Since the publication of 2006 Canadian Immunization Guide:
For further information, refer to the Committee to Advise on Tropical Medicine and Travel (CATMAT) Statement for Travellers and Yellow Fever.
Yellow fever (YF) is caused by a ribonucleic acid (RNA) virus from the family Flaviviridae.
Humans and non-human primates
YF virus is transmitted to humans through the bite of an infected mosquito, primarily Aedes or Haemogogus species. The incubation period is 3 to 6 days. Humans infected with YF virus experience the highest levels of viremia and are infectious to mosquitoes shortly before the onset of fever and for 3 to 5 days afterwards. Because of the high level of viremia in humans, bloodborne transmission of YF virus can occur through transfusion of blood products, intravenous drug use and needlestick injuries. Probable transmission of vaccine strain YF virus from a mother to her infant through breastfeeding has been reported. Vaccine-associated viremia occurs 4 to 10 days after primary YF vaccination and lasts for up to 5 days. Sustained transmission is not possible in Canada because the recognized mosquito vectors are not present.
A traveller’s risk for acquiring YF is determined by multiple factors including: immunization status, use of personal protection measures against mosquito bites, location of travel, duration of exposure, activities while travelling, and local rate of virus transmission. The risk for acquiring YF is low for most travellers, particularly those staying in highly developed major urban areas. Greater risk exists for travellers who:
For example, risk is greater for travellers who stay in a rural area of an endemic country for over two weeks, whereas risk is low for travellers staying in an urban area in a transitional country for one week.
In West Africa and South America, YF virus transmission is usually associated with the mid-to-late rainy season when the number of mosquitoes generally increases. However, YF virus can be transmitted during the dry season.
Spectrum of clinical illness
Clinical presentation of YF varies in severity from asymptomatic to fatal. When symptomatic, YF is typically characterized by an acute onset of symptoms including fever, chills, headache, backache, muscle pain, joint pain, nausea, vomiting, photophobia, mild jaundice, and epigastric pain. In about 85% of YF cases, the disease resolves when the acute symptoms subside. For others, after a brief remission lasting anywhere between hours to a day, symptoms worsen and the disease advances, eventually leading to renal failure, haemorrhagic symptoms, and thrombocytopenia. Treatment is symptomatic and supportive.
The World Health Organization (WHO) estimates that approximately 200,000 YF cases occur annually, with up to 30,000 deaths. YF is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America. In South America, transmission of YF virus occurs mainly in forest areas rather than in urban areas. In Africa, the majority of outbreaks have been reported from West Africa. The mosquito vectors are present in Asia; however, there have been no documented cases of transmission.
Since 1970, there have been nine cases of YF reported in unvaccinated international travellers from the United States and Europe who visited YF endemic areas of Africa and South America. Eight of the nine travellers died. One case of YF has been documented in a vaccinated traveller.
The risk of YF varies widely within areas of transmission. One mathematical model suggested that for an unimmunized person taking a two week trip to an area of epidemic YF activity the risk of becoming ill from YF could be as high as 1:267 and the risk of death from YF could be as high as1:1,333. Although the actual risk for most travelers is probably less, it is very hard to quantify. It is for this reason that revised guidelines were required in order to make it easier for health care providers to give advice and care to travellers.
YF is unique among diseases in that there are international health regulations which outline the requirements for proof of vaccination when travelling to specific areas. In 2011, the WHO published revised recommendations for YF vaccination for international travellers, in consultation with international travel medicine experts. The revisions include:
Central and South America
Designation of regions with risk of YF transmission is subject to change. Some countries require yellow fever vaccination if traveling from or transiting through a country with risk of YF transmission. View a complete listing of country-specific requirements available from the CDC or the WHO (PDF Document)
To date, there have been no cases of YF reported in Canada. YF is a nationally and internationally notifiable disease; therefore, cases diagnosed in Canada must be urgently reported through local public health officials.
Yellow fever outbreaks are reported in the WHO Disease Outbreak News available at: Global Alert and Response (GAR)
In Canada, YF vaccine is only available at Yellow Fever Vaccination Centres designated by the Public Health Agency of Canada (PHAC). A list of Yellow Fever Vaccination Centres in Canada can be obtained from the Public Health Agency of Canada or telephone at: (613) 957-8739 or email to: firstname.lastname@example.org
For complete prescribing information, consult the product leaflet or information contained within Health Canada’s authorized product monographs available through the Drug Product Database. Refer to Table 1 in General Considerations in Part 1 for a list of all vaccines available for use in Canada and their contents.
Efficacy studies of YF vaccine have not been performed; however, unpublished reports comparing YF incidence among vaccinated and unvaccinated populations during a 1986 epidemic in Nigeria estimated vaccine effectiveness to be approximately 85%.
More than 80% of persons immunized with YF vaccine develop neutralizing antibodies 10 days after vaccination and more than 99% by 28 days after vaccination. Immunity persists for more than 10 years.
YF vaccine is recommended for healthy children 9 months of age and older travelling to areas where YF is considered endemic or transitional (refer to Table 1).
YF vaccine is contraindicated in infants less than 6 months of age because of an increased risk of post-vaccination encephalitis; travel to YF endemic or transitional countries should be discouraged for children less than 6 months of age. If travel to an YF endemic or transitional country is unavoidable, the need for protection from mosquitoes at all times should be emphasized.
In children 6 to 8 months of age YF vaccination is generally not recommended due to continued increased risk of adverse events and decreased immunogenicity. Whenever possible, infants aged 6 to 8 months should not travel to countries where YF is transmitted. If travel is unavoidable, the decision to vaccinate needs to balance the risk of YF exposure with the risks of vaccination. Although the risk of serious adverse neurologic events is less than that of infants less than six months of age, it is still higher than that of infants 9 months and older. At 9 months of age, the risk of serious adverse events becomes much lower and antibody response improves, thus improving the safety and efficacy profiles of the YF vaccine.
If an infant receives YF vaccine at 6 to 8 months of age, and subsequently travels after 9 months of age, serology should be done (if available), and a booster dose considered. Personal protective measures should be emphasized.
YF vaccine is recommended for laboratory personnel who work with YF virus and for healthy adult travellers less than 60 years of age travelling to areas where YF is considered endemic or transitional (refer to Table 1).
Persons 60 years of age and older should be considered for primary YF vaccination only if travel to areas where YF is considered endemic or transitional cannot be avoided and a high level of protection against mosquito exposure is not feasible. Serious adverse reactions in older vaccinees have only occurred in primary vaccinations. Booster doses of YF vaccine may be given to people over 60 years of age. Refer to Other reported adverse events and conditions for additional information.
In general, YF vaccine, like other live viral vaccines, should be avoided in pregnancy. Pregnant or lactating women should be considered for YF immunization only if they are travelling to endemic or transitional areas, travel cannot be postponed, and a high level of protection against mosquito exposure is not feasible. While the effects of YF vaccine in pregnancy are not well documented, many pregnant women have received the vaccine without significant adverse events. In one study of women exposed to YF vaccine early in pregnancy there was slight increased risk noted for minor malformations (mainly skin) in the babies; no increased risk of major malformations was found. Inadvertent immunization of women in pregnancy is not an indication for termination of pregnancy.
Seroconversion rates are lower in pregnant women who are immunized, especially in the third trimester. Antibody titres should be checked post-immunization to ensure appropriate immune response in women who remain at risk for YF. If serology is not available and a woman is travelling to an endemic country after completion of her pregnancy, revaccination prior to travel should be considered.
If pregnant women must travel to a country that requires documentation for YF but is not endemic or transitional, a waiver or Certificate of Medical Contraindication to Vaccination should be provided. Refer to Travellers for additional information.
Probable transmission of vaccine strain of YF virus from a mother to her infant through breastfeeding has been reported; therefore, in general, lactating mothers should not be vaccinated. Refer to Contraindications and Precautions for additional information. Refer to Immunization in Pregnancy and Lactation in Part 3 for additional general information.
In general, immunocompromised persons should not receive YF vaccine because of the risk of disease caused by the vaccine strain. When considering immunization of an immunocompromised person, approval from the individual’s attending physician should be obtained before vaccination. For complex cases, referral to a physician with expertise in immunization and/or immunodeficiency is advised.
For the immune suppressed traveller, the potential risks associated with administering the YF vaccine should be weighed against the potential benefits. Where there is a country-specific vaccine requirement but the risks associated with vaccine administration outweigh the medical benefits, a Certificate of Medical Contraindication to Vaccination should be provided. Travellers thought to have mild to moderate degrees of immune suppression who will be at significant risk for acquiring YF (e.g., travel to an area of endemic or transitional transmission risk), should be offered YF vaccine and advised of the theoretical risks. Profoundly immune suppressed travellers who, in spite of being informed of the risks, plan a trip to an area of active YF risk, should obtain advice from a travel medicine expert and should rigorously adhere to mosquito protection measures.
YF vaccine is contraindicated in people with leukemia, lymphoma, thymoma, and generalized malignancies.
Hematopoietic stem cell transplantation (HSCT- autologous
HSCT recipients may receive YF vaccine if clearly indicated, if the recipient is at least 24 months post-transplant, has not received immunosuppressive medications for at least three months, and has no active graft versus host disease for the past three months. Persons should be considered immunocompetent by their HSCT specialist.
Solid organ transplantation
Solid organ transplant recipients should not receive YF vaccine at any time after transplantation.
YF vaccine is contraindicated for persons whose immunologic response is either suppressed or modulated by current or recent radiation therapies or drugs (e.g., high-dose systemic corticosteroids [2 mg/kg per day for a child or 20 mg/day or more of prednisone or its equivalent for an adult] for 14 days or more; chemotherapy; radiation therapy; azathioprine; cyclosporine; cyclophosphamide; infliximab).
If indicated, YF vaccine should be administered at least 4 weeks before the initiation of immunosuppressive therapy. If this cannot be done, a period of at least 3 months should elapse after immunosuppressive drugs (except high-dose systemic corticosteroids) have been stopped before administration of live vaccines. A period of at least 4 weeks should elapse between discontinuation of high-dose systemic steroids and the administration of live vaccines.
Corticosteroid therapy is not a contraindication to administering a live vaccine when steroid therapy is short-term (i.e., less than 14 days); or a low-to-moderate dose (less than 2 mg/kg/day for a child or less than 20 mg/day of prednisone or its equivalent for an adult); or long-term, alternate-day treatment with short-acting preparations; or maintenance physiologic replacement therapy; or administered topically, inhaled, or locally injected (e.g., joint injection).
A specialist in HIV infection should be consulted for advice on YF immunization in HIV-infected people. YF vaccine may be considered for people who have asymptomatic HIV infection and who are not severely immunosuppressed (i.e., CD4 count greater than 200 x 106/L) but vaccination should take place well in advance of travel in order to monitor potential adverse events, and antibody titres should be considered to assess efficacy of the vaccination. Persons with HIV respond suboptimally to YF vaccine with lower antibody titres, more often demonstrate non-protective titres, and may experience a more rapid decline in antibody titres following vaccination. Booster doses may be required.
Refer to Booster doses and re-immunization, Serologic testing, and Contraindications and Precautions for additional information. Refer to Immunization of Immunocompromised Persons in Part 3 for additional general information.
Hyposplenism or asplenia
Persons with hyposplenism or asplenia (congenital absence, surgical removal or functional [e.g., sickle cell disease]) may receive YF vaccine, if indicated.
Chronic renal disease/dialysis
Persons with chronic renal disease or undergoing dialysis may receive YF vaccine, if indicated.
Although definitive data are lacking, individuals with autoimmune disease not being treated with immunosuppressive drugs are not considered significantly immunocompromised and may receive YF immunization following consultation with a physician. Rheumatic disease modifying agents such as hydroxychloroquine, sulfasalazine, or auranofin are not considered immunosuppressive.
The safety and efficacy of live vaccines during low dose intermittent or maintenance therapy with immunosuppressive drugs (other than corticosteroids) for autoimmune disease is unknown. These drugs include therapeutic monoclonal antibodies, especially the anti-tumour necrosis factor agents adalimumab, infliximab, and etanercept and others (azathioprine, methotrexate, leflunomide, and abetacept). These have been reported to cause reactivation of latent tuberculosis infection and predisposition to other opportunistic infections. Therefore, until additional information becomes available, avoidance of live vaccines during intermittent or low dose chemotherapy or other immunosuppressive therapy is prudent.
There is an association between YF vaccine-associated viscerotropic disease (YEL-AVD) and a history of thymus disease. Therefore, YF vaccine is not generally recommended for persons with a history of thymoma, thymectomy or myasthenia gravis. Refer to Other reported adverse events and conditions for additional information.
YF vaccine is recommended for healthy travellers (9 months to less than 60 years of age) passing through, visiting or living in areas where YF is considered endemic or transitional (refer to Table 1) or if YF immunization is required to enter the country (refer to Table 1 and Table 2).
Transit times of 12 hours or less in an international airport poses very low risk for YF virus transmission irrespective of the YF risk classification of the country in which the airport is located. Thus, such a transit typically does not warrant vaccination. Recent updates in international health agreements suggest that travellers fitting this strict criteria are not required to be vaccinated. This includes those travellers transiting to a country with an entry requirement for YF vaccination but no history of endemic disease. Defining specific entry requirements is under the control of each individual country. Some countries will not allow entry without proper documentation of vaccination or certificate of medical contraindication. Travellers without proper documentation may be denied entry or subjected to vaccination at the airport. This should be considered during review of itineraries and pre-travel counseling. If there is concern that lack of documentation will put the traveller at risk, yet vaccination is not medically indicated, then providing a medical certificate of contraindication may be considered. Unfortunately, some countries may deny entry despite proper documentation of medical contraindication to vaccination.
YF vaccination is generally not recommended in areas where there is low potential for YF virus exposure (refer to Table 2). However, vaccination might be considered for a small subset of travellers to these areas who are at increased risk of exposure to mosquitoes because of prolonged travel, heavy exposure to mosquitoes, or inability to avoid mosquito bites. Vaccination is not recommended for travellers whose itineraries are restricted to areas with no risk.
The decision to immunize a traveller against YF should take into account the traveller’s itinerary and the associated risk for exposure to YF virus, the requirements of the country to be visited (including stopovers and airport transit), individual risk factors (e.g., age, immune status), and the potential for serious adverse events following vaccination. Vaccine providers should check either the CDC or WHO website for an updated list of countries considered endemic or transitional for YF and/or requiring YF vaccination for entry.
Under the WHO’s International Health Regulations, YF immunization (documented by an International Certificate of Vaccination or Prophylaxis) is required to enter certain countries in Africa and South America regardless of the traveller’s country of origin. Other countries require YF vaccination of travellers if the traveller has passed through endemic areas. In some Asian and tropical countries where YF disease does not exist but the transmitting mosquito is present, immunization is required for travellers arriving from an endemic country to prevent importation of the disease. Some countries do not require YF vaccination of infants younger than a certain age (e.g., less than 1 year).
The International Certificate of Vaccination or Prophylaxis is valid for 10 years, beginning 10 days after primary immunization and immediately after re-immunization, if re-immunized within the 10 year period. Travellers requiring the certificate but in whom the YF vaccine is medically contraindicated (refer to Contraindications and Precautions) can be provided with an International Certificate of Medical Contraindication to Vaccination by the Yellow Fever Vaccination Centre following an individual risk assessment. Travellers without a valid International Certificate of Vaccination or Prophylaxis or a Certificate of Medical Contraindication to Vaccination may be denied entry into a country requiring such documentation, quarantined, or offered immunization at the point of entry (e.g., at the airport), potentially putting the health of traveller at risk.
In Canada, only Yellow Fever Vaccination Centre clinics designated by PHAC can provide the International Certificate of Vaccination or Prophylaxis or International Certificate of Medical Contraindication to Vaccination. A list of Yellow Fever Vaccination Centres can be obtained from Public Health Agency of Canada (PHAC) or telephone at: (613) 957-8739 or email to: email@example.com
Additional and updated information regarding countries with risk of yellow fever transmission and requirements for YF vaccination is available from local public health officials, PHAC or the WHO:
Refer to Immunization of Travellers in Part 3 for additional general information.
Laboratory personnel who work with YF virus should receive YF vaccine. Refer to Immunization of Workers in Part 3 for additional general information.
Each dose is 0.5 mL.
YF vaccine should be administered subcutaneously. Refer to Vaccine Administration Practices in Part 1 for additional information.
One dose of YF vaccine should be administered.
Re-immunization is recommended every 10 years for immunocompetent individuals, 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. If vaccine is appropriate for an immunocompromised person, serologic testing and revaccination (if indicated based on serology results) should be considered two to five years post-immunization.
Serologic testing is not recommended for non-pregnant healthy persons before or after receiving YF vaccine. For immunocompromised persons, serologic testing should be considered two to five years post-immunization. For women vaccinated during pregnancy, antibody titres should be checked post-immunization to ensure appropriate immune response in those who remain at risk for YF. An antibody titre of greater than 1:10 indicates immunity.
Store YF vaccine in a refrigerator at +2°C to +8°C. Do not freeze. Refrigerate the reconstituted vaccine and use within 1 hour following reconstitution. Refer to Storage and Handling of Immunizing Agents in Part 1 for additional general information.
YF vaccine may be administered concomitantly with the following vaccines: measles, mumps, rubella, polio, diphtheria, tetanus, pertussis, hepatitis B, hepatitis A, oral cholera, and oral or parenteral typhoid. Different injection sites and separate needles and syringes must be used for concomitant parenteral injections. If not given concurrently, a minimal interval of 4 weeks is recommended between administration of YF vaccine and other live parenteral vaccines. Oral typhoid or oral cholera vaccine can be administered at any interval before or after YF vaccine. There are no data available regarding possible interference between YF vaccine and rabies, human papillomavirus, Japanese encephalitis, live attenuated influenza, or varicella vaccines. Refer to Timing of Vaccine Administration in Part 1 for additional general information.
Refer to Vaccine Safety Part 2 for additional general information.
In a comparative study, 71.9% of subjects vaccinated with YF vaccine reported one or more non-serious adverse events assessed as related to vaccination. Injection site reactions were reported by 5.7% to 39.4% of subjects (pain at the injection site 39.4%; inflammation 29.4%; edema 19.9% and other injection site reaction 5.7%). Systemic reactions were reported by 10.1% to 31.4% (chills 10.1%; fever 14.0%; weakness 29.5%; headache 31.4%; myalgia 25.1% and malaise 17.8%) of subjects up to 10 days post vaccination.
Serious adverse events are rare following immunization and, in most cases, data are insufficient to determine a causal association. Hypersensitivity reactions including rash, urticaria, asthma and anaphylaxis are very rare, with observations over the past decades of an incidence of less than 1 per million. However, reporting rates to the United States Vaccine Adverse Event Reporting System based on two reviews 10 years apart were higher: 0.8 per 100,000 doses distributed in the earlier study and 1.8 in the more recent study. The primary risk factor appears to be gelatin and egg protein sensitivity.
Two additional serious adverse events, YF vaccine associated neurotropic disease (YEL-AND) and YF vaccine associated viscerotropic disease (YEL-AVD), are described below.
YF vaccine-associated neurotropic disease (YEL-AND)
YEL-AND is a group of clinical syndromes that includes meningoencephalitis (neurotropic disease), acute disseminated encephalomyelitis, Guillain Barré syndrome, and acute bulbar palsy. Neurotropic disease occurs as a result of YF vaccine virus invasion of the central nervous system (CNS). The other syndromes are autoimmune manifestations in which antibodies and/or T-cells produced in response to the vaccine cross-react with neuronal epitopes leading to CNS or peripheral nerve damage. The clinical course is typically brief with generally complete recovery. Fatality is rare. YEL-AND can present in any age group, between 4 and 23 days post vaccination (typically 7 to 21 days) and is seen almost exclusively in primary vaccine recipients. Children less than six months of age and older persons are at greater risk for YEL-AND. The US CDC reports an incidence of YEL-AND of 0.8 per 100,000 doses administered. The rate is double for those 60 to 69 years of age (1.6 per 100,000 doses) and almost 4 times higher in those over 70 years of age (2.3 per 100,000 doses). When infants and elderly are not given the vaccine, recent surveillance data suggest population-based incidence rates drop close to zero.
YF vaccine-associated viscerotropic disease (YEL-AVD)
YEL-AVD is characterized by severe illness and multi-organ failure. It resembles wild-type YF infection with onset within 2 to 5 days of vaccination. The risk of YEL-AVD increases with age. Incidence is estimated to be 1.0-1.1 per 100,000 for those 60-69 years of age; 2.3-3.2 per 100,000 for those over 70 years of age; and 0.1 per 100,000 for those less than 60 years of age. The case fatality rate is 65% overall and is higher in women than men (90% vs. 50%). YEL-AVD is seen almost exclusively in primary vaccine recipients. Extensive investigations of cases suggest that YEL-AVD is linked to various host factors including older age, and thymus disease (thymoma, myasthenia gravis, thymectomy), and is not associated with a change in virulence of the vaccine virus.
Vaccine providers are asked to report the following AEFI in particular, through local public health officials:
Refer to Box 1 in Vaccine Safety in Part 2 and Reporting Adverse Events Following Immunization (AEFI) in Canada for additional information about AEFI reporting.
YF vaccine is contraindicated in persons with history of anaphylaxis after previous administration of the vaccine and in persons with proven immediate or anaphylactic hypersensitivity to any component of the vaccine or its container. Refer to Table 1 in General Considerations in Part 1 for a list of all vaccines available for use in Canada and their contents. For YF-VAX® vaccine, potential allergens include chick protein, egg protein, gelatin, and latex in the stopper of diluent vial.
Individuals requiring YF immunization who have suspected hypersensitivity or non-anaphylactic allergy to vaccine components, should be referred to an allergist for evaluation.
In general, infants under the age of 9 months should not be vaccinated against YF. Infants less than six months of age are at greater risk for YEL-AND following YF vaccination and should not receive YF vaccine. However, the Advisory Committee on Immunization Practices (ACIP) in the United States recommends that for infants 6 to 8 months of age travelling to an endemic or transitional area, when travel is unavoidable, the decision to vaccinate needs to balance the risks of YF virus exposure with the risk for adverse events following vaccination.
Persons 60 years of age and older
Persons 60 years of age and older are at greater risk for YEL-AND and YEL-AVD following primary YF vaccination; therefore, primary YF vaccination is not generally recommended. Booster doses may be given.
Pregnancy and lactation
The effects of live YF vaccine in pregnancy are not well documented and vaccination should be avoided if possible. If a pregnant woman must travel to a highly endemic or epidemic area, the risk of actually contracting the disease may outweigh the risks of vaccination to the mother and fetus.
Probable transmission of vaccine strain of YF virus from a mother to her infant through breastfeeding has been reported; therefore, in general, lactating mothers should not be vaccinated. Until recently, there was only a theoretical risk of transmission of the live virus in breast milk and no cases reported despite many breastfeeding women having been immunized during emergency vaccination campaigns. Two recent cases have documented the possibility of transmission through breast milk. A case in Brazil demonstrated laboratory confirmed evidence of yellow fever virus transmission in breast milk. In Canada, there was a case of yellow fever in an infant who had been breast fed by a recently vaccinated mother, which was highly suggestive of breast milk transfer. These two cases should raise the level of caution when considering vaccinating women who are actively breastfeeding. If there is no risk of acquiring yellow fever in the region to be visited, a waiver of vaccination should be given. If travel is to a highly endemic area, then the risks of vaccination should be weighed against the risk of disease.
In general, YF vaccine should not be given to immunosuppressed individuals. Refer to Immunocompromised persons.
There is an association between YEL-AVD and a history of thymus disease; therefore, YF vaccine is not generally recommended for persons with a history of thymoma, thymectomy or myasthenia gravis.
Administration of YF vaccine should be postponed in persons with moderate or severe acute illness. Persons with minor acute illness (with or without fever) may be vaccinated.
Refer to General Contraindications and Precautions in Part 2 for additional general information.
The effect of YF vaccine on tuberculin reactivity is unknown. Until data are available, if tuberculin skin testing or an Interferon Gamma Release Assay (IGRA) is required, it should be done on the same day as immunization or delayed for at least 4 weeks after YF vaccination. Vaccination with YF vaccine may take place at any time after tuberculin skin testing has been performed and/or read.
Persons who receive YF vaccines in countries other than the US and Canada should be considered protected against YF. Refer to Principles of Vaccine Interchangeability in Part 1 for additional general information.