Canadian Immunization Guide
Seventh Edition - 2006

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Part 4
Active Immunizing Agents

Yellow Fever Vaccine

Epidemiology Preparations approved for use in Canada Efficacy and immunogenicity Recommended usage Schedule and dosage Route of administration Booster doses and re-immunization

Serologic testing Storage requirements Simultaneous administration with other vaccines Adverse reactions Contraindications and precautions Selected references

Yellow fever (YF) is a zoonotic hemorrhagic fever caused by a flavivirus transmitted by Aedes aegypti mosquitoes. YF evolves though a spectrum of three periods of illness, from a non-specific febrile illness with headache, malaise, weakness, nausea and vomiting, through a brief period of remission, to a hemorrhagic fever with gastroin testinal tract bleeding and hematemesis, jaundice, hemorrhage, cardiovascular instability, albuminuria, oliguria and myocarditis. There is a 20% to 30% case fatality rate.

YF is a quarantinable disease subject to international health regulations. It must be reported to the World Health Organization (WHO) within 24 hours through the Travel Medicine Program of the Public Health Agency of Canada (PHAC). The Program must be contacted immediately in the event of a suspected YF case, at telephone number: (613) 941-6195. After hours, contact the PHAC duty officer on call, at telephone number: 1-800-545-7661.

Key changes since the publication of the 2002 Canadian Immunization Guide include a change in the age at which infants can be immunized, the addition of a contraindication to vaccine for persons with thymus disease and a precaution for immunizing older persons, aged ≥ 60 years. Yellow fever vaccine associated viscerotropic disease (YFV-AVD) and yellow fever vaccine associated neurotropic disease (YFV-AND) are new terms for adverse reactions to immunization previously referred to as post-vaccinal multiple organ system failure and post-vaccinal encephalitis respectively. YFV-AVD is a recently described adverse reaction and clinically resembles YF disease.

Epidemiology

YF is endemic in the tropical areas of equatorial sub-Saharan Africa, Panama in Central America and the tropical region of South America (see Figures 18 and 19). It does not occur in Asia, although the vector, Aedes aegypti, is present there. Many countries have endemic Aedes mosquitoes but do not have the virus. They are able, by means of the international health regulations, to request proof of YF immunization as a requirement of entry.

Worldwide, 90% of YF cases occur in Africa and 10% in the Americas. The disease manifests itself in two epidemiologic forms, the urban and the sylvatic or jungle, both forms caused by the same virus. Urban outbreaks occur as a result of transmission by A. aegypti, which is widely distributed throughout the tropics. Urban disease is a particular problem in Africa and a potential problem in South America. Jungle YF is a disease transmitted by tree-hole breeding mosquitoes (Haemogogus mosquitos) to monkeys in the forests of South America and Africa, and can be transmitted to humans.

A recent resurgence of YF in certain countries prompted the WHO to include YF vaccine routinely within the Expanded Program on Immunization.

Disease control includes protection from Aedes mosquitoes, which are primarily day-biting, elimination of A. aegypti from urban areas and immunization of those at risk of exposure. Unimmunized Canadians can acquire YF when travelling abroad but cannot transmit the disease on their return to Canada, since the recognized mosquito vectors are not present in this country.

Since 1996 there have been reports of YF occurring in American and European travellers visiting YF endemic areas of Africa and South America. Notably, none of these tourists had received YF vaccine. There have been no cases of YF reported to the PHAC since surveillance began in 1924.

Source: WHO. On-line map at http://www.who.int/csr/disease/yellowfev/impact1/en/. Reprinted with permission.

Preparations approved for use in Canada

This chapter will deal only with vaccines that are currently marketed in Canada.

• YF-VAX^®, Sanofi Pasteur Ltd

YF-VAX^®, a live virus vaccine, is prepared in chick embryos from the attenuated 17D strain, is lyophilized and contains sorbitol and gelatin as stabilizers. There is no preservative in the vaccine or the accompanying diluent.

For a list of all approved products in Canada, please refer to Table 1 in the General Considerations chapter.

Efficacy and immunogenicity

Immunity develops 10 days after primary immunization and persists for more than 10 years. More than 90% of persons immunized develop neutralizing antibodies.

Recommended usage

The vaccine is recommended for all travellers ≥ 9 months of age passing through or living in countries in Africa, Central America and South America where YF infection is officially reported or YF immunization is required. It is also recommended for travel outside of urban areas of countries that do not officially report YF but lie in the YF endemic zones (see Figures 18 and 19). Immunization is also recommended for laboratory personnel who work with YF virus.

Pregnant women, immunocompromised people and those aged ≥ 60 years should be considered for immunization only if they are travelling to high-risk areas, if travel cannot be postponed and if a high level of prevention against mosquito exposure is not feasible. Infants < 9 months of age should not be given YF vaccine.

Immunization is required by law upon entry to certain countries irrespective of the traveller's country of origin and in other countries when travellers have passed through endemic areas. In some cases, immunization against YF is recommended, even though not required by law, e.g., if the disease has been reported in the country of destination. In some Asian and other tropical countries where YF does not exist but the transmitting mosquito is present, immunization is required for arrivals from an endemic country to prevent importation of the disease. Current information on the countries for which an International Certificate of Vaccination is required can be obtained from local health departments or from the PHAC Travel Medicine Program through the Internet at http://www.phac-aspc.gc.ca/tmp-pmv/info/yf-fj-eng.php.

Only designated Yellow Fever Vaccination Centre clinics approved by the PHAC carry out YF immunization, which is then recorded on an appropriately validated International Certificate of Vaccination. A list of centres can be obtained from the PHAC's Travel Medicine Program Web site, http://www.travelhealth.gc.ca, or by telephone at: (613) 957-8739. The period of validity of the International Certificate of Vaccination for YF is 10 years, beginning 10 days after primary immunization and immediately after re-immunization.

Travellers requiring the certificate but in whom the YF vaccine is contraindicated (see Contraindications and Precautions) should be provided an exemption from a designated Yellow Fever Vaccination Centre after completion of an individual risk assessment. Health care providers should note that travellers without a valid International Certificate of Vaccination may be denied entry into a country requiring such documentation or reasons for exemption. It is also possible that they may be offered immunization at the point of entry (e.g., at the airport), where immunization practices fall below Canadian standards.

Schedule and dosage

The vaccine is given as a single dose of 0.5 mL of reconstituted vaccine.

Route of administration

The vaccine is administered subcutaneously. Care should be taken to avoid exposure of the vaccine to disinfectants, allowing the skin to dry after antiseptic preparation before YF vaccine is administered.

Booster doses and re-immunization

Re-immunization is recommended every 10 years, if indicated. Re-immunization boosts antibody titre, although evidence from several studies suggests that immunity persists for at least 30 to 35 years after a single dose and probably for life.

Serologic testing

There is no indication for pre- or post-immunization serology.

Storage requirements

The lyophilized preparation should be maintained continuously at +5° to -30° C until reconstituted for use. Given that it is difficult to guarantee refrigerated temperatures between 1° C and 5° C, YF vaccine is most commonly stored in the frozen state in Canada. Once thawed, do not refreeze vaccine. The diluent (sodium chloride injection - contains no preservative) should not be allowed to freeze. Any unused reconstituted vaccine must be discarded 1 hour after reconstitution.

Simultaneous administration with other vaccines

Concurrent administration of other live vaccines does not inhibit the serologic response to YF vaccine. If live vaccines are not given concurrently, they should be spaced at least 4 weeks apart. Inactivated vaccines may be given concurrently or at any interval after YF vaccine.

Adverse reactions

Overall, the vaccine has proved to be very safe and effective. Local reactions have been reported after administration, and 2% to 5% of vaccinees have mild headache, myalgia, low-grade fever or other minor symptoms 5 to 10 days after immunization. Less than 0.2% of vaccinees curtail regular activities. Immediate hypersensitivity reactions, characterized by rash, urticaria and reactive airways, are rare (estimated incidence of 1/130,000 to 1/250,000) and occur principally in people with a history of egg or other allergies. Recently, gelatin stabilizers have been implicated as a cause of allergic reactions in other vaccines.

In 2001, a syndrome of fever and multisystem organ failure was first described in recipients of YF vaccine and is now referred to as vaccine associated neurotropic disease (YFV-AND). All affected persons have required care in an intensive care unit, and the associated mortality rate is estimated to be between 70% and 80%. YFV-AND has previously been reported in young infants but has now also been reported in older adults. The risk of YFV-AND increases with age: the rate is estimated to be 1.1 per 100,000 doses in persons ≥ 60 years and 3.2 per 100,000 doses in those ≥ 70 years. From data collected through a passive surveillance system for adverse events following immunization in the United States, the reporting rate of any serious adverse event following YF immunization was higher among those ≥ 60 years than younger adults (4.2 per 100,000 doses compared with 0.7 per 100,000 doses, respectively). For YFV-AND specifically, the rate was 1.6 per 100,000 doses in persons ≥ 60 years.

Other serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association.

Contraindications and precautions

Allergy to any vaccine component or previous anaphylactic reaction to the YF vaccine is a contraindication to immunization. Because YF vaccine is prepared from chick embryos, it should not be given to individuals with known anaphylactic hypersensitivity to hens' eggs, manifested as urticaria, swelling of the mouth and throat, difficulty breathing or hypotension. A referral to an allergist should be made for those with a questionable history of egg hypersensitivity who are at high risk of exposure to the YF virus. Persons who have an anaphylactic allergic reaction to chicken or gelatin should not receive YF vaccine or should first be evaluated by an allergist to determine whether they can safely receive it.

Recent evidence suggests that persons with thymus disease, including thymoma, thymectomy or myasthenia gravis, are at increased risk of adverse outcomes and should not be immunized with YF vaccine.

Use in infants and seniors

Infants < 9 months of age are more susceptible to serious adverse reactions (encephalitis) to YF vaccine than older children. The risk of this complication appears to be age related and, for this reason, YF vaccine should not be given to infants < 9 months of age. YF vaccine should be used with caution in persons ≥ 60 years of age.

Use in pregnant women and nursing mothers

As the effects of YF vaccine in pregnancy are not well documented, it should not be administered to pregnant women if possible. If a pregnant woman must travel to an endemic area, however, the risk of disease far outweighs the potential risk to the mother or fetus. Historically, many pregnant women have received YF vaccine without significant adverse events. One small study demonstrated that the vaccine virus can infect the developing fetus, but the potential risk of adverse events associated with congenital infection is unknown. Inadvertent immunization of women in pregnancy is not an indication for termination of pregnancy. Seroconversion rates for pregnant women who are immunized have been shown to be lower.

There is a theoretical risk of transmission of the live virus in breast milk, therefore, vaccination of nursing mothers should also be avoided. If travel to an endemic area is required then vaccination with YF vaccine is a lesser risk than that of acquiring the disease.

Use in immunocompromised persons

Generally, YF vaccine should not be given to immunosuppressed individuals. When the primary reason for vaccination is a local vaccine requirement rather than significant risk, a waiver letter should be provided. Immunocompromised travelers should be made aware of the risk of visiting areas of active YF transmission. Travellers thought to have a mild to moderate degree of immunosuppression, e.g., HIV infection with CD4 count > 200 cells/mm³, who will be at risk of acquiring YF, for example travelling to an area of documented recent activity, should be offered the vaccine and advised of the theoretical risks. WHO advises withholding YF vaccine in children with symptomatic HIV infection. For more information on the use of live virus vaccines in immunocompromised travellers, please refer to the chapter on Immunization of Immunocompromised Persons.

On the basis of the recent reports of adverse events in older travellers, already discussed, immunization in those ≥ 60 years of age should be carried out only after an individual risk assessment.

Selected references

Barnett ED, Chen R. Children and international travel: immunizations. Pediatric Infectious Disease Journal 1995;14(11):982-92.

Barwick Eidex R, for the Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever vaccination. Lancet 2004;364(9438):936.

Centers for Disease Control and Prevention. Fatal yellow fever in a traveler returning from Venezuela, 1999. Morbidity and Mortality Weekly Report 2000;49(14):303-5.

Centers for Disease Control and Prevention. Fever, jaundice and multiple organ system failure associated with 17D-derived yellow fever vaccination, 1996-2001. Morbidity and Mortality Weekly Report 2001;50(30):643-45.

Centers for Disease Control and Prevention. Health information for international travel 2005-2006. U.S. Department of Health and Human Services, 2005:308-24.

Choudri Y, Walop W. Review of adverse events reported following use of yellow fever vaccine - Canada, 1987-2000. Canada Communicable Disease Report 2002;28(2):9-15.

Keystone JS, Kozarsky PE, Freedman DO et al. Travel medicine. Elsevier, 2004.

Khromava AY, Barwick Eidex R, Weld LH et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005;23(25):3256-63.

Lawrence GL, Burgess MA, Kass RB. Age-related risk of adverse events following yellow fever vaccination in Australia. Communicable Diseases Intelligence 2004;28(2):244-48.

Marfin AA, Barwick Eidex RS, Kozarsky PE et al. Yellow fever and Japanese encephalitis vaccines: indications and complications. Infectious Disease Clinics of North America. 2005;19(1):151-68.

Martin M, Tsai TF, Cropp B et al. Fever and multisystem organ failure associated with 17D204 yellow fever vaccination: a report of four cases. Lancet 2001;358(9276):98-104.

McFarland JM, Baddour LM, Nelson JE et al. Imported yellow fever in a United States citizen. Clinical Infectious Diseases 1997; 25(5):1143-47.

Monath TP. Yellow fever. In: Plotkin SA, Orenstein WA, eds. Vaccine, 4^th edition. Philadelphia, Pennsylvania: WB Saunders, 1095-1176.

Struchiner CJ, Luz PM, Dourado I et al. Risk of fatal adverse events associated with 17DD yellow fever vaccine. Epidemiology and Infection 2004;132(5):939-46.

Tsai TF, Paul R, Lynberg MC et al. Congenital yellow fever virus infection after immunization in pregnancy. Journal of Infectious Diseases 1993;168(6):1520-23.

World Health Organization. International travel and health: vaccination requirements and health advice. Geneva: World Health Organization, 2005.

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