The Australian Immunisation Handbook 10th Edition

4.23 Yellow fever

Page last updated: 08 April 2016

This chapter has been amended on 22 June 2015.

4.23.1 Virology

Yellow fever is a viral haemorrhagic fever caused by an RNA 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.

4.23.2 Clinical features

The clinical spectrum of yellow fever varies from a non-specific febrile illness to 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 more than 20% in local populations.2

4.23.3 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 past decades.3 Most of this increase was in Africa, particularly in West African countries.3,4 In 2008, there were 24 cases of yellow fever reported near Asunción in Paraguay with 8 deaths.5

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 reported cases of yellow fever, all fatal, in unvaccinated travellers to Africa and South America.6

4.23.4 Vaccine

  • Stamaril – Sanofi Pasteur Pty Ltd (live attenuated yellow fever virus [17D strain]). Lyophilised powder in a monodose vial with a pre-filled diluent syringe. Each 0.5 mL reconstituted dose contains ≥1000 mouse LD50 units; 16.0 mg lactose; 8.0 mg sorbitol; 0.833 mg L-histidine hydrochloride. May contain traces of egg proteins.

Yellow fever vaccine is a live, freeze-dried preparation of attenuated 17D strain yellow fever virus cultured in, and harvested from, embryonated chicken eggs. The vaccine does not contain antibiotics, preservatives or gelatin.

Vaccination elicits protective levels of neutralising antibodies in approximately 90% of adult vaccine recipients by day 14, and in virtually all by day 28.7 Immunity is long-lasting and perhaps life-long;8-10 regardless, revaccination is required after 10 years under International Health Regulations for a valid International Certificate of Vaccination or Prophylaxis (ICVP) against yellow fever. Because the vaccine produces a transient very low level viraemia in healthy adult recipients, they cannot serve as a source of infection for mosquitoes.7

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.7

4.23.5 Transport, storage and handling

Transport according to National vaccine storage guidelines: Strive for 5.11 Store at +2°C to +8°C. Do not freeze. Protect from light.

Stamaril must be reconstituted by adding the entire contents of the diluent syringe to the vial and shaking until the powder is completely dissolved. Reconstituted vaccine must be used within 1 hour.

4.23.6 Dosage and administration

The dose of yellow fever vaccine for children and adults is 0.5 mL, to be given by either IM or SC injection.

Test doses of yellow fever vaccine should never be used (refer to 4.23.13 Variations from product information below).

Co-administration with other vaccines

If administration of both yellow fever and other parenteral live viral vaccines is indicated, the vaccines should be given either on the same day or at least 4 weeks apart (refer to 4.23.10 Precautions below).

Inactivated vaccines and oral live vaccines relevant to travel (e.g. cholera, typhoid) can be given with, or at any time before or after, yellow fever vaccine.

Yellow fever vaccine can be given at the same time as the Imojev Japanese encephalitis vaccine,12 using separate syringes and separate injection sites.

4.23.7 Recommendations

Children aged <9 months

Yellow fever vaccine is contraindicated in infants aged <9 months.

Children aged ≥9 months and adults

A single dose of yellow fever vaccine is recommended for:

  • persons ≥9 months of age travelling to, or iving in, areas with a risk of yellow fever virus transmission. Information about the risk for specific destinations should be sought from a reputable source, such as the World Health Organization (WHO),13 prior to travel.
  • laboratory personnel who routinely work with yellow fever virus.

Vaccination is generally not recommended when travelling to areas where there is low potential for yellow fever virus exposure (i.e. no human yellow fever cases ever reported and evidence to suggest only low levels of yellow fever virus transmission in the past). However, vaccination might be considered for a small subset of travellers to these areas who are at increased risk of exposure to mosquitoes or unable to avoid mosquito bites.

Booster vaccination

A booster dose of yellow fever vaccine is required for those at continued risk of yellow fever if 10 years or more have passed since a previous vaccine dose. Although data indicates that, in the majority of recipients, a single dose of yellow fever vaccine induces protective antibody levels that persist for many decades,8-10 travellers arriving from yellow fever endemic countries still require evidence of vaccination within the prior 10 years to meet entry requirements for many countries (refer to ‘International travel requirements’ below).Booster doses will also provide additional benefit to individuals who do not respond optimally to the primary vaccine dose.

International travel requirements

All those travelling to, or living in, countries with a risk of yellow fever virus transmission should be informed that the mosquito vectors of yellow fever usually bite during the day. They should be advised of the necessity for mosquito avoidance measures, even if vaccinated. 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.

Under International Health Regulations, many countries require travellers arriving from countries with a risk of yellow fever virus transmission to provide a valid International Certificate of Vaccination or Prophylaxis against yellow fever, or a valid letter of exemption, prior to entry. A country may require such documentation even for travellers who are only in transit through that country. This is because importation of the virus into these countries by an infected traveller could result in introduction and establishment of the virus in local Ae. aegypti mosquitoes. The most recent WHO list of individual country yellow fever vaccination requirements and recommendations for travellers can be found at (www.who.int/ith/en). As yellow fever disease patterns, like other diseases, are constantly changing, it is recommended that the entry requirements for yellow fever vaccination for the countries a traveller intends to enter or transit through be confirmed by contacting the country’s foreign missions in Australia.

Australia requires that travellers >1 year of age entering the country within 6 days of leaving a country on Australia’s list of yellow fever declared places have a valid International Certificate of Vaccination or Prophylaxis with proof of valid yellow fever vaccination. A list of yellow fever declared places is available from the Australian Government Department of Health’s yellow fever fact sheet (www.health.gov.au/yellowfever). Travellers who do not have a valid certificate are provided with information on yellow fever and required to promptly seek medical assessment if they develop relevant symptoms within 6 days of leaving the declared place.

Yellow fever vaccination and an International Certificate of Vaccination or Prophylaxis can only be provided by Yellow Fever Vaccination Centres approved by the relevant state or territory health authorities. The certificate becomes valid 10 days after vaccination and remains valid for 10 years. It must include the vaccinated person’s name and signature (or the signature of a parent or guardian of 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.

Note: People with a true contraindication to yellow fever vaccine (refer to 4.23.9 Contraindications below) who intend to travel to yellow fever risk countries 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. Arriving travellers who possess an exemption from the yellow fever vaccination are provided with information on yellow fever and required to promptly seek medical assessment if they develop relevant symptoms.

4.23.8 Pregnancy and breastfeeding

Yellow fever vaccine is not recommended for pregnant women or women breastfeeding infants aged <9 months.

As with all live attenuated virus vaccines, unless there is a risk of exposure to the virus, yellow fever vaccine should not routinely 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, where travel to an at-risk country is unavoidable, such women should be vaccinated (refer to 4.23.7 Recommendations above).14-17

The yellow fever vaccine has been given to considerable numbers of pregnant women7,14,15 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.7

Administration of yellow fever vaccine to women who are breastfeeding infants aged <9 months (and therefore unable to be vaccinated) should be avoided, except in situations where exposure to yellow fever virus cannot be avoided or postponed.16,17 While extremely rare, there have been several case reports of transmission of the vaccine strain of yellow fever virus via breast milk.16,17

Refer to 3.3 Groups with special vaccination requirements, Table 3.3.1 Recommendations for vaccination in pregnancy for more information.

4.23.9 Contraindications

Anaphylaxis to vaccine components

Yellow fever vaccine is contraindicated in persons who have had:

  • anaphylaxis following a previous dose of the vaccine
  • anaphylaxis following any vaccine component.

In particular, the vaccine is contraindicated in persons with a known anaphylaxis to eggs. Persons with a known allergy to eggs wishing to receive yellow fever vaccination should discuss this with either an immunologist/allergist or be referred to a specialised immunisation adverse events clinic. Contact a specialist travel medicine clinic or your local state or territory health authority for further details (refer to Appendix 1 Contact details for Australian, state and territory government health authorities and communicable disease control).

Infants

Routine yellow fever vaccine is contraindicated in infants <9 months of age. Countries experiencing a mass outbreak of yellow fever may elect to immunise infants from as young as 6 months of age.

Altered immune status

As with all live viral vaccines, the yellow fever vaccine should generally not be given to people who are immunocompromised due to either disease or medical treatment (refer to 3.3.3 Vaccination of immunocompromised persons). However, studies of small numbers of HIV-infected participants, mainly travellers with CD4+ counts >200 per μL, have shown reduced immune response, but good tolerability.18

Thymus disorders

People with a history of any thymus disorder, including myasthenia gravis, thymoma, thymectomy and DiGeorge syndrome, or thymic damage from chemoradiotherapy or graft-versus-host disease, should not be given the yellow fever vaccine due to the increased risk of yellow fever vaccine-associated viscerotropic disease (refer to 4.23.11 Adverse events below).

4.23.10 Precautions

Adults aged ≥60 years

The risk of severe adverse events following yellow fever vaccine is considerably greater in those aged ≥60 years than in younger adults.19-22

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.

Vaccination with other live attenuated parenteral vaccines

The administration of other parenteral live viral vaccines (e.g. MMR, MMRV, varicella or zoster vaccine) should be on the same day as yellow fever vaccine, or separated by a 4-week interval.

4.23.11 Adverse events

Mild adverse events

Adverse events following yellow fever vaccine are generally mild. Vaccine recipients often report mild headaches, myalgia and low-grade fevers or other minor symptoms in the first 5 days after vaccination, which can last up to 2 weeks9. In clinical trials in which symptoms are actively elicited, up to 25% of vaccine recipients report mild adverse events and up to 1% curtail regular activities.7,22,23

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.7,21,22 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,24 Stamaril does not contain gelatin.

Vaccine-associated neurotropic adverse events

Yellow fever vaccine-associated neurotropic disease (YF-AND) is rare.21 At least 25 cases of meningoencephalitis following yellow fever vaccination have been reported.7 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.7 Nevertheless, these adverse events, albeit very rare, still occur in adults; the risk is greater in persons ≥60 years of age.19,21

Vaccine-associated viscerotropic adverse events

Recently, an apparently very rare (and often fatal) complication, yellow fever vaccine-associated viscerotropic disease (YF-AVD), characterised by multi-organ 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.7,21

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 persons, it is apparent that the risk is increased with advanced age, particularly in those aged ≥60 years.19,20,22 Another host factor associated with an increased risk of a viscerotropic adverse event is pre-existing thymus disease. Published reports of YF-AVD cases have indicated that 4 of the 27 reported cases had a history of thymic tumour and thymectomy, both uncommon conditions.21,25

4.23.12 Public health management of yellow fever

Yellow fever is a notifiable and quarantinable disease in all states and territories in Australia.

Further instructions about the public health management of yellow fever, including management of cases of yellow fever and their contacts, should be obtained from state/territory public health authorities (refer to Appendix 1 Contact details for Australian, state and territory government health authorities and communicable disease control).

4.23.13 Variations from product information

The product information states that pregnancy is a contraindication to the yellow fever vaccine. The ATAGI recommends instead that pregnant women who insist on travelling 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. The ATAGI instead recommends 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. World Health Organization (WHO). Yellow fever fact sheet (revised in December 2009). Weekly Epidemiological Record 2010;85:33-6.
  3. Robertson SE, Hull BP, Tomori O, et al. Yellow fever: a decade of reemergence. JAMA 1996;276:1157-62.
  4. World Health Organization (WHO). The yellow fever situation in Africa and South America in 2004. Weekly Epidemiological Record 2005;80:250-6.
  5. World Health Organization (WHO). Outbreak news: Yellow fever, Paraguay. Weekly Epidemiological Record 2008;83:105.
  6. Monath TP, Cetron MS. Prevention of yellow fever in persons traveling to the tropics. Clinical Infectious Diseases 2002;34:1369-78.
  7. Monath TP, Cetron MS, Teuwen DE. Yellow fever vaccine. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia, PA: Saunders Elsevier, 2008.
  8. World Health Organization. Meeting of the Strategic Advisory Group of Experts on immunization, April 2013 – conclusions and recommendations. Weekly Epidemiological Record 2013;88:201-16.
  9. Monath TP, Nichols R, Archambault WT, et al. Comparative safety and immunogenicity of two yellow fever 17D vaccines (ARILVAX and YF-VAX) in a phase III multicenter, double-blind clinical trial. American Journal of Tropical Medicine and Hygiene 2002;66:533-41.
  10. Poland JD, Calisher CH, Monath TP, Downs WG, Murphy K. Persistence of neutralizing antibody 30–35 years after immunization with 17D yellow fever vaccine. Bulletin of the World Health Organization 1981;59:895-900.
  11. National vaccine storage guidelines: Strive for 5. 2nd ed. Canberra: Australian Government Department of Health and Ageing, 2013.
  12. Nasveld PE, Marjason J, Bennett S, et al. Concomitant or sequential administration of live attenuated Japanese encephalitis chimeric virus vaccine and yellow fever 17D vaccine: randomized double-blind phase II evaluation of safety and immunogenicity. Human Vaccines 2010;6:906-14.
  13. World Health Organization (WHO). International travel and health. Available at: (ww.who.int/ith/en/) (accessed Nov 2014).
  14. 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.
  15. Cavalcanti DP, Salomão MA, Lopez-Camelo J, Pessoto MA, Campinas Group of Yellow Fever Immunization during Pregnancy. Early exposure to yellow fever vaccine during pregnancy. Tropical Medicine and International Health 2007;12:833-7.
  16. Kuhn S, Twele-Montecinos L, MacDonald J, Webster P, Law B. Case report: Probable transmission of vaccine strain of yellow fever virus to an infant via breast milk. CMAJ Canadian Medical Association Journal 2011;183:E243-5.
  17. Centers for Disease Control and Prevention (CDC). Transmission of yellow fever vaccine virus through breast-feeding – Brazil, 2009. MMWR Morbidity and Mortality Weekly Report 2010;59:130-2.
  18. Veit O, Hatz C, Niedrig M, Furrer H. Yellow fever vaccination in HIV-infected patients. HIV Therapy 2010;4:17-26.
  19. 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.
  20. 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.
  21. Lindsey NP, Schroeder BA, Miller ER, et al. Adverse event reports following yellow fever vaccination. Vaccine 2008;26:6077-82.
  22. Domingo C, Niedrig M. Safety of 17D derived yellow fever vaccines. Expert Opinion on Drug Safety 2009;8:211-21.
  23. 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.
  24. Kelso JM, Mootrey GT, Tsai TF. Anaphylaxis from yellow fever vaccine. Journal of Allergy and Clinical Immunology 1999;103:698-701.
  25. Barwick Eidex R. History of thymoma and yellow fever vaccination [letter]. The Lancet 2004;364:936.