travel Med Infect Dis. 2010;8(3):155-160.
  27. Staples JE, Gershman M, Fischer M; Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010;59(RR-7):1-27.
  28. Centers for Disease Control and Prevention (CDC). The Yellow Book. CDC Health Information for International Travel 2012. New York, NY: Oxford University Press; 2011.
  29. Centers for Disease Control and Prevention. Prevention of plague: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 1996;45(No. RR-14). Available at: ftp://ftp.cdc.gov/pub/Publications/mmwr/rr/rr4514.pdf. Accessed April 26, 2012.
  30. American Academy of Pediatrics Committee on Infectious Diseases. Poliovirus. Pediatrics. 2011;128(4):805-808.
  31. Ahmed T, Bhuiyan TR, Zaman K, et al. Vaccines for preventing enterotoxigenic Escherichia coli (ETEC) diarrhoea. Cochrane Database Syst Rev. 2013;7:CD009029.
  32. Wanke CA. Travelers' diarrhea. Last reviewed march 2014. UpToDate Inc., Waltham, MA.


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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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