Yellow fever is a vaccine-preventable, vector-borne illness caused by a virus from the family Flaviviridae. In its most severe form, it causes a hemorrhagic fever which has a high case fatality rate despite aggressive supportive measures. Yellow fever virus is the prototype of the flavivirus genus, made up of approximately 70 other viruses, including dengue fever virus, Japanese encephalitis virus, and West Nile virus, to name a few (1)(2)(3).
The World Health Organization (WHO) estimates that approximately 200,000 yellow fever cases occur per year, resulting in up to 30,000 deaths. The disease is presently endemic and intermittently epidemic in South America and Africa (1;4). Historically, yellow fever has been an important pathogen. Much of the early research into the disease was prompted by the outbreaks during the building of the Panama Canal and the Spanish-American War. However, yellow fever epidemics plagued North America into the early part of the 20 th century. Aggressive vector control measures and eventually vaccination eliminated urban transmission in North America and Europe (5).
Vaccination of susceptible populations has dramatically decreased infection in human populations. Because yellow fever virus is spread by a mosquito vector, mosquito control and personal protective measures against mosquito bites are also an important part of preventing yellow fever infection, and are used in tandem with vaccination to lessen the impact of disease in endemic areas (1;6-9).
Yellow fever is endemic and intermittently epidemic in parts of Africa and South America. While the mosquito vectors are present in Asia, there have been no documented cases of transmission on this continent. There are three transmission cycles which describe the occurrence of yellow fever: Nine cases of yellow fever were reported in unvaccinated international travellers from the United States and Europe between 1970 to 2010. Four of these cases were acquired in South America (Brazil = 3, Venezula = 1), and five were acquired in Africa (Senegal = 2, Ivory Coast = 1, the Gambia = 1, West Africa = 1) (7;11-15). In 1987, there was one reported case of yellow fever in a vaccinated traveller from Spain who had travelled in western Africa. To date, there have not been any diagnosed yellow fever cases in returned Canadian travellers (16).
As yellow fever is maintained within a non-human primate host population (as demonstrated by the jungle transmission cycle), eradication of the disease is impossible. It also makes global monitoring of the disease difficult (2;11). Concerns have also been expressed in recent years that environmental, geographical, and human-driven changes may factor into the distribution of yellow fever: changing rainfall patterns affect mosquito populations and locations, growing deforestation increases human proximity to natural yellow fever hosts (i.e. primates) and may increase number of sylvatic and/or intermediate outbreaks. Increased urbanization may allow for more concentrated human epidemics, and increased international travel and trade creates the theoretical possibility of importation or exportation of the disease (11;17-19).
In 2011, the WHO published revised yellow fever vaccination recommendations for travellers, as a result of consultations with international travel medicine experts and a comprehensive review of available data (20;21). The revisions included:
- Updated criteria for the designation of areas with risk of yellow fever virus activity. The classification of geographical areas, according to risk of transmission of yellow fever, was outlined in four categories: (i) endemic, (ii) transitional, (iii) low potential for exposure, and (iv) no risk. For definitions for each category, refer to Appendix 1a.
- Countries and geographic areas with a risk of yellow fever transmission were reassessed with the new criteria, and vaccine recommendations were made based on the level of risk.
- Yellow fever vaccination is recommended for travellers visiting endemic or transitional areas.
- Yellow fever vaccination is generally not recommended for travel to areas with low potential for exposure; however, vaccination may be considered for a small subset of travellers whose itineraries would place them at an increased risk for exposure to yellow fever virus (e.g., prolonged travel, heavy exposure to mosquitoes, inability to avoid mosquito bites).
- Yellow fever vaccination is not recommended for travellers whose itineraries are restricted to areas with no risk.
- Revision of maps to illustrate yellow fever vaccination recommendations rather than yellow fever risk. For maps, refer to Appendix 1c and Appendix 1d.

# Disease Characteristics
The clinical presentation of the disease varies in severity from asymptomatic to fatal. For those who present with symptoms, yellow fever is typically characterized by an acute onset after an incubation period of three to six days. Initial symptoms include fever, chills, headache, backache, muscle pain, joint pain, nausea, vomiting, photophobia, mild jaundice, and epigastric pain. Faget's sign may be present (slow weak pulse, contrasting with high fever). Jaundice worsens as disease progresses (3;4). In an estimated 85% of yellow fever cases, the disease resolves itself at this time (7). For others, after a brief remission lasting anywhere between hours to a day, conditions worsen and the disease advances in the liver eventually leading to renal failure, haemorrhagic symptoms, and thrombocytopenia. Treatment is symptomatic and supportive (3;4;7).
In travellers, clinical features and patient history (travel dates, locations, and activities) usually inform the initial diagnosis (7). Diagnosis is confirmed in both travellers and non-travellers by the isolation of virus from blood by inoculation of special media (1). Techniques identifying antigen or nucleic acid components using enzyme linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) tests are also used (22;23). Serological cross reaction may occur with other flaviviruses, and should be considered during diagnosis (3). Also, virus is sometimes difficult to isolate after the fourth day of illness (7). All yellow fever diagnoses made in Canada are required to be reported to public health authorities, as yellow fever is both a notifiable disease in Canada, and internationally, as defined by the 2005 International Health Regulations (IHR) (19).

# Risk to Travellers
Estimating the risk of acquiring yellow fever in the individual traveller is very difficult, as it is dependent on many variables including destination, season, occupational and recreational activity, and local yellow fever virus activity (11;20;21).
A traveller's destination factors into yellow fever risk in many ways. Yellow fever is unique amongst communicable diseases in that it has international regulations that govern its control (See Preventive Measures). These are set out by the World Health Organization in the form of International Health Regulations (IHR) last updated in 2005. Some countries require travellers to be vaccinated against yellow fever to enter the country, as outlined in the IHR. IHR requirements also stipulate that proof of vaccination is necessary for travellers arriving from or through a country where yellow fever is endemic. Some countries where yellow fever circulates do not require vaccination for entrance (e.g. Brazil) and therefore unvaccinated travellers may be at greater risk, especially if visiting a yellow fever risk area.
The number of mosquitoes generally increases during and following a "wet season" (2). Vertical transmission occurs with the yellow fever virus from female mosquito to her larvae (2;5). This can increase the risk for travellers as more vectors may be present to transmit disease.

# Occupational and recreational activity:
Activities which expose travellers to the outdoors during prime mosquito biting hours can increase risk of yellow fever transmission (24).

# Local yellow fever virus activity:
Yellow fever virus activity fluctuates. As surveillance infrastructure is poor in many countries where yellow fever is found, and difficulties are inherent in closely monitoring non-human hosts, this variable is particularly difficult to quantify (11;17;18). There have been sporadic outbreaks in the last few years in Africa and South America (6;9;10;25;26).
These risks should all be taken into consideration by travellers and travel health practitioners during pre-travel consultation to determine the need for yellow fever vaccination. As with many aspects of travel medicine, a clinical decision requires up-to-date epidemiologic data to make informed choices.
The careful examination of risk is important when dealing with those populations in which there is a higher risk of adverse events with vaccination (See section on Vaccine and Special Populations). When counselling these patients, accurate information as to travel itinerary, activity within the area of risk and up-to-date yellow fever epidemiology is required. This information is used to weigh the risks and benefits to determine the need for vaccination on a case by case basis.

# Preventive Measures

# International Health Regulations and yellow fever control measures
Yellow fever is unique among diseases in that there are international health regulations which outline the requirements for proof of vaccination when travelling to specific countries, or when entering some countries from a yellow fever endemic region (19). As stated by the WHO in International Travel and Health (27), there are two main objectives to yellow fever vaccination:
- To prevent the international spread of the disease by protecting countries from the risk of importing or spreading the yellow fever virus. These are mandatory requirements established by the country.
- To protect individual travellers who may be exposed to yellow fever infection.
For this reason, the traveller may present to a health care professional with a request for yellow fever vaccination from a travel agency or tour provider without specifics as to why the vaccine is required. A proper risk assessment needs to be carried out as to the actual itinerary of the traveller (see section on Risk to Travellers) to determine whether the need is for actual traveller protection or to correspond with the entry requirements of the destination country.
Global control measures have been very successful in eliminating the risk of yellow fever in many areas. However, many regions (e.g. Southeast Asia) have both the mosquito vector and non-human primates that are required to support a possible yellow fever outbreak. It is for this reason that a number of countries require proof of yellow fever vaccination as an entry requirement, despite no reported disease within their territory (refer to Appendix 1) (7). These requirements are generally for those travellers arriving from, or who have travelled through, regions with known yellow fever transmission. A recent update from WHO (27) recommends that a transit of less than 12 hours through an international airport would not put a traveller at risk for contraction of yellow fever. Thus, if the only travel to a region of transmission of yellow fever is such a transit, then it really should not be considered an actual exposure by subsequent destination countries. These recommendations have been published by WHO, but it is the right of each country to define its entry requirements. Travellers should confirm carefully prior to departure.

# Yellow fever vaccination in Canada

# Yellow fever vaccine
The yellow fever vaccine is a live attenuated preparation grown in chick embryos inoculated with the 17D yellow fever virus strain. Worldwide, vaccine lineages include the 17D-204, 17-213 and the 17DD types (1). In Canada, there is only one yellow fever vaccine approved for use: the 17D-204 lineages, marketed as YF-VAX, produced by Sanofi Pasteur Limited (30). YF-VAX is lyophilized and contains sorbitol and gelatin as stabilizers. There is no preservative in the vaccine or the accompanying diluent (30).
According to Sanofi Pasteur, the vaccine must be maintained at temperatures between two and eight degrees Celcius (2-8 C) (30). This requires closely monitored refrigeration to ensure that the vaccine maintains viability. The vaccine should not be allowed to freeze, nor should the diluent (30). Once reconstituted, the vaccine should be refrigerated and used within one hour. All vaccine not used within the one hour window should be discarded (30).
The yellow fever vaccine may be simultaneously administered with the following vaccines: measles, polio (oral polio vaccine), diphtheria, tetanus, pertussis, hepatitis B, hepatitis A, oral cholera, and oral or parenteral typhoid. Different syringes are to be used and the vaccines are to be injected at different sites on the body. When not given simultaneously, live vaccines should be administered at least four weeks prior to or after the yellow fever vaccination. This recommendation is based on the assumption that interferon released in response to the first vaccine may have a temporary inhibitory effect on other live virus vaccines (1).

# Risks associated with vaccination
In the last few years, a number of rare, but serious reactions to yellow fever vaccination have been documented (31)(32)(33)(34)(35). This has led to a review of the various vaccine preparations and their use and indications (1;30;35). As with any therapy, there are major and minor adverse events associated with a certain percentage of the population receiving the intervention. The goal of any therapy is to employ it only when the benefits of the intervention outweigh potential harms.

# MILD VACCINE-RELATED ADVERSE EVENTS
Yellow fever vaccines are generally well tolerated.
Reactions to the vaccine are usually mild and transient in nature and include headaches, myalgias and low-grade fevers (1;7;30;36).
Reports on vaccine safety and efficacy are published in the Canadian Immunization Guide (CIG), the YF-VAX product monograph, as well by both the Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO). All report that the vaccine is safe and effective.
Reactions usually begin a few days after vaccination and last five to ten days post dose (1;7). There is a wide variability (2-30%) in the frequency of report of mild adverse events i.e. headache, myalgia, low-grade fever. Less than one percent of recipients had to curtail daily activities due to an adverse event following vaccination (30;37).

# SERIOUS ADVERSE EVENTS
Although rare, there have been a range of serious adverse events which have been recorded following yellow fever vaccination, including:
- Hypersensitivity reactions: Immediate type hypersensitivity reactions (rash, urticaria, asthma, anaphylaxis) to the yellow fever vaccine can occur. The Vaccine Adverse Event Reporting System (VAERS) in the United States report the rate of 43 adverse events following yellow fever vaccine reported to VAERS per 100,000 doses distributed (38). These are rare events: the CIG provides rates of one in 250,000 to one in 300,000 (37). Hypersensitivity reactions occur primarily in people with sensitivity to egg proteins and/or chicken (4;11;37;39;40). The gelatin stabilizer used in the vaccine has also been implicated (1;11;39). Therefore, people with allergies to eggs, chicken, or gelatin should not receive the vaccine. Anaphylaxis can also occur in persons with no known allergy to vaccine components. For those individuals with suspected sensitivity and a need for immunization, such persons may be referred to an allergist for evaluation if vaccination against yellow fever is considered (30).
- Yellow fever vaccine associated neurotropic disease (YEL-AND): YEL-AND was once a syndrome characterized by fever and encephalitis in young children. These adverse events were largely reduced once the yellow fever vaccine was no longer administered to children less than six months old (36). YEL-AND now describes a grouping of clinical syndromes: meningoencephalitis, auto-immune involvement of the central nervous system and/or auto-immune involvement of the peripheral nervous system (Guillain Barre syndrome), which can present in any age group, between four and 23 days post vaccination (1;7). The CIG does not provide statistics on YEL-AND in Canadian vaccinees. The WHO reports that there have been 26 proven or probable cases of YEL-AND since 1945, with two fatalities (1). The CDC reports 0.8 cases per 100,000 doses of yellow fever vaccine administered (7). Studies suggest that older age is a risk factor for a serious adverse events including YEL-AND following yellow fever vaccination (41).
- Yellow Fever Vaccine Associated Viscerotropic Disease (YEL-AVD): YEL-AVD is characterized by severe illness and multi-organ failure, similar to that seen in yellow fever disease (36;42;43). According to the CIG, the risk of YEL-AVD increases with age: for those 60-69 years of age, the risk is estimated to be 1.0-1.1 per 100,000; for those 70 years or older, the risk is estimated to be 2.3-3.2 per 100,000 (38;41). According to the WHO, risk of death from YEL-AVD is estimated to be one per 10 million doses of vaccine (1). Similar events were noted with five different preparations of 17D vaccine (44)(45)(46). Extensive investigations following a number of these cases suggest that this is due to various host factors, and not a change in virulence of the vaccine virus. Once again, the frequency of these severe (and often fatal) reactions is extremely low. These reactions have been linked to host characteristics including older age (60 years) (34;41) and thymus disease associated with abnormal immune function (e.g. thymoma and myasthenia gravis (47), and are noted with primary vaccination. YEL-AVD tends to develop two to five days post-vaccination. There is no specific treatment for YEL-AVD except supportive care, usually in an intensive care setting (11;38;42;47).
Despite the emerging information on YEL-AND and YEL-AVD, the yellow fever vaccine is highly effective and safe. In the June 2008 meeting of the Global Advisory Committee on Vaccine Safety it was reiterated "that the recommendations for the use of yellow fever vaccine should remain unchanged" (48). The important message here is to ensure that the exact reason for vaccination is understood (risk of exposure versus international regulations). It is also crucial to avoid exposing travellers to the very small, but non-negligible, risk of yellow fever vaccination if there is no actual risk or requirement for vaccination (7;27;48).

# Vaccine and special populations:
Caution should be exercised in special groups as discussed below:
- Children: Children under the age of nine months typically should not be vaccinated against yellow fever (30). Preliminary studies (30;49;50) suggest that although the incidence of adverse events in children older than six months does not appear to be significantly increased compared to infants greater than nine months of age, seroconversion is not optimal and there was still a small increase in adverse neurologic events in some small study populations. Children less than six months of age are at greater risk for YEL-AND (1;36). The Advisory Committee on Immunization Practices (ACIP) in the United States of America recommends that for children six to eight months old travelling to an endemic area, when travel is unavoidable, the decision to vaccinate needs to balance the risks of yellow fever virus exposure with the risk for adverse events following vaccination. For children under the age of six months, the vaccine is contraindicated (51).
- The older traveller: The aspect of primary vaccination in persons over 60 years of age has been discussed above with respect to the possibility of adverse events (YEL-AND and YEL-AVD). Discussion about the relative risk of vaccination versus the risk of contracting the disease should form the basis of any decision to vaccinate in this age group (7;36-38;41). Whereas the risk of an adverse outcome is small, it is not negligible. The best estimate of current disease prevalence/transmission in the country(ies) to be visited (based on the revised WHO/CDC vaccine recommendation maps), as well as the actual itinerary, should be assessed as accurately as possible. If there is a considerable risk of yellow fever transmission, then the decision to immunize can be made, understanding the small increased risk of serious adverse events. This decision is particularly important in those older travellers whose itineraries may take them to countries with strict yellow fever vaccination entry requirements, but little or no risk of actual disease exposure. If it is decided not to vaccinate based on minimal/no risk, then a waiver may be provided and personal protective measures against mosquitoes will need to be emphasized (see section 'Personal Protective Measures', below). Travellers will also have to be reminded that the need for vaccination must be re-evaluated for future travel to new destinations (34;41;52-54).
- Pregnant women: As the effects of this live vaccine in pregnancy are not well documented, 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 or fetus (7;37). Preliminary surveys in the developing world have demonstrated some deleterious outcomes with respect to congenital transmission of disease and spontaneous abortion with vaccination (55-57), but these have been small studies. These have been counterbalanced by other studies showing no negative outcomes in pregnant women who were inadvertently vaccinated early in pregnancy (58)(59)(60)(61). When travel is to a country that requires vaccine documentation in accordance with the IHR, but is not yellow fever endemic, a waiver should be provided rather than vaccination (4).
- Breastfeeding women: Until recently, there was only a theoretical risk of transmission of the live virus in breast milk. A recent incident in Brazil has now given laboratory confirmed evidence of yellow fever virus transmission in breast milk (62). As well, there was a case of a potential adverse outcome in an infant who was being breastfed by a mother who received yellow fever vaccination in Canada (63). These two cases should raise the level of caution when considering vaccinating women who are actively breastfeeding. Certainly, 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 will have to be weighed against the risk of disease (37;64).
- Immuno-compromised individuals: Travellers who have a disease causing lack of immune response or those on immune modulating medications should avoid vaccination with any live virus. In addition, their response to the antigen may not be sufficient to be protective. Yellow fever vaccine is contraindicated in individuals with severe underlying diseases such as leukemia, lymphoma, thymoma, generalized malignancy, gamma-globulin deficiency, symptomatic Human Immunodeficiency Virus (HIV) infections or Acquired Immunodeficiency Syndrome (AIDS) (CD4 count 200 cells/ml or 15-24% of total cells in children< 6years of age) can be administered the vaccine, but these individuals should be inoculated well in advance of travel in order to monitor potential adverse events, and neutralizing antibody titres should be considered to assess efficacy of the vaccination (65;68-71). Although study numbers are still small, use of yellow fever vaccine in persons with HIV have shown patients respond to the vaccine with lower neutralizing titres, more often demonstrate non-protective neutralizing titres and may experience a more rapid decline in these titres following vaccination. Also, the booster recommendations for immuno-competent travellers (i.e. every 10 years) are probably not adequate for those who are immuno-compromised. Neutralization titres or even revaccination at two to five years should be considered (72).There is no contraindication to vaccinating family members and travelling companions of immuno-compromised individuals as the virus is spread by mosquitoes, not person to person contact. Low dose steroids (<20mg prednisone equivalent or less than 2mg/ kg in children under 10kg), topical steroid use or shortterm (<2 weeks) steroid should not prevent vaccination (7). For more information, refer to the CATMAT statement on The Immunocompromised Traveller (73).
- Thymus disease: A review of deaths attributed to vaccination (YEL-AVD) has demonstrated an association with a history of thymus disease associated with abnormal immune function (7;36). These numbers are very small, but the association appears to be relevant and would preclude individuals with a history of thymoma, myasthenia gravis or thymectomy (for these conditions or unknown cause) from receiving yellow fever vaccine (74).

# Personal Protective Measures (PPM)
All travellers should be advised on routine insect protection and precautions while travelling, regardless of yellow fever vaccination status. The mosquitoes that transmit yellow fever can be active throughout the day; therefore travellers should protect themselves against bites at all times. This is also good practice to prevent infection from other arthropod-borne diseases. For more information, refer to the CATMAT statement, "Personal Protective Measures to Prevent Arthropod Bites" (24). PPM as the sole prevention method would only be indicated for those at risk of contracting yellow fever, who cannot be vaccinated.

# Potential Consequences of Inappropriate Documentation
Travellers must also be made aware that, even with a certificate or letter of yellow fever vaccine contraindication, they may still be denied entry or quarantined by border health and/or immigration authorities upon arrival at the destination country (19). Travellers also need to be counseled as to the potential risks of receiving local vaccination at the destination.

# Summary of Recommendations
Moderate evidence to support a recommendation for use.
Poor evidence to support a recommendation for or against use.
Moderate evidence to support a recommendation against use.
Good evidence to support a recommendation against use.
Categories for the quality of evidence on which recommendations are made Grade Definition I Evidence from at least one properly randomized, controlled trial.
Evidence from at least one well-designed clinical trial without randomization, from cohort or case-controlled analytic studies, preferably from more than one centre, from multiple time series, or from dramatic results in uncontrolled experiments.
Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees. Vaccination contraindicated E II Immuno-compromised individuals (lymphoma, HIV (CD4 count<200 cells/mm 3, immunosuppressive therapies, primary immunosupression, autoimmune disorders)

# Vaccination not recommended E II
Persons with a life-threatening allergy to eggs or chicken or other vaccine components
Vaccination contraindicated E III  Vaccination in these populations carries a potential of increased risk of adverse events (either to patient or offspring), and thus a general recommendation cannot be made. Consideration for vaccination must be done on a case-by-case basis. Delaying travel may be considered. If travel cannot be avoided and if the person is travelling to a highly endemic or epidemic area where the risk of yellow fever transmission is high, then the risks of contracting the disease may outweighed by the risks vaccination. Please see text for detailed discussion of vaccination in these groups.