Yellow fever

Latest update: - Authors: Nele Alders, Ula Maniewski-Kelner

Yellow fever is a life-threatening infection that is caused by an arbovirus of the flavivirus genus. The ‘yellow’ in the name refers to the jaundice that affects some patients.

Transmission

Vector

Mosquitoes belonging to the Aedes and Haemogogus species that primarily bite during the day. The virus is transmitted by these vector species in a forest or rural cycle, and by Aedes aegypti in an urban environment.

Reservoirs

Monkeys are the primary reservoirs. Humans are only infected occasionally (sporadic infection of forest yellow fever). Large epidemics of yellow fever occur when infected people introduce the virus into heavily populated areas with high mosquito density and where most people have little or no immunity, due to a lack of vaccination. In these conditions, infected mosquitoes of the Aedes aegypti species transmit the virus from person to person.

Incubation period 

Short, 3 to 6 days.

Symptoms 

Most infections (80-85%) are subclinical or have minor symptoms, like fever, muscle pain, headache, loss of appetite, nausea or vomiting, which disappear after three to four days. After a short remission of symptoms, lasting up to 48 hours, a smaller proportion (20-15%) will develop a severe life-threatening disease with fever, jaundice, renal failure and hemorrhage. Approximately half ( 20% -60%)  of those die within seven to ten days. 

Risk areas

The virus is endemic in tropical areas of Africa and Central and South America. There is no risk above an altitude of 2300 metres

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Prevention

Prevention is important, since there is no cure for yellow fever, and only supportive treatment to ease the symptoms is available. 
Travellers at risk for yellow fever should be advised on:

Yellow fever vaccine (Stamaril ®)

Product: Stamaril, against 17 D-204 strain.
Type: Live-attenuated vaccine, produced by the inoculation of embryonated chicken eggs.
Route of administration: Subcutaneous.  
Immunity: Effective immunity within 10 days for 80-100% of people vaccinated, and within 30 days for more than 99% of people vaccinated. Testing of neutralizing antibodies is not recommended routinely but is sometimes useful in immune compromised patients, a titer of 1:10 is assumed to be protective.

Indication

Decisions regarding the use of yellow fever vaccine for travellers must take several factors into account including the risk of travel-associated yellow fever virus disease, country requirements and individual risk factors for serious adverse events after yellow fever vaccination (e.g., immune status).

Travel in endemic areas 
Vaccination is recommended in countries where there is a risk of yellow fever transmission, either due to a potential risk because of the presence of the mosquitos and the animal reservoir or because of currently reported cases. Not all countries where yellow fever is endemic will demand a proof of vaccination on entry but the fact that vaccination is not obligatory does not imply that there is no risk of yellow fever transmission and it is strongly recommended to be to vaccinated prior to visiting countries where travellers may be exposed to yellow fever. According to Belgian guidelines, vaccination is recommended when travelling to an endemic country, even when one does not plan a visit to an endemic region in that country, as travel plans change easily. Only for Argentina, vaccination is not recommended when visiting non endemic regions. 

Obligatory proof of vaccination
In accordance with the International Health Regulations (2005) some countries demand a proof of vaccination on entry: 
In Asia and in some areas of Africa and Latin America there is no yellow fever but because of the presence of the mosquitos vector and the animal reservoir there is a risk of introducing it into the country. For that reason, vaccination is sometimes required for travellers having visited an endemic country within 7 days before their arrival. 
Some endemic countries demand a yellow fever vaccination for everyone older than 9 months or 1 year entering the country regardless of their travel history. Other countries will require proof of vaccination if arriving from countries with a risk of yellow fever transmission or in case of a transit more than 12 hours (sometimes only 4 hours or less) through an airport of a country with a risk of yellow fever transmission. If a traveller remains at the airport for less than 12 hours he would strictly not require to be vaccinated, however some countries have a very strict entry policy and might demand proof of vaccination, even if the traveller hasn’t left the plane.
Keep in mind that unexpected travel issues can arise which might lead to a prolonged stay in a transit area and a therefore a prolonged exposure to yellow fever, in which case there is a risk of infection. Often during travel boarders are crossed so the yellow fever risk and local policy of adjacent countries should be taken into account.

Future travellers
It might be beneficial to vaccinate people pre-emptively who travel frequently on short notice
Young people without active travel plans but who will require immune modulating medication in the near future (ex. Crohn’s disease, kidney transplant,…)  could be vaccinated prior to starting treatment. It’s advised to respect a four-week waiting period between administering the vaccine and initiating immunosuppressive medication.   

Schedule 

The vaccine must be administered at least ten days prior to arrival and must be registered in an International Certificate of Vaccination or Prophylaxis. A second vaccination is valid immediately. 
The WHO decided in June 2016 that the proof of vaccination against yellow fever is administratively valid for life. However, it is not certain that everyone is effectively protected for life after a single vaccination. Therefore, the Belgian Study Group on Travel Medicine, under the auspices of the Belgian High Health Council, proposes a single reinforcement of vaccination at the occasion of a future travel. This can be at any time after the first dose (months or years, one does not have to wait ten years anymore) but at least 28 days after the first dose.  
Vaccination in children, pregnant woman and immunosuppressed patients deviate from the routine schedule, in which case the following advice is recommended:

Traveller Recommendation Length of protection

Travellers to endemic areas

Single booster vaccination, at the occasion of a future travel to an endemic region (1) 

Lifelong

Exceptions

Traveller Recommendation Length of protection

Children younger than 1 year

Repeat vaccination after the age of 2 years

Until the day of 2nd birthday

Children between 1 and 2 years

Repeat next travel

1 year

Pregnant women

Repeat next travel

1 year

Interval <28 days between measles and yellow fever vaccination

Repeat next travel

1 year

HIV

Repeat every 10 years

10 years

Immunosuppression

Measure neutralizing antibodies

10 years

After bone marrow transplantation

Restart (if no contra-indications)

Not applicable

Lab worker manipulating live yellow fever virus

Single reinforcing vaccinations (1)

Lifelong

The column "recommendation" shows what we advice in practice. The column "length of protection" shows what we write in the International Certificate of Vaccination or Prophylaxis.
(1) The booster vaccination can be administered at any time after the first dose (months or years, one does not have to wait 10 years anymore), but at least 28 days after the first dose.

Side- effects

Up to 20% will have a short period (<24hrs) with mild flue like symptoms, this usually presents between day five and ten and is self-limiting. Less than 1 per 100 will temporarily be unable to go into work. 

Anaphylaxis
It's estimated in five to twenty per one million patients (1/50 000 – 1/200 000). This is most likely due to an allergy to egg or gelatine components. The tip caps of the prefilled syringes contain a natural rubber latex derivative, which may cause allergic reactions in latex sensitive individuals.

Yellow fever vaccine- associated neurologic disease (YEL-AND)
YEL-AND is rare with an overall risk of 0.8 per 100 000 vaccinations according to CDC, 2/3 of the cases occurred in children younger than 6 months. It consists of different neurological complications (e.g., meningoencephalitis, Guillain-Barré syndrome, acute disseminated encephalomyelitis, cranial nerve palsies) due to an immunological reaction or due to invasion of the vaccine virus in neurological tissue. This complication is seen 2 to 56 days after vaccination.

Yellow fever vaccine- associated viscerotropic diseases (YEL-AVD)
YEL-AVD is a syndrome of fever with multi- organ failure that resembles severe yellow fever disease. It was first described in 2001 and over a hundred confirmed cases have been reported worldwide,  death has occurred in more than 60% of reported cases. It has only been seen with people receiving their first vaccination and develops 3 to 5 days (range 1 to 18 days) following administration.  
YEL-AVD has been estimated to be reported in 0.3 cases per 100 000 doses distributed according to CDC. The rates increase with increasing age: from 1 per 100 000 vaccines in people aged 60-70 year up to 2.3 per 100 000 vaccines when older than 70 years. Risk factors for developing YEL-AVD are increasing age, thymus disorders and removal of the thymus gland. 
The estimated overall risk for complicated or fatal yellow fever infections for travellers to endemic areas is estimated between 0.5 to 5 per 1 000 000 travellers per month. This risk can increase up to 100 per 1 000 000 travellers per month when staying in rural areas in West Africa between July and October (end of rain season and start of dry season). 
The small risk of complications due to vaccination often outweighs the risk of potential complication due to infection when traveling to countries where yellow fever is present. 
In case a patient would present with a clinical picture suggestive of YEL-AND or YEL-AVD (at least 38,5°C for more than 24hr) further laboratory investigations are required to confirm the diagnosis. It’s advised to contact the medical team of Institute of Tropical Medicine to discuss this further.  The federal agency for medicines and Health Products (FAGG) should be notified and this can be done through their website

Contraindications

Absolute contraindications

  • Severe allergy to eggs or latex or any other component
  • Child under the age of six months
  • Thymus dysfunction with abnormal immune cell function
  • (Severe) immune disorders (such as HIV with CD4< 200/µl, post-transplant, treatment with immune modulators or suppressants, primary immune deficiency)

Relative contraindications

  • Primo-vaccination ≥60 years of age
  • Child between six and nine months old
  • Pregnancy
  • Breastfeeding in infants under six months
  • Asymptomatic HIV with CD4 200 - 500/mm³

Allergy to egg products (anaphylaxis)
The vaccine often can be administered after a small test dose (percutaneous or intradermal). This should be done in a hospital setting where adequate resuscitation support is readily available.
When it’s not possible to proceed with the subcutaneous dose due to anaphylaxis to the test dose, there is still a good chance that the small intradermal test dose will result in protective neutralizing antibodies.
However, the World Health Organization notes that a fractional dose of yellow fever vaccine does not meet the requirements of a vaccine dose according to the International Health Regulations, and therefore proof of vaccination may not be issued to a person who only received a fractional dose.  

Patients with primary or secondary acquired immunodeficiencies 
Due to potential serious side effects, vaccination is not recommended in patients with severe immunodeficiencies (e.g., HIV CD4< 200/µl, post-transplant, immune modulating or suppressive therapy, primary immune deficiency). The guideline of vaccination of immunocompromised patients of the Superior Health Council should be consulted for more detailed information.
In those particular cases that vaccination is contra-indicated, it should be documented in the official vaccination booklet that “vaccination is contra-indicated for medical reasons” and/or a separate certificate should be provided. This should always have a limited duration of validity.  
It’s unclear due to the lack of data if immunocompromised patients will be able to mount a protective immune response and maintain it for ten years after vaccination. Protective neutralising antibodies can be measured one to two months after vaccination. 

Thymus dysfunction with abnormal immune cell function
Vaccination is contraindicated in patients who have a thymus disorder associated with abnormal immune cell function (e.g., thymoma, Di George). There is no evidence of immunodysfunction or increased risk of yellow fever vaccine-associated serious adverse events in people who have undergone incidental thymectomy, or who have had indirect radiation therapy, so these people can be vaccinated.

Precautions 

Children
In Belgium, the vaccine can be administered to children starting from 9 months of age. In cases there is a high risk (e.g., visiting friends and relatives who will be spending several weeks to months in rural areas) it might be exceptional administered to children from the age of 6 months. The dose for children is 0.5ml of the reconstituted vaccine and is the same as adult dosing.

  • < 6 months: Absolute contra-indication
  • 6-9 months: Only after expert advice in very specific circumstances
  • >9 months: Licensed

Pregnancy
Non-vaccinated pregnant woman should be advised against travel to a high-risk area. When travel is unavoidable the risk from the disease and the risk from the vaccine (theoretical risk of foetal infection from the live virus vaccine) should be assessed on an individual basis.
Studies performed in Nigeria (Nasidi 1993) and Brazil (Suzano 2006) during mass vaccination campaigns in outbreaks showed no adverse foetal outcomes.
In general, it’s advised to delay pregnancy until one month after a live vaccine administration. In case a non-vaccinated pregnant woman travels to an endemic area, and therefor has a true risk of contracting yellow fever, the benefits of vaccination are likely to far outweigh the risk of the vaccine and therefor the vaccine is usually advised.
In case of travel to a country with a low risk (yellow area) where proof of yellow fever vaccination is obligatory on entry, but without an endemic risk, vaccination is not recommended and a certificate of medical contraindication can be issued. 
In case of a second dose, there is usually no viraemia (or only very minimal and short) so theoretically there is less foetal risk, but booster vaccinations are in general not advised during pregnancy.
The immunological response to the vaccine can be diminished in the third trimester and the duration of protection is uncertain therefor a booster before next travel to an endemic area is recommended. 

Breastfeeding
The yellow fever virus and vaccine can be transmitted into breastmilk. Breastfeeding is a relative contraindication for yellow fever vaccination, especially if the nursing infant is less than 6 months old. Transmission of the vaccine virus was demonstrated in 3 infants (< 1 months) who developed transient meningo- encephalitis but without long term consequences. Administration of yellow fever vaccine to breast-feeding woman ideally should be avoided but could be considered if exposure to yellow fever viruses cannot be avoided. It is recommended that breastfeeding is suspended for two weeks post-vaccination.  
It is advised that infants over 9 months of age receive the vaccine if they will be traveling with their mother to a yellow fever endemic area. Exposure to the yellow fever vaccine via breastmilk does not present an increased risk to an infant who also receives the vaccination. 

Adults 60 years of age or older
There is an increased risk of YEL-AND and YEL-AVD in people older than 60 years of age, mainly reported in primary vaccine recipients. The rate of reported serious adverse events in people ≥60 years is 7.7 per 100 000 doses compared to 3.8 per 100 000 in the overall population, so caution should be exercised with older travellers who might receive the vaccine for the first time. The decision to vaccinate needs to weigh the risks and benefits of the vaccination in the context of their destination-specific risk for exposure to yellow fever.
Considerations for travellers over 60 years of age to a low-risk country (yellow):

  PROs CONs
Future travel plans to yellow fever area. No other travel to endemic areas in the future.
Visit neighbouring countries: problems at border crossings or countries where yellow fever is endemic. Serious adverse reaction after yellow fever vaccination in a relative.
Prolonged travel or travel with unavoidable exposure to mosquitoes. -

Other vaccines and medication
The vaccine can be administered at the same time as other non-live vaccinations (hepatitis A or B , tetanus, inactivated polio, inactivated typhoid, Japanese encephalitis …).
Vaccination against measles (live attenuated vaccine) is preferably given with an interval of 4 weeks since the immune response might be reduced when they are given concomitantly. It can be administered together with immunoglobulins and antimalaria medication.

Tuberculosis intradermal skin test (Mantoux)
The vaccine can interfere with a tuberculosis intradermal skin test, as any live virus vaccine, with a risk of a false-negative test result due to a possible suppressed immune response. Therefore the vaccine should preferably not be administered in a period of four weeks before a tuberculin skin test.

Blood donations 
Blood donations should be deferred until 4 weeks after vaccination. 

Additional information

References

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