March 2013 • Volume 39 • ACS-2
Committee to Advise on Tropical Medicine and Travel (CATMAT)†
For readers interested in the PDF version, the document is available for download or viewing: Statement for Travellers and Yellow Fever(PDF document - 679 kb - 20 pages)
The Committee to Advise on Tropical Medicine and Travel (CATMAT) provides the Public Health Agency of Canada with ongoing and timely medical, scientific, and public-health advice relating to tropical infectious disease and health risks associated with international travel. The Agency 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.
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 (Footnote 1-Footnote 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 (Footnote 1;Footnote 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 20th century. Aggressive vector control measures and eventually vaccination eliminated urban transmission in North America and Europe (Footnote 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 (Footnote 1;Footnote 6-Footnote 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:
The most recently published data available from the WHO indicate that in 2010 there were 42 cases of yellow fever reported to WHO. Nine yellow fever outbreaks were reported in six countries. In Central and West Africa, a total of 20 cases with no deaths were reported in 2010 from the following countries: Cameroon (n=7), Democratic Republic of the Congo (n=2), Guinea (n=9), and Senegal (n=2). In South America, 22 confirmed cases with 17 deaths were reported during 2010 (Bolivia, n=2; Brazil, n=2; Peru, n=18); the case-fatality rate was 77.3% (Footnote 6;Footnote 10). True incidence 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 (Footnote 2).
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) (Footnote 7;Footnote 11-Footnote 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 (Footnote 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 (Footnote 2;Footnote 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 (Footnote 11;Footnote 17-Footnote 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 (Footnote 20;Footnote 21). The revisions included:
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 (Footnote 3;Footnote 4). In an estimated 85% of yellow fever cases, the disease resolves itself at this time (Footnote 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 (Footnote 3;Footnote 4;Footnote 7).
In travellers, clinical features and patient history (travel dates, locations, and activities) usually inform the initial diagnosis (Footnote 7). Diagnosis is confirmed in both travellers and non-travellers by the isolation of virus from blood by inoculation of special media (Footnote 1). Techniques identifying antigen or nucleic acid components using enzyme linked immunosorbent assay (ELISA) or polymerase chain reaction (PCR) tests are also used (Footnote 22;Footnote 23). Serological cross reaction may occur with other flaviviruses, and should be considered during diagnosis (Footnote 3). Also, virus is sometimes difficult to isolate after the fourth day of illness (Footnote 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) (Footnote 19).
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 (Footnote 11;Footnote 20;Footnote 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”(Footnote 2). Vertical transmission occurs with the yellow fever virus from female mosquito to her larvae (Footnote 2;Footnote 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 (Footnote 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 (Footnote 11;Footnote 17;Footnote 18). There have been sporadic outbreaks in the last few years in Africa and South America (Footnote 6;Footnote 9;Footnote 10;Footnote 25;Footnote 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.
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 (Footnote 19). As stated by the WHO in International Travel and Health (Footnote 27), there are two main objectives to yellow fever vaccination:
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) (Footnote 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 (Footnote 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 vaccines administered in Canada are available only at designated Yellow Fever Vaccination Centres. Presently, the Public Health Agency of Canada designates Yellow Fever Vaccination Centres across the country (Footnote 28). A list of Yellow Fever Vaccination Centres can be obtained on the Agency’s website. One exception to this is the Yellow Fever Vaccination Centres with the Canadian Forces that are designated by the Directorate of Force Health Protection. These Centres administer the yellow fever vaccine and provide an International Certificate of Vaccination or Prophylaxis (see Appendix 2A) 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 (Footnote 29).
For those people who cannot be vaccinated, the traveller may be provided with a waiver outlining the medical reason for not receiving the vaccination. This can be documented on the letterhead of the health care site or on a Certificate of Medical Contraindication to Vaccination (see Appendix 2B), that the Agency issues to Yellow Fever Vaccination Centres.
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 (Footnote 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 (Footnote 30). YF-VAX® is lyophilized and contains sorbitol and gelatin as stabilizers. There is no preservative in the vaccine or the accompanying diluent (Footnote 30).
According to Sanofi Pasteur, the vaccine must be maintained at temperatures between two and eight degrees Celcius (2°- 8° C) (Footnote 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 (Footnote 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 (Footnote 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 (Footnote 1).
In the last few years, a number of rare, but serious reactions to yellow fever vaccination have been documented (Footnote 31-Footnote 35). This has led to a review of the various vaccine preparations and their use and indications (Footnote 1;Footnote 30;Footnote 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 (Footnote 1;Footnote 7;Footnote 30;Footnote 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 (Footnote 1;Footnote 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 (Footnote 30;Footnote 37).
Serious adverse events
Although rare, there have been a range of serious adverse events which have been recorded following yellow fever vaccination, including:
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” ( Footnote 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 (Footnote 7;Footnote 27;Footnote 48).
Caution should be exercised in special groups as discussed below:
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”(Footnote 24). 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 contraindication, they may still be denied entry or quarantined by border health and/or immigration authorities upon arrival at the destination country (Footnote 19). Travellers also need to be counseled as to the potential risks of receiving local vaccination at the destination.
Table 1: Strength and quality of evidence of summary (Footnote 75)
|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.|
|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.|
|Population||Pre-travel Recommendation||Strength of Evidence|
|* 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.|
|Healthy adult travellers (< 60 years), travelling to an area where yellow fever is considered endemic or transitional||Vaccination recommended.||A II|
|Healthy adult travellers (> 60 years), travelling to an area where yellow fever is considered endemic or transitional presenting for primary vaccination||Careful assessment of risk recommended.
May vaccinate in cases of elevated risk of transmission.*
|Healthy children (> 9 months) travelling to an area where yellow fever is considered endemic or transitional||Vaccination recommended||A II|
|Children less than 6 months of age||Vaccination contraindicated||E II|
|Children between 6 and 9 months of age||Careful assessment of risk recommended
May vaccinate in cases of elevated risk of transmission.*
|Pregnant women||Careful assessment of risk recommended
May vaccinate in cases of elevated risk of transmission.*
|Breastfeeding women||Careful assessment of risk recommended
May vaccinate in cases of elevated risk of transmission.*
|Persons with asymptomatic HIV infection whose CD4 count is > 200cells/mm3 (or 15-24% of total cell in children < 6years of age).||Careful assessment of risk recommended
May vaccinate in cases of elevated risk of transmission.*
|Persons with a history of thymus disease associated with abnormal immune function (e.g. thymoma or myasthenia gravis)||Vaccination contraindicated||E II|
|Immuno-compromised individuals (lymphoma, HIV (CD4 count < 200 cells/mm3 ), 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|
|Classification||Description||Risk of Infection||Vaccination Recommendation|
|* Vaccination might 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, with heavy exposure to mosquitoes, inability to avoid mosquito bites)|
||Moderate to high||Recommended|
|Low potential for exposure||
||Low||Generally not recommended*|
|Africa||Central and South America|
|*Designation of regions with risk of yellow fever transmission is subject to change. Travellers and health care providers should refer to current information available from the WHO
+Countries in bold-type require proof of yellow fever vaccination and are subject to change. Additional countries require proof of yellow fever vaccination from travellers arriving from an endemic country. A complete listing of country-specific requirements is available from the CDC or the WHO
†Only a portion of the country has risk of yellow fever transmission. Refer to the WHO maps in Appendix 1C and Appendix 1D
|Central African Republic||Mauritania†||French Guyana|
|Democratic Republic of the Congo||Senegal||Peru†|
|Equatorial Guinea||Sierra Leone||Suriname|
|Ethiopia||Sudan†||Trinidad and Tobago†|
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" (Footnote 19). 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 Centres Program
Travel and Migration Health Division
Infectious Disease Prevention and Control Branch
Public Health Agency of Canada
380 Hunt Club Road, AL 6503B
Ottawa, Ontario, K1A 0K9
Phone: (613) 957-8739
Fax: (613) 952-8286
For a list of the Yellow Fever Vaccination Centres, refer to the Public Health Agency of Canada’s Web site.
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; for complete recommendations please refer to “Procedures for Yellow Fever Vaccination Centres in Canada(Footnote 28).
In an effort to assist health care providers, the Public Health Agency of Canada provides Yellow Fever Vaccination Centres with Certificates of Medical Contraindication to Vaccination to document contraindications to the yellow fever vaccine. For complete recommendations on filling out this document please refer to “Procedures for Yellow Fever Vaccination Centres in Canada (Footnote 28).
Members: Dr. A. McCarthy (Chair); Dr. A.K. Boggild; Dr. J. Brophy; Dr. Yen-Gaing Bui; Dr. M. Crockett; Dr. W. Ghesquiere; Dr. C. Greenaway; Ms. A. Henteleff; Dr. Michael Libman; Dr. P.J. Plourde; Dr. P. Teitelbaum.
Ex-Officio Representatives: Dr. P. Charlebois; Dr. P. McDonald; Dr. S. Schofield; Dr. M. Tepper.
Liaison Representatives: Dr. G. Brunette; Dr. C. Hui.
Member Emeritus: Dr. C.W.L. Jeanes.