Vaccine-Preventable Diseases

Yellow Fever

Yellow fever (YF) is a zoonotic hemorrhagic fever caused by an arbovirus spread by Aedes aegypti mosquitoes. YF evolves though a spectrum of three periods of illness, from a nonspecific febrile illness with headache, malaise, weakness, nausea and vomiting, through a brief period of remission, to a hemorrhagic fever with gastrointestinal tract bleeding and hematemesis, jaundice, hemorrhage, cardiovascular instability, albuminuria, oliguria and myocarditis. There is a 50% case fatality rate.

YF is a quarantinable disease subject to international health regulations. It must be reported to the WHO within 24 hours through Health Canada's Division of Quarantine, Travel and Migration Health. The Division must be contacted immediately in the event of a suspected YF case (telephone 613-954-3236). After hours, contact the medical officer on call, at 613-545-7661.

Epidemiology

Yellow fever is endemic in the tropical areas of equatorial subSaharan Africa and tropical South America between latitudes 15 degrees north and 10 degrees south (see maps 1 and 2). It does not occur in Asia, although the vector Aedes aegypti is present. 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 Aedes 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 of monkeys in the forests of South America and Africa; the virus that causes it is transmitted by forest Aedes mosquitoes to humans, such as forestry or oil company employees.

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 the day-biting Aedes mosquitoes, 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 Health Canada since surveillance began in 1924.

Preparations Licensed For Immunization

A live YF vaccine (YF-VAX^®), produced by Aventis Pasteur, is licensed in Canada. It 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.

Efficacy and Immunogenicity

Immunity develops 10 days after primary immunization and persists for more than 10 years.

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 Maps 1 and 2). Immunization is also recommended for laboratory personnel who work with YF virus.

Infants 4 to 9 months of age, pregnant women, immunocompromised people and those over the age of 65 years should be considered for immunization only if they are travelling to high-risk areas, travel cannot be postponed and a high level of prevention against mosquito exposure is not feasible. Infants < 4 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 Health Canada's Travel Medicine Program through the Internet (http://www.travelhealth.gc.ca).

Only Yellow Fever Vaccination Centre clinics approved by Health Canada carry out immunization, which is then recorded on an appropriately validated International Certificate of Vaccination. A list of Centres can be obtained from the Travel Medicine Program at Health Canada (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., airport), where immunization practices fall below Canadian standards.

Route of Administration

Subcutaneous injection.

Booster Doses

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

Serologic Testing

Not required or recommended.

Storage Requirements

The lyophilized preparation should be stored in a freezer at the temperature specified by the manufacturer until it is reconstituted by the addition of the diluent (sterile, physiologic saline) supplied. The diluent 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, including live oral cholera and live oral typhoid 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. An exception is the inactivated parenteral cholera vaccine (no longer used in Canada), which should be given separately from YF vaccine by 3 or more weeks to avoid interference with antibody responses.

The administration of immune globulin and YF vaccine either simultaneously or within a short span of time does not alter the immunologic response, because immune globulin is unlikely to contain antibody to YF virus.

Although chloroquine inhibits replication of YF virus in vitro, it does not adversely affect antibody responses to the vaccine in humans receiving chloroquine for antimalarial prophylaxis.

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/or asthma, are uncommon (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 the U.S. there have been two cases of encephalitis temporally associated with immunization (out of 34 million doses distributed). In one of these cases, which was fatal, the 17D virus was isolated from the brain.

Worldwide from 1996 to 2001, there have been seven cases of sepsis-like syndrome temporally associated with 17D YF vaccine administration, an adverse event not previously reported. Of those seven, four were U.S. citizens (aged 63, 67, 76 and 79 years) and one an Australian citizen (aged 53 years), all of whom became ill 3 to 4 days after receiving 17D 204 vaccine. Two Brazilian citizens (aged 5 and 22 years) became ill 3 to 4 days after receiving 17DD vaccine (note that this is a different vaccine from the one used in Canada, the U.S. or Australia). All these individuals experienced severe illness requiring intensive medical care; their sepsis-like syndrome included fever, hypotension, renal failure, elevated hepatocellular enzymes, hyperbilirubinemia, lymphocytopenia and thrombocytopenia. Six of them (85.7%) died. An estimate of the reported incidence of sepsis-like syndrome in the U.S. was 2.5/1,000,000 and in Brazil was 1/11,500,000. At the time of these adverse events there was no formal adverse event reporting system in Brazil. In four of the cases vaccine strain virus was isolated from tissues other than blood, including cerebrospinal fluid, heart, brain, liver, kidney or spleen.

The conclusion reached after expert consultation was that the live attenuated YF vaccine must be considered as a possible cause of the sepsis-like syndrome in these cases. Studies are in progress to better define the cause and risk factors for these rare adverse events temporally associated with two subtypes of the 17D YF vaccine.

In Canada, vaccine-associated adverse events are reported by health care providers through a passive voluntary system. Health Canada reviewed all adverse events reported after use of YF vaccine in Canada between 1987 and 2000. There were 159 reports of adverse events, either alone (67 cases) or in combination with other vaccines (92 cases). Of these, 61.8% occurred in females, and 65.6% were between the ages of 20 and 49 years (mean 37.3 years). The most frequent adverse events reported were local reaction or pain in the arm and shoulder (54.3%), systemic symptoms such as allergic reaction (32.1%), and fever (27%). In most cases the adverse events were mild and self-limiting, although 43 (27%) of the patients had consulted their doctor and 12 (7.6%) were hospitalized.

Outcome data were unavailable in 51 (32.1%) of these reports. Of those with outcome data, 102/108 (94.4%) had fully recovered and 6/108 (5.6%) had residual damage at the time of reporting. Most of the cases were healthy, although 26 (16.4%) noted a history of allergies. A recent review in the U.S. of adverse events passively reported to the Vaccine Adverse Event Reporting System between 1990 and 1998 suggested that people aged ≥ 65 years may be more at risk of systemic adverse events after YF immunization than younger people.

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. If immunization of an individual with a questionable history of egg hypersensitivity is considered essential because of a high risk of exposure, an intradermal test dose (as per the package insert) may be administered under close medical supervision. As well, a graded challenge can be considered, as outlined on page 13 of the Canadian Immunization Guide.

Infants < 4 months of age should not be given YF vaccine because of the risk of encephalitis.

Pediatric use

Infants < 4 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. Whenever possible, immunization should be delayed until 9 months of age. For children 4 to 9 months old, immunization should be avoided unless there is a significant risk of exposure to an ongoing epidemic of YF.

Use in pregnant women and nursing mothers

Animal reproductive studies have not been conducted with YF vaccine. The use of the vaccine in pregnant women should be avoided unless clearly indicated by the risk of acquiring natural infection. 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 therapeutic abortion.

YF virus is not excreted in breast milk following immunization, and there is no contraindication to immunizing breast-feeding mothers with YF vaccine.

Use in immunocompromised hosts

Infection with the vaccine virus poses a theoretical risk to patients with immunosuppression due to HIV infection/AIDS, leukemia, lymphoma or generalized malignancy, or to those whose immunologic responses are suppressed by corticosteroids, alkylating drugs, antimetabolites or radiation. Therefore, the vaccine should be used with caution in immunosuppressed individuals. An individual risk assessment should be carried out, weighing the true risk of disease and the degree to which the person is immunocompromised before proceeding with immunization.

When a certificate of YF vaccination is required but this vaccine is contraindicated, the traveller should be provided an exemption from a designated Yellow Fever Vaccination Centre. For more information on the use of live virus vaccines in immunocompromised travellers, please refer to Part 6 of the Canadian Immunization Guide.

On the basis of the recent reports of adverse events in older travellers, already discussed, immunization in those over the age of 65 should be carried out only after an individual risk assessment.

Summary of Recommendations

• YF vaccine is recommended for travellers ≥ 9 months of age passing through or living in countries in Africa, Central America and South America where the 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 Maps 1 and 2).

• Immunization is also recommended for laboratory personnel who work with YF virus.

• YF vaccine should not be administered to children < 4 months of age because of the risk of encephalitis.

• YF vaccine should not routinely be administered to children aged 4 to 9 months, to travellers > 65 years of age, or to those who are immunocompromised. An individual risk assessment is required before the vaccine is given to these individuals.

• Travellers requiring an International Certificate of Vaccination in whom the YF vaccine is contraindicated should be provided with an exemption from a designated Yellow Fever Vaccination Centre.

Selected References

Barnett ED, Chen R. Children and international travel: immunizations. Pediatr Infect Dis J 1995;14:982-92.

CDC. Fever, jaundice and multiple organ system failure associated with 17D-derived yellow fever vaccination, 1996-2000. MMWR 2001;50(30):643-5.

CDC. Fatal yellow fever in a traveler returning from Venezuela, 1999. MMWR 2000;49(14):303-5.

Choudri Y, Walop W. Review of adverse events reported following use of yellow fever vaccine - Canada, 1987-2000. CCDR 2002;28:9-15.

Coursaget P, Fritzell B, Blondeau C et al. Simultaneous injection of plasma derived or recombinant hepatitis B vaccines with yellow fever and killed polio vaccines. Vaccine 1995;13:109-11.

Döller C. Vaccination of adults against travel-related infections, diseases, and new developments in vaccines. Infection 1993;21:7-23.

Kollavitsch H, Que JU, Wiedermann X et al. Safety and immunogenicity of live oral cholera and typhoid vaccines administered alone or in combination with antimalaria drugs, oral polio vaccine and yellow fever vaccines. J Infect Dis 1997;175:871-75.

McFarland JM, Baddour LM, Nelson JE et al. Imported yellow fever in a United States citizen. Clin Infect Dis 1997; 25:1143-47.

Monthan TP. Yellow fever. In: Plotkin SA, Orenstein WA, eds. Vaccine.3^rd edition. Philadelphia, Pennsylvania: WB Saunders, 1999:815-879.

Teichmann D, Grobusch MP, Wesselmann H et al. A haemorrhagic fever from Côte d'Ivoire. Lancet 1999;354(9190):1608.

Tsai TF, Paul R, Lynberg MC et al. Congenital yellow fever virus infection after immunization in pregnancy. J Infect Dis 1993;163:15220-23.

WHO. International travel and health: vaccination requirements and health advice. Geneva: World Health Organization, 2000.