Yellow Fever Vaccination

See also separate article on Yellow Fever.

Yellow fever is a mosquito-borne viral haemorrhagic fever. Symptoms develop 3-6 days after being bitten by an infected mosquito. It produces a spectrum of illness, with approximately one in seven people infected developing a rapidly progressive (or 'toxic phase') illness characterised by hepatitis, renal failure, haemorrhagic and cardiovascular shock. Of these severely affected cases, approximately half will die. The World Health Organisation (WHO) estimates that there are about 200,000 cases globally and 30,000 deaths due to the disease per year despite there being an effective vaccine available for more than half a decade.¹

Without a specific treatment, vaccination is the best method of preventing and controlling the disease. The main preventative strategies employed against yellow fever are:

• Giving yellow fever vaccine as part of routine infant immunisation (usually at the same time as measles vaccine) in countries where the disease is endemic.
• The use of mass vaccination campaigns to prevent outbreaks in high-risk areas.
• Control of Aedes aegypti mosquitoes in urban centres.

Yellow fever is endemic in many parts of sub-Saharan Africa and tropical South America, where both sporadic cases and epidemic outbreaks may occur. Yellow fever is rare in travellers to these regions and, since 1996, there have been just six fatal imported cases in European and US travellers. All were in unvaccinated travellers.

Yellow fever vaccination is recommended for travel to all countries in the endemic zones, whether or not an international certificate is required, and especially if rural areas will be visited. (Consult up-to-date country specific advice.)²

This vaccination is not available on the National Health Service and is given by registered Yellow Fever Centres.³

• The 17D live attenuated vaccine was developed in 1936 by Max Theiler and his team and became widely available in 1951. It has been one of the most successful antiviral vaccines to date and over 540 million doses have been used worldwide.⁴
• Wherever high vaccination rates (>80%) have been achieved the incidence of yellow fever has declined. However, whilst the majority of countries with endemic yellow fever do have vaccination programmes, few achieve vaccination coverage of more than half of their population.^1,5
• Expansion of travel to these areas has increased demand for the vaccine and every year there are shortages.

• It is administered as a single dose by deep subcutaneous route and provides immunity in 95-100% of travellers.²
• Immunity probably persists for life, but re-vaccination is advised after 10 years for those whose risk of contracting the disease persists.⁶
• The vaccine can only be given at specialist centres.
• Proof of yellow fever vaccination, recorded on an International Certificate of Vaccination, is now the only vaccination certificate that should be required in international travel. Many countries require this of travellers, including those in transit, arriving from infected areas or from countries with infected areas.⁷ Some countries require evidence of vaccination from all entering travellers, even when they have come direct from a non-endemic country. This can be strictly enforced, particularly for people arriving in Asia from Africa or South America. Failure to comply may result in being quarantined for several days. The certificate is valid from the tenth day after primary vaccination and lasts for 10 years. If vaccination is contra-indicated, dispensation is possible and an exemption certificate of WHO standard should be issued.
• Live vaccines can be given at the same time as inactivated ones. Other live vaccines can be administered at the same time as yellow fever vaccine, but must be given at different sites and in different syringes. If they are not given on the same day, they should be separated by an interval of at least three weeks.
• It is good practice to obtain written or verbal consent, prior to vaccination.
• Patient details, together with date, time, batch number and site of vaccination should be recorded, and an immunisation certificate issued, which is signed by patient and stamped by issuing centre.

• Anaphylaxis or serious hypersensitivity reactions:
  • It should not be given to those who have had a confirmed anaphylactic reaction or serious hypersensitivity reaction following a previous dose of the same vaccine.⁸
  • Do not give if an individual has had a confirmed reaction to a constituent of the vaccine including a history of oral intolerance to eggs or chicken protein or gelatin. These patients should have allergy testing with diluted vaccine, and have de-sensitisation procedure if necessary.
• Immunosuppression, whether congenital, idiopathic or as a result of treatment with systemic steroids (excluding standard dose of topical or inhaled steroids), radiotherapy or cytotoxic drugs. Solid organ transplant recipients should not receive live vaccine.⁹
• History of thymus dysfunction (including thymoma, thymectomy) - thymic disorders predispose to viscerotropic adverse events.
• Symptomatic HIV infection, or HIV-positive with signs of impaired immunity. Some travel clinics decide whether to administer the vaccine on the basis of the CD4 count.¹
• Current severe febrile illness.
• Breastfeeding - the WHO has recommended that the vaccine be used with caution in breast-feeding mothers. In the UK the labelling states this is a contra-indication.
• Other severe adverse reactions. This means an extensive area of redness and swelling affecting a large area of the arm or leg, accompanied by a fever of 39.5° or higher, within 48 hours of the injection.
• Age is a relative contra-indication:
  • >60 years - in patients aged 60-69, the rate of any serious adverse event following vaccination is 1.5 times higher than the average and 3 times higher for those aged 70 years or older.¹⁰ In particular, there is concern that the rare but serious risk of viscerotropic adverse events is increased (see below). Carefully consider the benefits of vaccination in the context of the patient's risk for exposure to yellow fever virus based on the destination.
  • <6 months - do not give the vaccine.⁸ The decision to immunise infants who are 6-8 months old must balance the infant's risk of exposure to yellow fever with the risk for vaccine-associated encephalitis.¹⁰

The following do not contra-indicate vaccination:

• A personal or family history of asthma, allergy, hay fever or eczema
• Prematurity
• Stable neurological conditions, e.g. cerebral palsy, Down's syndrome or epilepsy
• Contact with infectious disease
• Treatment with antibiotics or local corticosteroids
• A child who is being breast-fed
• Being underweight
• Taking replacement corticosteroids

• Acute illness - postpone immunisation until recovered. Minor infections, without fever or systemic upset are not reasons to postpone.¹¹
• Pregnancy - the WHO and the Advisory Committee on Immunization Practices (ACIP) recommend that live vaccines should be used only when the benefits clearly outweigh the risks .There is a much lower sero-conversion rate in pregnancy.¹² Vaccination whilst pregnant is not an indication for abortion.
• Immunosuppression - see above. Immunosuppression increases the likelihood of severe adverse reactions. People at risk include patients receiving chemotherapy or generalised radiotherapy; patients on systemic corticosteroids for one week (high-dose) or long-term low-dose. Consult expert advice as to risk. Patients with asymptomatic HIV infection, can be given live vaccines but these individuals may not be able to mount a full immune response.¹³

The most commonly reported symptoms include:

• Headache, fatigue and malaise - these are also commonly reported by placebo patients.¹⁴
• Injection site erythema.
• Acute meningo-encephalitis - the disease is self-limiting, though long-term sequelae have been noted.¹⁵
• Yellow fever vaccine-associated neurotropic disease (YEL-AND) e.g. Guillain-Barré syndrome, Bell's palsy, optic neuritis.^16,17 This suggests the vaccine may elicit autoimmune reactions - and is more common in those over 60 years of age. Its incidence is estimated at four cases per million doses of vaccine.
• Yellow fever vaccine-associated viscerotropic disease (YEL-AVD) - this rare reaction was first recognised in 1996. It is characterised by hepatitis and multi-organ failure, like wild-type yellow fever. It also has similarly high fatality rates. It is extremely rare (three cases per million doses of vaccine). There is a genetic basis to susceptibility and old age or history of thymic disease or related conditions (e.g. myasthenia gravis) have also been implicated.^17,18

Yellow fever vaccine is highly effective and its benefits far outweigh the risks for those people with a true risk of exposure to wild-type yellow fever virus.¹⁹ Nonetheless, there have been calls for the development of a new inactivated (and so safer) vaccine.²⁰

1. WHO Yellow fever vaccine
2. Department of Health; 'Yellow Book': Health information for overseas travel; 2001.
3. Yellow Fever Centres (by postcode) - NaTHNaC
4. Barrett AD, Teuwen DE; Yellow fever vaccine - how does it work and why do rare cases of serious adverse events take place? Curr Opin Immunol. 2009 Jun;21(3):308-13. Epub 2009 Jun 10. [abstract]
5. Tolle MA; Mosquito-borne diseases. Curr Probl Pediatr Adolesc Health Care. 2009 Apr;39(4):97-140. [abstract]
6. Poland JD, Calisher CH, Monath TP, et al; Persistence of neutralizing antibody 30-35 years after immunization with 17D yellow fever vaccine.; Bull World Health Organ. 1981;59(6):895-900.
7. WHO List of countries with risk of yellow fever transmission and countries requiring yellow fever vaccination, 2007.
8. Summary of Product Characteristics - Stamaril® (yellow fever vaccine) Sanofi Pasteur MSD Limited; Updated April 2008
9. Ballout A, Goffin E, Yombi JC, et al; Vaccinations for adult solid organ transplant recipient: current recommendations.; Transplant Proc. 2005 Jul-Aug;37(6):2826-7. [abstract]
10. CDC Traveller's health - yellow fever, 2010.
11. Immunisation against infectious disease - 'The Green Book', Department of Health (various dates)
12. Nasidi A, Monath TP, Vandenberg J, et al; Yellow fever vaccination and pregnancy: a four-year prospective study.; Trans R Soc Trop Med Hyg. 1993 May-Jun;87(3):337-9. [abstract]
13. Veit O, Niedrig M, Chapuis-Taillard C, et al; Immunogenicity and safety of yellow fever vaccination for 102 HIV-infected patients. Clin Infect Dis. 2009 Mar 1;48(5):659-66. [abstract]
14. Monath TP, Guirakhoo F, Nichols R, et al; Chimeric live, attenuated vaccine against Japanese encephalitis (ChimeriVax-JE): phase 2 clinical trials for safety and immunogenicity, effect of vaccine dose and schedule, and memory response to challenge with inactivated Japanese encephalitis antigen.; J Infect Dis. 2003 Oct 15;188(8):1213-30. Epub 2003 Oct 3. [abstract]
15. Merlo C, Steffen R, Landis T, et al; Possible association of encephalitis and 17D yellow fever vaccination in a 29-year-old traveller.; Vaccine. 1993;11(6):691.
16. Vital C, Vital A, Gbikpi-Benissan G, et al; Postvaccinal inflammatory neuropathy: peripheral nerve biopsy in 3 cases.; J Peripher Nerv Syst. 2002 Sep;7(3):163-7. [abstract]
17. Barwick R; History of thymoma and yellow fever vaccination.; Lancet. 2004 Sep 11-17;364(9438):936.
18. WHO: Yellow fever vaccine safety, as in Weekly Epidemiological Record (WER) 7 January 2005
19. Domingo C, Niedrig M; Safety of 17D derived yellow fever vaccines. Expert Opin Drug Saf. 2009 Mar;8(2):211-21. [abstract]
20. Barnett ED, Wilder-Smith A, Wilson ME; Yellow fever vaccines and international travelers. Expert Rev Vaccines. 2008 Jul;7(5):579-87. [abstract]

• National Travel Health Network and Centre - NaTHNaC
• NaTHNaC Yellow fever endemic areas - South America
• NaTHNaC Yellow fever endemic areas - Africa
• Immunizations - travel vaccinations, Clinical Knowledge Summaries (2007)