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3.25 Yellow Fever

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Virology

Yellow fever is a viral haemorrhagic fever caused by a flavivirus that is transmitted by mosquitoes. Aedes aegypti, a highly domesticated mosquito found throughout the tropics, is the vector responsible for person-to-person transmission of the yellow fever virus in urban and inhabited rural areas in endemic countries.

Clinical features

The clinical spectrum of yellow fever varies from a non-specific febrile illness to a fatal haemorrhagic fever.1 After an incubation period of 3 to 6 days, the disease begins abruptly with fever, prostration, myalgia and headache. The patient appears acutely ill with congestion of the conjunctivae; there is an intense viraemia during this ‘period of infection’ which lasts 3 to 4 days.1 This may be followed by the ‘period of remission’ in which the fever and symptoms settle over 24 to 48 hours during which the virus is cleared by immune responses.1

Approximately 15 to 25% of patients may then relapse with a high fever, vomiting, epigastric pain, jaundice, renal failure and haemorrhage: ‘the period of intoxication’.1 These complications can be severe, and reflect the viscerotropic nature of the yellow fever virus (its ability to infect the liver, heart and kidneys). The case-fatality rate varies widely, but can be as high as 20% in local populations.

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Epidemiology

Yellow fever occurs in tropical regions of Africa and Central and South America. In both regions the virus is enzootic in rainforest monkeys and canopy mosquito species; sporadic human cases occur when people venture into these forests (‘sylvatic or jungle yellow fever’).1

In moist savannah regions in Africa, especially those adjacent to rainforests, tree hole-breeding Aedes mosquito species are able to transfer yellow fever virus from monkeys to people and then between people, leading to small-scale outbreaks (‘intermediate yellow fever’).

Ae. aegypti occurs in both heavily urbanised areas and settled rural areas in tropical Africa and the Americas.1 Epidemics of ‘urban yellow fever’ occur when a viraemic individual (with yellow fever) infects local populations of Ae. aegypti; such epidemics can be large and very difficult to control. Although Ae. aegypti also occurs throughout much of tropical Asia and Oceania (including north Queensland), yellow fever has never been reported from these regions.

Although yellow fever is undoubtedly markedly under-reported, it is clear that there has been a considerable increase in the reported number of outbreaks, and therefore cases, of yellow fever in recent decades.2 Most of this increase has been in Africa, particularly in West African countries.2,3 Between 2000 and 2004, 18 of the 25 countries at risk in Africa reported cases of yellow fever, with 13 of the 14 countries at risk in West Africa reporting cases.3 During this time, West Africa experienced 5 epidemics of urban yellow fever, 3 of which affected capital cities (Abidjan (Côte d’Ivoire, 2001), Conakry (Guinea, 2002), Dakar and Touba (Senegal, 2002) and Bobo-Dioulasso (Burkina Faso, 2004)).3

The risk of susceptible travellers acquiring yellow fever varies considerably with season, location, duration of travel and utilisation of mosquito avoidance measures. There have been at least 6 reported cases of yellow fever, all fatal, in unvaccinated travellers to Africa and South America since 1996.3

Vaccine

  • Stamaril – Sanofi Pasteur Pty Ltd (live attenuated yellow fever virus (17D-204 strain) lyophilised vaccine). Each 0.5 mL monodose of reconstituted, lyophilised vaccine contains not less than 1000 mouse LD50 units; lactose; sorbitol. May contain traces of egg proteins. The vaccine is supplied as a single dose ampoule with 0.5 mL diluent syringe.

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Yellow fever vaccine is a live, freeze-dried preparation of the 17D attenuated strain of yellow fever virus cultured in, and harvested from, embryonated chicken eggs. The vaccine contains neither antibiotics nor preservatives, and does not contain gelatin.

Vaccination elicits protective levels of neutralising antibodies in approximately 90% of adult vaccinees by day 14, and in virtually all by day 28.4 Immunity is long-lasting and perhaps life-long; regardless, revaccination is required after 10 years under International Health Regulations for a valid International Certificate of Vaccination. Because the vaccine produces a transient very low level viraemia in healthy adult recipients, they cannot serve as a source of infection for mosquitoes.4

Although the efficacy of the yellow fever vaccine has never been determined in prospective clinical trials, there is considerable observational evidence that it is very effective in preventing the disease.4

Transport, storage and handling

Transport according to National Vaccine Storage Guidelines: Strive for 5.5 The vaccine and diluent should be stored at +2oC to +8oC. Do not freeze. Protect from light. The vaccine should be used within 1 hour of reconstitution.

Dosage and administration

The vaccine can be given to those ≥9 months of age. The dose is 0.5 mL of reconstituted vaccine regardless of age, given by either IM or SC injection.

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Recommendations

Yellow fever is considered to be endemic in 32 African and 11 Central and South American countries (Table 3.25.1). Of these, 25 African and 9 South American countries are currently considered at risk because they have reported cases since 1950; of particular concern are the countries in West Africa (Table 3.25.1).3,6

Table 3.25.1: Yellow fever endemic countries


West African countries

Other endemic countries

Benin *

Angola *

Guyana *

Burkina Faso *

Bolivia *

Kenya *

Côte d'Ivoire *

Brazil *

Niger

Gambia *

Burundi

Panama

Ghana *

Cameroon *

Peru * †

Guinea *

Central African Republic *

Rwanda

Guinea-Bissau *

Chad

Sao Tome and Principe

Liberia *

Colombia *

Somalia

Mali *

Congo *

Sudan *

Mauritania *

Democratic Republic of the Congo *

Suriname *

Nigeria *

Ecuador *

Trinidad and Tobago

Senegal *

Equatorial Guinea *

Uganda *

Sierra Leone *

Ethiopia *

United Republic of Tanzania

Togo *

French Guiana *

Venezuela *

 

Gabon *

 


* Countries with cases reported since 1950.
† Travellers who will visit only the cities of Cuzco and Machu Picchu do not need vaccination.

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The yellow fever vaccine is recommended for:

  • those ≥9 months of age travelling or living in any country in West Africa (see Table 3.25.1), regardless of where they will be in that country,
  • those ≥9 months of age travelling or living outside urban areas of all other yellow fever endemic countries (see Table 3.25.1), and
  • laboratory personnel who routinely work with yellow fever virus.

All those travelling or living in endemic countries should be informed that the mosquito vectors of yellow fever usually bite during the day, and they should be advised of the necessary mosquito avoidance measures. These include the use of insect repellents, coils and sprays, the use of mosquito nets (preferably those that have been treated with an insecticide), and adequate screening of residential (and work) premises.

As well as the above recommendations, many countries outside the endemic regions require evidence of vaccination for those travellers arriving from endemic countries. Because Ae. aegypti exists in many of these non-endemic countries, there is a potential for yellow fever virus transmission; a listing of these countries is available in an annex at www.who.int/ith/en/.

Travellers >1 year of age arriving into Australia within 6 days of leaving a yellow fever endemic country are required to have a valid International Certificate of Vaccination against Yellow Fever (see below). Such travellers who do not have a valid certificate are placed under quarantine surveillance until 6 days have passed after leaving the endemic country. Quarantine surveillance does not place restrictions on the traveller’s movements, but does require prompt medical assessment should the traveller develop relevant symptoms.

Yellow fever vaccine can be administered only by Yellow Fever Vaccination Centres approved by the relevant State or Territory health authorities. Each yellow fever vaccination is to be recorded in an International Certificate of Vaccination against Yellow Fever; the certificate must include the vaccinee’s name and signature (or the signature of a parent or guardian if the vaccinee is a child), and the signature of a person approved by the relevant health authority. The date of the vaccination must be recorded in day-month-year sequence with the month written in letters, and the official stamp provided by the State or Territory health authority must be used. The certificate becomes valid 10 days after vaccination, and remains valid for 10 years.

NB. People with a true contraindication to yellow fever vaccine (see below) who intend to travel to endemic countries (as recommended above) should obtain a letter from a doctor, clearly stating the reason for withholding the vaccine. The letter should be formal, signed and dated, and on the practice’s letterhead.

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Contraindications

(i) Known anaphylactic sensitivity

The yellow fever vaccine is contraindicated in those who have had either:

  • anaphylaxis following a previous dose, or
  • anaphylaxis following any of the vaccine components.

In particular, the vaccine is contraindicated if there is a known anaphylaxis to eggs.

(ii) Infants

Yellow fever vaccine is contraindicated in infants <9 months of age.

(iii) Altered immune status

As with all live virus vaccines, the yellow fever vaccine should not be given to people with impaired immunity due to either disease or medical treatment (see Chapter 2.3, Groups with special vaccination requirements).

(iv) Thymus disorders

People with a history of any thymus disorder, including myasthenia gravis, thymoma, thymectomy and DiGeorge syndrome, should not be given the yellow fever vaccine.

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Precautions

(i) Adults ≥60 years of age

The risk of severe adverse events following yellow fever vaccine is considerably greater in those aged ≥60 years than in younger adults.7,8

Adults ≥60 years of age should be given yellow fever vaccine only if they intend to travel to endemic countries (as recommended above) and they have been informed about the (albeit very low) risks of developing a severe complication.

(ii) Pregnancy

As with all live virus vaccines, unless there is a risk of exposure to the virus, yellow fever vaccine should not be given to pregnant women. Pregnant women should be advised against going to the rural areas of yellow fever endemic areas (and to urban areas of West African countries as well). However, pregnant women who insist on travelling, against medical advice, to endemic countries should be vaccinated.

The yellow fever vaccine has been given to considerable numbers of pregnant women4,9 with no evidence of any adverse outcomes. Therefore, women vaccinated in early pregnancy can be reassured that there is no evidence of risk to themselves and very low (if any) risk to the fetus; there are no grounds for a termination of pregnancy.4

(iii) Administration of other vaccines on the same day

The administration of other live virus vaccines (MMR, varicella vaccine [and MMRV when available]) should be on the same day as yellow fever vaccine, or separated by a 4-week interval. Other vaccines relevant to travel can be given with, or at any time before or after, yellow fever vaccine.

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Adverse events

(i) Common adverse events

Adverse events following yellow fever vaccine are generally mild. Vaccinees often report mild headaches, myalgia and low-grade fevers or other minor symptoms for 5 to 10 days post vaccination. In clinical trials in which symptoms are actively elicited, up to 25% of vaccinees report mild adverse events and up to 1% curtail regular activities.4,10

(ii) Immediate hypersensitivity reactions

Immediate hypersensitivity reactions, including anaphylaxis, following yellow fever vaccine are very rare with an incidence of less than 1 in 1 million and occur principally in people with anaphylactic sensitivity to eggs.4 Although it has been suggested that an anaphylactic sensitivity to gelatin (added as a stabiliser to some yellow fever vaccines) may also precipitate anaphylaxis following vaccination,11 Stamaril does not contain gelatin.

(iii) Vaccine-associated neurotropic adverse events

At least 25 cases of meningoencephalitis following yellow fever vaccination have been reported.4 However, 15 of these cases occurred in the 1950s in infants ≤7 months of age; following recommendations in the early 1960s not to vaccinate young infants, the incidence of vaccine-associated meningoencephalitis declined considerably.4 Nevertheless, these adverse events, albeit very rare, still occur in adults; the risk is greater in vaccinees ≥60 years of age.7,8

(iv) Vaccine-associated viscerotropic adverse events

Recently, an apparently very rare (and often fatal) complication, characterised by multiorgan system failure, has been recognised following yellow fever vaccination; it appears that overwhelming infection with the 17D vaccine-virus is responsible for these viscerotropic adverse events.4 Up to October 2004, 25 such cases had been reported worldwide; the exact incidence is unknown but may be less than 1 in 400 000 doses of vaccine.4

Vaccine-associated viscerotropic adverse events do not appear to be caused by altered virulence of the vaccine-virus, but rather appear to be related to host factors. Although cases have occurred in younger people, it is apparent that the risk is increased with advanced age, in particular in those aged ≥60 years.7,8 Another host factor associated with an increased risk of a viscerotropic adverse event is pre-existing thymus disease. Four of the 25 reported cases had a history of thymic tumour and thymectomy, both uncommon conditions.12

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Use in pregnancy

Pregnant women, who insist on travelling to either a West African country, or outside urban areas of any other endemic country, should be vaccinated (see ‘Precautions’ above).

Variations from product information

The product information states that pregnancy is a contraindication to the yellow fever vaccine. However, NHMRC recommends that pregnant women who insist on travelling, against medical advice, to endemic countries, should be vaccinated.

The product information suggests that a 0.1 mL test dose of yellow fever vaccine can be used intradermally to assess an individual with suspected allergy to the vaccine. However, NHMRC states that (with the exception of Q fever vaccine) test doses should never be used.

References

  1. Monath TP. Yellow fever: an update. The Lancet Infectious Diseases 2001;1:11-20.
  2. Robertson SE, Hull BP, Tomori O, et al. Yellow fever: a decade of reemergence. JAMA 1996;276:1157-62.
  3. World Health Organization. The yellow fever situation in Africa and South America in 2004. Weekly Epidemiological Record 2005;80:250-6.
  4. Monath TP. Yellow fever vaccine. In: Plotkin SA, Orenstein WA, eds. Vaccines. 4th ed. Philadelphia, PA: Saunders, 2004.
  5. National vaccine storage guidelines. Strive for 5. Canberra: Australian Government Department of Health and Ageing, 2005. Available at: http://www.immunise.health.gov.au/internet/immunise/publishing.nsf/Content/provider-store (accessed Nov 2006).
  6. World Health Organization. Yellow fever situation in Africa and South America, 2005. Weekly Epidemiological Record 2006;81:317-24. \
  7. Khromava AY, Barwick Eidex R, Weld LH, et al. Yellow fever vaccine: an updated assessment of advanced age as a risk factor for serious adverse events. Vaccine 2005;23:3256-63.
  8. Lawrence GL, Burgess MA, Kass RB. Age-related risk of adverse events following yellow fever vaccination in Australia. [erratum appears in Commun Dis Intell. 2004;28(3):348]. Communicable Diseases Intelligence 2004;28:244-8.
  9. Suzano CE, Amaral E, Sato HK, Papaiordanou PM, Campinas Group on Yellow Fever Immunization during Pregnancy. The effects of yellow fever immunization (17DD) inadvertently used in early pregnancy during a mass campaign in Brazil. Vaccine 2006;24:1421-6.
  10. Marfin AA, Barwick Eidex RS, Kozarsky PE, Cetron MS. Yellow fever and Japanese encephalitis vaccines: indications and complications. Infectious Disease Clinics of North America 2005;19:151-68.
  11. Kelso JM, Mootrey GT, Tsai TF. Anaphylaxis from yellow fever vaccine. Journal of Allergy & Clinical Immunology 1999;103:698-701.
  12. Barwick Eidex R, Yellow Fever Vaccine Safety Working Group. History of thymoma and yellow fever vaccination [letter]. Lancet 2004;364:936.

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