CATMAT Statement: Travellers and yellow fever

Volume 36 ACS-11, October 2010

Committee to Advise on Tropical Medicine and Travel

Statement for Travellers and Yellow Fever

Contributors

*Members: Dr. P.J. Plourde (Chair); Dr. C. Beallor; Dr. A. Boggild; Dr. J. Brophy; Dr. M. Crockett; Dr. W. Ghesquiere; Ms. A. Henteleff; Dr. A. McCarthy; Dr. K. L. McClean.

Ex-Officio Representatives: Dr. G. Brunette; Dr. J. Creaghan; Dr. P. Charlebois, Dr. M. Tepper; Dr. P. McDonald; Dr. J. Given; Dr. JP. Legault.

Liaison Representatives: Dr. C. Greenaway; Dr. A. Pozgay; Dr. C. Hui; Dr. P. Teitelbaum.

Member Emeritus: Dr. C.W. L. Jeanes.

Consultant: Dr. S. Schofield.

†  This statement was prepared by P. Charlebois and approved by CATMAT.

DOI

https://doi.org/10.14745/ccdr.v36i00a11

Table Of Contents

• Preamble
• Introduction
• Epidemiology
• Disease Characteristics
• Risk for Travellers
• Preventative Measures
• Summary of Recommendations
• Appendix 1: Yellow Fever Risk Areas
• Appendix 2: List of Yellow Fever Vaccination Centres in Canada
• Appendix 3: Example of Government of Canada Yellow Fever Vaccination Documentation
• References

Preamble

The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada (PHAC) with ongoing and timely medical, scientific, and public-health advice relating to tropical infectious disease and health risks associated with international travel. PHAC acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge and medical practices, and is disseminating this document for information purposes to both travellers and the medical community caring for travellers.

Persons administering or using drugs, vaccines, or other products should also be aware of the contents of the product monograph(s) or other similarly approved standards or instructions for use. Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) or other similarly approved standards or instructions for use by the licensed manufacturer(s). Manufacturers have sought approval and provided evidence as to the safety and efficacy of their products only when used in accordance with the product monographs or other similarly approved standards or instructions for use.

Introduction

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, which includes approximately 70 other viruses, including dengue fever virus, Japanese encephalitis virus, and West Nile virus, to name a few ^(1-3).

The World Health Organization (WHO) estimates that approximately 200,000 yellow fever cases occur per year, with up to 30,000 deaths. The disease is presently endemic in South America and Africa, with over 90% of the cases recorded from 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 up until the early part of the 20th century, until 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)}.

Epidemiology

Yellow fever is endemic 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:

1. Jungle or Sylvatic transmission: occurs in jungle environments where multiple mosquito species (including Aedes spp., Haemagogus spp.) transmit the virus between non-human primate hosts. As transmission is ongoing, humans are infected sporadically if and when exposed to jungle mosquitoes. Humans living and working within or near the jungle are at risk of acquiring the disease within the jungle/sylvatic cycle^{(1) (3) (10)};
2. Urban transmission: occurs in more metropolitan areas where the Aedes aegypti mosquito acts as the main vector. Urban yellow fever cycles usually result in an epidemic after the virus has been introduced either by an infective mosquito or a human carrying the yellow fever virus. Due to the greater density of people in urban areas, urban yellow fever cycles can result in explosive epidemics^{(1) (3) (10)};
3. Intermediate transmission: occurs in smaller rural villages, where humans and monkeys live in close proximity to each other, and semi-domestic mosquitoes (Aedes spp.) infect both human and primates with the yellow fever virus. This cycle typically produces small-scale epidemics and is seen only in Africa.

The most recently published data available from the WHO reports that in 2005 there were 117 cases of yellow fever recorded in South America, with 52 deaths. The case-fatality rate was 44.4%. In 2005, Brazil, Bolivia, Colombia, Peru, and Venezuela were all affected by yellow fever outbreaks ⁽⁸⁾. In Central and West Africa, 2,058 cases were recorded, with 106 deaths. Countries affected included: Benin, Burkina Faso, Cameroon, Central African Republic, Congo, Cote d'Ivoire, Democratic Republic of the Congo, Gambia, Ghana, Guinea, Liberia, Mali, Niger, Senegal, Sierra Leone, and Togo. The case-fatality rate reported from the main epidemics in six of these countries was 26.9% (reported cases = 849, reported deaths = 228) ⁽⁸⁾. True incident rates in both South America and Africa are believed to be 10 to 50 fold higher than what is officially recorded due to high levels of underreporting, surveillance and diagnostic limitations, and infections with little to no clinical symptoms ⁽²⁾.

Nine cases of yellow fever were reported in unvaccinated international travellers from the United States and Europe between 1970 to 2002. Four cases of yellow fever 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)^{(6) (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) (17)}.

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) (18 - 20)}.

Currently, the WHO and the United States Centers for Disease Control and Prevention (CDC) are working to produce and harmonize the mapping of yellow fever risk. More specifically, they are attempting to better quantify the risk within regions and countries. It must be stressed that the prevalence of yellow fever in the areas outlined as areas of risk on the map available at the WHO is quite variable ⁽²¹⁾. Some countries within the endemic zone have had very few reported outbreaks in the last few years (e.g. the countries of East Africa) ⁽¹⁸⁾.  However, there have been recent epidemics in other areas and examination of these epidemics have re-enforced concern about the difficulty in predicting outbreaks. Estimation of risk of yellow fever virus is hampered by the natural fluctuation of the disease by year and season, vaccine coverage of the local population and incomplete surveillance data^{(11) (22) (23)}.

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 ⁽⁶⁾. 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) (6) (17)}.

In travellers, clinical features and patient history (travel dates, locations, and activities) usually inform the initial diagnosis ⁽⁶⁾. Diagnosis is confirmed in both travellers and non-travellers by the isolation of virus from blood by inoculation ⁽¹⁾. Techniques identifying antigen or nucleic acid components using enzyme linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) tests are also used^{(24) (25)}. 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 ⁽⁶⁾. All 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) ⁽²⁰⁾.

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^{(8) (11)}.

Destination

A traveller's destination factors into yellow fever risk in many ways. 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 the vaccine for entrance (i.e. Brazil) and therefore unvaccinated travellers may be at greater risk, especially if visiting a yellow fever risk area.

Season

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 ⁽²⁶⁾.

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) (18) (19)}. There have been sporadic outbreaks in the last few years in Africa and South America^{(7) (8) (27 - 29)}.

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 quantification 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.

As mentioned, the WHO and CDC are currently working together to develop a more detailed map of yellow fever risk. The proposed format will divide the globe into endemic, transitional, low risk and no risk areas. Vaccination recommendations will be based on the level of risk in each region. Practitioners are advised to be on the look out for these recommendations that are anticipated to be available late in 2010.

Preventative 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 ⁽²⁰⁾. As stated by the WHO in International Travel and Health ⁽²¹⁾, there are two main objectives to yellow fever vaccination:

1. 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.
2. 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) ⁽⁶⁾.

Yellow Fever Vaccination in Canada

Yellow fever vaccines administered in Canada are available only at designated yellow fever vaccination centres. Presently, the Public Health Agency of Canada (PHAC) designates Yellow Fever Vaccination Centres across the country ⁽³⁰⁾. A list of Yellow Fever Vaccination Centres can be obtained at the following website: www.phac-aspc.gc.ca/tmp-pmv/yf-fj/index-eng.php. These Centres administer the yellow fever vaccine and provide the approved International Certificate of Vaccination or Prophylaxis that will accompany the traveller. The certificate of vaccination is valid for a period of 10 years, commencing 10 days after the initial vaccination or immediately upon re-immunization. Re-immunization should be considered at 10 year intervals; however there is evidence that seroconversion bestows longer protection and may be lifelong ⁽³¹⁾. For those people who cannot be vaccinated, PHAC provides Yellow Fever Vaccination Centres with certificates of medical contraindication to vaccination, or alternatively, a written document, in English or French, outlining the medical reason for not receiving vaccination can be provided (see Appendix 3).

The 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. ⁽¹⁷⁾. YF-VAX® is lyophilized and contains sorbitol and gelatin as stabilizers. There is no preservative in the vaccine or the accompanying diluent ⁽¹⁷⁾.

According to sanofi pasteur, the vaccine must be maintained at temperatures between two and eight degrees Celcius (2°-8° C) ⁽³²⁾. This requires closely monitored refrigeration to ensure that the vaccine maintains viability. The vaccine should not be allowed to freeze, nor should the diluent ⁽³²⁾. Once reconstituted, the vaccine should be refrigerated and used within one hour. All vaccine not used within the one hour window should be discarded^{(17) (32)}.

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) (7)}.

Risk associated with vaccination

In the last few years, a number of rare, but serious reactions to yellow fever vaccination have been documented ^(33-37). This has led to a review of the various vaccine preparations and their use and indications^{(1) (17) (32) (37)}. 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.

1. 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) (6) (17) (32) (38)}. Differing data on adverse reactions have been reported:

   • The Canadian Immunization Guide (CIG) and the YF-VAX® product monograph both report that the vaccine is safe and effective. Five to ten days after immunization, two to five percent (2%-5%) of vaccinees have reported one or more of the symptoms listed above. Less than 0.2% had to curtail daily activities due to adverse event following vaccination^{(17) (32)};

   • The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) suggest that 10% to 30% of those vaccinated with YF-VAX® report mild adverse events, i.e. headache, myalgia, low-grade fever. Reactions usually begin a few days after vaccination and last five to ten days post dose^{(1) (6)}. The CDC suggests that approximately one percent of vaccine recipients had to curtail daily activities due to a mild adverse event ⁽⁶⁾.

2. 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. These are rare events: the CIG provides rates of one in 250,000 to one in 300,000 ⁽¹⁷⁾. Hypersensitivity reactions occur primarily in people with sensitivity to egg proteins and chicken^{(1) (11) (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 ⁽³²⁾.

   • 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 ⁽³⁸⁾. 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 Barré syndrome), which can present in any age group, between four and 23 days post vaccination^{(1) (6) (17)}. 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 ⁽⁶⁾. It has been suggested 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): Characterized by severe illness and multi-organ failure, similar to that seen in yellow fever disease^{(38) (42) (43)}. According to the CIG, the risk of YEL-AVD increases with age: for those 60 years or older, the risk is estimated to be 1.1 per 100,000; for those 70 years or older, the risk is estimated to be 3.2 per 100,000⁽¹⁷⁾. 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^{(32 - 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)^{(36) (41)} and thymus disease (thymoma, myasthenia gravis, thymectomy)⁽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) (42) (47) (48)}.

Despite the emerging information on yellow fever vaccine associated neurotropic disease (YEL-AND) and yellow fever vaccine associated viscerotropic disease (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" ⁽⁴⁹⁾. 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 not expose patients to the very small, but not negligible, risk of yellow fever vaccination if there is no actual risk or requirement for vaccination^{(6) (21) (49)}.

Vaccine and Special Populations

Caution should be exercised in special groups as discussed below:

1. Children: Children under the age of nine months typically should not be vaccinated against yellow fever^{(17) (32)}. Preliminary studies ^{(32) (50) (51)} suggest that although the incidence of adverse events in children older than six months does not appear to increase in limited size populations, seroconversion is not optimal. Children less than six months of age are at greater risk for YEL-AND^{(1) (38)}. The CIG does not recommend children under nine months be immunized ⁽¹⁷⁾, however the Advisory Committee on Immunization Practices (ACIP) 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 YFV exposure with the risk for adverse events following vaccination ⁽⁵²⁾.
2. 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^{(6) (17) (38) (41) (48)}. Whereas the risk of an adverse outcome is small, it is not negligible. The best estimate of current disease prevalence in the country visited, as well as the actual itinerary, should be assessed as accurately as possible. If it is decided not to vaccinate based on low risk, then a waiver may be provided and personal protective measures against mosquitoes will need to be emphasized (see Section 6.f, below). Travellers will also have to be reminded that the need for vaccination must be re-evaluated for future travel to new destinations^{(36) (41) (53 - 55)}.
3. 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^{(6) (17)}. Preliminary surveys in the developing world have demonstrated some deleterious outcomes with respect to congenital transmission of disease and spontaneous abortion with vaccination ^(56-58), but these have been small studies. These have been counterbalanced by other studies showing no negative outcomes in pregnant women who were vaccinated early in pregnancy ^(59-62). 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⁾.
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 ⁽⁶³⁾. As well, there is currently a case of a potential adverse outcome in an infant who was being breastfed by a mother who received yellow fever vaccination in Canada ⁽⁶⁴⁾. 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^{(17) (65)}.
5. 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 those receiving significant immunosuppressive drugs^{(6) (17) (38) (32 - 68)}. In these cases travel to a yellow fever endemic area should be avoided. If travel is not avoidable, these patients should be counselled about insect precautions (see Section 6.f, below) and the risk of yellow fever transmission at their travel destination, and issued a vaccination waiver. There are data suggesting that individuals with asymptomatic HIV infection (CD4>200 cells/ml) 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^{(66) (69 - 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), local steroid use or short-term (<2 weeks) steroid should not prevent vaccination ⁽⁶⁾. For more information, refer to the CATMAT statement on the Immunocompromised Traveller ⁽⁷³⁾.

6. Thymus Disease: A review of deaths attributed to vaccination (YEL-AVD) has demonstrated an association with a history of thymus disease^{(6) (38)}. These numbers are very small, but the association appears to be relevant and would preclude individuals with a history of thymoma, thymectomy or myasthenia gravis 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. 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"⁽²⁶⁾. PPM as the sole prevention method would only be indicated for those at risk of contracting yellow fever, who cannot be vaccinated. Travellers must also be made aware that, even with a certificate or letter of yellow fever vaccine contra-indication, they may still be vaccinated or quarantined by border health and/or immigration authorities upon arrival at the destination country ⁽²⁰⁾.

Summary of Recommendations

Table 1. Strength and quality of evidence of summary sheet ⁽⁷⁵⁾

Categories for the strength of each recommendation

Category	Definition
A	Good evidence to support a recommendation for use.
B	Moderate evidence to support a recommendation for use.
C	Poor evidence to support a recommendation for or against use.
D	Moderate evidence to support a recommendation against use.
E	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.
II	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.
III	Evidence from opinions or respected authorities on the basis of clinical experience, descriptive studies, or reports of expert committees.

Table 2:  Recommendations for the Use of Yellow Fever Vaccination

Population	Recommendation on Pre-travel Vaccination	Strength of Evidence
Healthy adult travellers (< 60 years), travelling to an area where yellow fever is considered endemic	Recommended	A II
Healthy children (> 9 months) travelling to an area where yellow fever is considered endemic	Recommended	A II
Persons with a life-threatening allergy to eggs or chicken	Not recommended	E III
Children less than 6 months of age	Not recommended	E II
Children between 6 and 9 months of age	Generally not recommended	DIII
Pregnant women	Generally not recommended *	D II
Breastfeeding women	Generally not recommended *	D III
Healthy adults over 60 years of age presenting for primary vaccination	Generally not recommended *	D II
Persons with a history of thymus disease, thymoma or myasthenia gravis	Generally not recommended *	D III
Immuno-compromised individuals (lymphoma, HIV, immunosuppressive therapies)	Generally not recommended *	D II
* Although vaccination is generally not recommended, consideration for vaccination must be done on a case-by-case basis. If the person is travelling to a highly endemic or epidemic area where the risk of yellow fever is high, then the risks of vaccination may be outweighed by the risks of contracting the disease.

Appendix 1: Yellow fever risk areas

Appendix 1a: Yellow Fever countries at risk, 2008 ⁽²¹⁾

Appendix 1B: Countries with risk of Yellow Fever transmission by continent, 2010 ⁽²¹⁾

Countries listed in bold-type require proof of vaccination against yellow fever.

Appendix 2: List of Yellow Fever Vaccination Centres in Canada

Under Annex 7 of the International Health Regulations (2005), "States Parties shall designate specific yellow fever vaccination centres within their territories in order to ensure the quality and safety of the procedures and materials employed" ⁽²⁰⁾. As a signatory to the International Health Regulations, Canada must designate Yellow Fever Vaccination Centres. This is coordinated by the Public Health Agency of Canada, contact information below.

Yellow Fever Vaccination Program
Travel Health Division
Infectious Disease Prevention and Control Branch
Public Health Agency of Canada
130 Colonnade Road, AL 6503B
Ottawa, Ontario, K1A 0K9
yfinfofj@phac-aspc.gc.ca
(613) 957-8739

For a list of the Yellow Fever Vaccination Centres, refer to the Public Health Agency of Canada's Web site at http://www.phac-aspc.gc.ca/tmp-pmv/travel/clinic-eng.php.

Appendix 3: Example of Government of Canada Yellow Fever Vaccination Documentation

Appendix 3a: Example of a Completed Copy of the International Certificate of Vaccination or Prophylaxis Issued by the Public Health Agency of Canada

Although there are currently no internationally agreed-upon guidelines for the completion of the certificate, the Public Health Agency of Canada provides Yellow Fever Vaccination Centres recommendations to complete the certificate ⁽³⁰⁾.

Appendix 3b: Example of a Completed Copy of the Certificate of Medical Contraindication to Vaccination Issued by the Public Health Agency of Canada

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