Yellow fever

What

Yellow fever is a viral disease that is transmitted by infected mosquitoes. Complications from yellow fever can be severe and can cause death.

Who

Yellow fever vaccine is recommended for:

• people who work in laboratories with the yellow fever virus
• people aged ≥9 months who are travelling to an area with a risk of yellow fever virus transmission

How

Yellow fever vaccine is recommended for laboratory workers who work with the yellow fever virus. Workers should have their antibody titres measured if their last vaccine dose was 10 years ago or more to check that they still have protective antibody levels.

Yellow fever vaccine is recommended for people ≥9 months of age who are travelling to an area with a risk of yellow fever virus transmission.

The following travellers are recommended to receive a booster dose if their last vaccine dose was 10 years ago or more:

• women who were pregnant (in any trimester) when they received their 1st dose of yellow fever vaccine
• people who had HIV when they received their 1st dose of yellow fever vaccine
• people who will be staying in a high-risk location for an extended period of time
• people travelling to an area with ongoing outbreaks

People who have had a haematopoietic stem cell transplant after a dose of yellow fever vaccine are recommended to receive an extra vaccine dose if they will be in an area with a risk of yellow fever virus transmission.

Why

Yellow fever virus is endemic in tropical and subtropical regions of Africa and South America where it causes significant illness and death. Vaccination prevents international spread of the disease and some countries require documented evidence of yellow fever vaccination as a condition for entry.

The Therapeutic Goods Administration website provides product information for each vaccine.

See also Vaccine information and Variations from product information for more details.

Dose and route of administration

The dose of yellow fever vaccine in children and adults is 0.5 mL given by either intramuscular or subcutaneous injection.

Only Yellow Fever Vaccination Centres can provide yellow fever vaccination. These centres must be approved by the relevant state or territory health authorities. See International travel requirements.

Co-administration with other vaccines

Children and adults can receive yellow fever vaccine at any time before or after, or with, inactivated vaccines and oral live vaccines relevant to travel (such as cholera and typhoid).

Children and adults can receive yellow fever vaccine and most other parenteral live vaccines either:

• on the same day, or
• at least 4 weeks apart

If a person receives yellow fever vaccine at the same time as other live vaccines, this does not affect their immune response to any of the vaccine antigens. This includes co-administration with:

• Japanese encephalitis vaccine⁷
• BCG (bacille Calmette–Guérin) vaccine

One Brazilian study suggested that co-administration of yellow fever and MMR vaccines on the same day resulted in lower seroconversion rates to the vaccine antigens than when the vaccines were given at least 4 weeks apart.⁸ A more recent study showed lower antibody concentrations for two of the antigens, but non-inferior seroconversion for all antigens, when the vaccines were co-administered as compared with a 4 week interval.⁹ While it is preferable to give yellow fever and MMR vaccines 4 weeks apart, if protection is required rapidly or there is a concern about a missed opportunity for vaccination, the two vaccines can be given at the same visit. An additional dose of MMR should be considered and re-vaccination with the yellow fever vaccine can also be considered on a case-by-case basis for those at on-going risk. See Immunogenicity in children in Vaccine information.

Contraindications

Anyone with a true contraindication to yellow fever vaccination should be advised against going to an area with a risk of yellow fever virus transmission.

However, if such travel is unavoidable, the person should receive information about avoiding mosquitoes (see Avoiding mosquitoes) and a medical exemption letter which is required for crossing borders – see Exemptions to vaccination and International travel requirements.

Anaphylaxis to vaccine components

Yellow fever vaccine is contraindicated in people who have had:

• anaphylaxis after a previous dose of any yellow fever vaccine
• anaphylaxis after any component of a yellow fever vaccine
• anaphylaxis to eggs

Yellow fever vaccine has been safely given to some children with anaphylaxis to eggs.^10,11 People with a known allergy to eggs who want to receive yellow fever vaccine should discuss this with an immunologist or allergist, or be referred to a specialised immunisation adverse events clinic.

Contact a specialist travel medicine clinic or your state or territory health authority for more details.

Infants

Routine yellow fever vaccine is generally contraindicated in infants <9 months of age. This is because of the risk of severe adverse events after vaccination (see Adverse events).

However, countries experiencing a mass outbreak of yellow fever may choose to immunise infants from as young as 6 months of age.¹²

People who are immunocompromised

The yellow fever vaccine is a live viral vaccine. It should generally not be given to people who are immunocompromised.

However, vaccination can be considered case by case. This needs to take into account factors such as risk of exposure and level of immunocompromise. See Vaccination for people who are immunocompromised.

People who are immunocompromised may not mount a sufficient immune response after vaccination. They may also be at risk of vaccine-related adverse events. However, few studies have assessed yellow fever vaccine immunogenicity in people who are immunocompromised (see Vaccine information).

Some people who have HIV and are at risk of yellow fever virus infection can receive the vaccine. See People with HIV.

People with thymus disorders

People with a history of any thymus disorder should not receive yellow fever vaccine. This is due to the increased risk of yellow fever vaccine–associated viscerotropic disease.¹³ See Adverse events.

Relevant thymus conditions include:

• myasthenia gravis
• thymoma
• thymectomy
• DiGeorge syndrome
• thymic damage from chemoradiotherapy or graft-versus-host disease

Precautions

Adults aged ≥60 years

Adults aged ≥60 years have a higher risk of severe adverse events after yellow fever vaccination than younger adults.^14-18 See Vaccine-associated neurotropic adverse events and Vaccine-associated viscerotropic adverse events.

Adults ≥60 years of age should receive yellow fever vaccine only if they intend to travel to endemic countries (see Recommendations). They should also receive information about the risk of developing a severe complication, even though this risk is very low.

Haematopoietic stem cell transplant recipients

People who have had a haematopoietic stem cell transplant after a dose of yellow fever vaccine are recommended to receive an extra vaccine dose if they will be in an area with a risk of yellow fever virus transmission. This is regardless of when they received their last dose.

People with HIV

People with HIV can receive a yellow fever vaccine, unless they are immunocompromised or symptomatic. See Vaccination for people who are immunocompromised. 

Studies of yellow fever vaccine in small numbers of people with HIV suggest a reduced immune response, but vaccination is well tolerated.^19,20 See Vaccine information.

There are few studies of yellow fever vaccine in people with HIV who have CD4⁺ counts of <200 per µL. These people should receive yellow fever vaccine only if they cannot avoid the risk of yellow fever infection. This should be considered case by case.

People with possible IFNAR1 deficiency

IFNAR1 deficiency is a rare inherited condition affecting some people of Western Polynesian heritage including Tongan, Samoan and Niuean. It is associated with severe illness and death from certain viral infections and also potentially from some live attenuated viral vaccines including the measles, mumps and rubella (MMR) vaccine and yellow fever vaccine.^21,22 Currently, diagnosis of IFNAR1 deficiency prior to vaccination is challenging and there is no established treatment.

Healthcare providers need to be aware that people of Western Polynesian heritage who present for medical attention and are very unwell in the 1-2 weeks following a yellow fever vaccine may need further investigation by an immunologist to assess for an immune deficiency. Any suspected adverse event following immunisation should be reported. Family members of individuals who have had a severe reaction to a live attenuated viral vaccine, or are related to someone with known IFNAR1 deficiency, should be referred to an immunologist before having these vaccines.

Advice on vaccination of children or adults who have been diagnosed with IFNAR1 or any other specific immune deficiency should be sought from their immunologist.

Women who are pregnant or breastfeeding

Yellow fever vaccine is not recommended, other than in exceptional circumstances, for:

• pregnant women
• women who are breastfeeding infants aged <9 months

See Table. Vaccines that are not recommended in pregnancy in Vaccination for women who are planning pregnancy, pregnant or breastfeeding for more details.

Pregnant women

Yellow fever vaccine is a live viral vaccine (see Vaccine information). Live viral vaccines are generally contraindicated in pregnant women except in extenuating circumstances. Pregnant women are not recommended to receive yellow fever vaccine unless there is a risk of exposure to the virus.

Pregnant women should be advised against travelling to an area with a risk of yellow fever virus transmission. However, if travel is unavoidable, pregnant women should receive the vaccine.^23-26

Women who received their 1st dose of yellow fever vaccine while pregnant may need booster doses if they remain at risk of yellow fever virus infection. See Recommendations.

Many pregnant women have received the yellow fever vaccine^23,26,27 with no evidence of any adverse outcomes. This means that women who are vaccinated in early pregnancy can be reassured that there is:²⁷

• no evidence of risk to themselves 
• very low — if any — risk to the fetus

Breastfeeding women

Women who are breastfeeding infants aged <9 months should avoid being vaccinated against yellow fever.

However, breastfeeding women who cannot avoid or postpone potential exposure to yellow fever virus should receive a yellow fever vaccine.^24,25

Several case reports have shown that the vaccine strain of yellow fever virus can be transmitted through breast milk. This has resulted in probable vaccine-associated neurotropic disease in infants. This adverse event is extremely rare. On follow-up of these infants, their neurological development was normal.^24,25 See Adverse events.

Mild adverse events

Adverse events after receiving yellow fever vaccine are generally mild, such as:

• headaches
• myalgia
• low-grade fevers
• other minor symptoms

Symptoms usually appear in the first 5 days after vaccination, and can last up to 2 weeks.²⁸ In clinical trials in which people were specifically asked about their symptoms:^14,27,29

• up to 25% of vaccine recipients reported mild adverse events
• up to 1% restricted their regular activities

Immediate hypersensitivity reactions

Immediate hypersensitivity reactions, including anaphylaxis, after yellow fever vaccination are very rare — less than 1 in 1 million. These reactions mainly occur in people with an anaphylactic sensitivity to eggs.^14,17,27 

An anaphylactic sensitivity to gelatin may also trigger anaphylaxis after vaccination.³⁰ Some yellow fever vaccines contain gelatin as a stabiliser. Stamaril does not contain gelatin.

Vaccine-associated neurotropic adverse events

Yellow fever vaccine–associated neurotropic disease (YF-AND) is a severe adverse event that can be fatal in rare cases. YF-AND has several distinct clinical syndromes, including:^31,32

• meningoencephalitis (neurotropic disease)
• Guillain–Barré syndrome
• acute disseminated encephalomyelitis
• bulbar palsy

Between 1992 and 2014, more than 200 cases of neurological adverse events after yellow fever vaccination were reported worldwide.²⁷

YF-AND is more likely to occur in very young infants and older people. Of 23 cases of meningoencephalitis reported between 1945 and 2001, 16 (70%) were infants <9 months of age. Most were <4 months of age.³³

In the 1960s, recommendations against immunising infants aged <6 months led to fewer reports of encephalitis.^34,35 Although YF-AND is rare in adults, adults ≥60 years of age have the highest risk.^15,17,36

Vaccine-associated viscerotropic adverse events

Yellow fever vaccine–associated viscerotropic disease (YF-AVD) is a rare but severe adverse event after yellow fever vaccination. YF-AVD is characterised by multiorgan system failure. It occurs in 3–4 cases per million doses of vaccine. YF-AVD mimics naturally acquired yellow fever disease. The vaccine virus proliferates and disseminates throughout the body.³⁷

2 risk factors have been identified for YF-AVD:

• older age
• history of thymus disease or thymectomy

A systematic review of YF-AVD among older people showed that older travellers have an increased risk of YF-AVD. However, the risk among older people in endemic populations is unknown.¹⁸ Of the initial 27 reported cases of YF-AVD worldwide, 4 occurred in people who had thymectomies performed for thymomas.¹³ The prevalence of thymomas in the general population is low.^13,38

Several cases of YF-AVD have involved a history of autoimmune disease or diseases with potential autoimmune aetiology. However, in several of these cases, the person also had another known risk factor. More information is needed to assess the risk of YF-AVD in people with autoimmune disease.³³

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

Pathogenesis

The incubation period is typically 3–6 days. Humans infected with yellow fever virus are infectious to mosquitoes shortly before the onset of fever and for 3–5 days after that.³⁹

Transmission

The virus is transmitted by mosquitoes (mainly Aedes aegypti) through 2 zoonotic transmission cycles:

• jungle (sylvatic), between non-human primates and mosquitoes
• urban, between humans and mosquitoes

In Africa, an intermediate transmission cycle exists between humans or non-human primates and Aedes species mosquitoes that breed in tree holes in savanna areas. ⁴⁰

Initial symptoms of yellow fever

The clinical spectrum of yellow fever varies from a non-specific febrile illness to fatal haemorrhagic fever.⁴¹ The disease begins abruptly with:

• fever
• prostration
• myalgia
• headache
• eye congestion

The patient appears acutely ill.

The symptoms indicate a ‘period of infection’. During this time, there is an intense viraemia that lasts 3–4 days.⁴¹

This may be followed by the ‘period of remission’. During this time, the fever and symptoms settle over 24–48 hours, and the immune response clears the virus.⁴¹

Relapse and complications of yellow fever

Approximately 15–25% of patients relapse. This is called the ‘period of intoxication’. Symptoms and complications include:⁴¹

• high fever
• vomiting
• epigastric pain
• jaundice
• renal failure
• haemorrhage

These complications can be severe. The period of intoxication reflects the viscerotropic nature of the yellow fever virus — that is, its ability to infect the liver, heart and kidneys. The case-fatality rate varies widely. It has been reported as 14% in African countries and 48% in South American countries.²⁷

Yellow fever virus occurs in tropical and subtropical regions of Africa and South America. It is endemic and intermittently epidemic in these regions.

Endemic areas

The epidemiology of yellow fever is dynamic due to changes in:⁴⁰

• climate, such as rainfall patterns
• human factors, such as migration and air travel

West Africa has the highest burden of yellow fever disease. Fewer cases occur in other regions of Africa and South America.²⁷

In 2016, 1080 cases of yellow fever, including 171 deaths, were reported to the World Health Organization (WHO) from 6 countries:⁴²

• Angola
• Democratic Republic of the Congo
• Uganda
• Brazil
• Colombia
• Peru

In 2006, WHO introduced the Yellow Fever Initiative, which aims to control and eliminate epidemic yellow fever in Africa. Strategies include:

• including yellow fever vaccine in routine childhood immunisation programs
• mass vaccination campaigns

South America has used a similar approach.⁴³ While in endemic areas with high vaccination coverage, yellow fever outbreaks decreased substantially, outbreaks still occur. For example, a 2017–2018 epidemic in urban states in Brazil involved 3028 suspected cases and 176 deaths⁴⁴ and was attributed to an unusually severe drought.⁴⁵

Risk to travellers

The risk of susceptible travellers acquiring yellow fever varies considerably. It depends on:

• season
• location of travel
• duration of travel
• use of mosquito avoidance measures 

Importantly, the 2017–2018 outbreak in Brazil demonstrates that urban areas can present a transmission risk to travellers.

Some cases of yellow fever in unvaccinated travellers to Africa and South America have been fatal.^46,47

Travellers should seek up-to-date information about yellow fever virus activity and risk of yellow fever in their travel destinations from reputable sources, such as: 

• the WHO web page on international travel and health¹
• the Centers for Disease Control and Prevention web page on travellers’ health²

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

Efficacy and immunogenicity

No studies have directly assessed the efficacy of yellow fever vaccine. Immunogenicity is used as a surrogate for protection. Thresholds for protective immunity are defined as either: ⁴⁸

• log₁₀ neutralisation index (LNI) >0.7, or
• a titre of >1:10 using plaque reduction neutralisation tests

Immunogenicity in adults

After a single dose of yellow fever vaccine, approximately 90% of healthy adult vaccine recipients develop protective levels of neutralising antibodies by day 14. Virtually all recipients develop these levels by day 28.²⁷

Immunogenicity in children

In children, the proportion of vaccine recipients who achieve protective yellow fever antibody levels after a single dose of vaccine is similar to that in adults. ^49,50

1 randomised trial suggested lower seroconversion rates (70%) against yellow fever virus in children <2 years of age. However, this was when yellow fever vaccine was co-administered with MMR vaccine.⁸ In comparison, 87% of children who received yellow fever and MMR vaccines seroconverted when the 2 vaccines were given at least 30 days apart. This study did not report on the proportion of participants with protective levels of neutralising antibodies on the basis of commonly applied definitions.

Immunogenicity in people with medical conditions

Immunogenicity studies in people with underlying medical conditions are limited. Some data suggest that pregnant women and people with HIV do not respond well to yellow fever vaccination.

Pregnant women

38.6% of pregnant women who received yellow fever vaccine in their 3rd trimester achieved protective levels of neutralising antibodies. In comparison, 81.5–93.7% of non-pregnant women of child-bearing age and other adults achieved protective levels of neutralising antibodies.⁵¹

A better response to the yellow fever vaccine was reported in a separate study of women who were vaccinated in their 1st trimester of pregnancy. This suggests that antibody response to vaccination in pregnant women may depend on the stage of gestation.²⁶

People with HIV

2 studies reported lower rates of neutralising antibodies among HIV-infected people than in uninfected controls.^19,20 Some observational studies have reported that seroconversion rates in people with HIV were similar to those reported in healthy adults (>90%). However, the number of participants in these studies was small and there were no healthy controls.^52-56 When reported, CD4⁺ counts of HIV-infected participants were >200 cells per µL. Several studies found that higher antibody titres were associated with higher CD4⁺ counts and lower HIV RNA levels.^54,57

People who are immunocompromised

Only a few small, low-quality studies and case reports provide data on the immunogenicity of yellow fever vaccine in people who are immunocompromised, other than people with HIV.^58,59

A reduced immune response to yellow fever vaccine was reported among people who received immunosuppressive therapy for rheumatoid disease.⁶⁰ Immunosuppressive therapy given after administration of yellow fever vaccine, did not affect immunogenicity.⁶¹

Duration of immunity

A single dose of yellow fever vaccine should provide lifelong immunity in most healthy adults and children. Protective levels of neutralising antibodies have been detected in 75–100% of healthy adults from endemic and non-endemic yellow fever areas when measured 10–69 years after the 1st vaccination.^3-5

Although vaccinated people have contracted yellow fever disease, it has only been reported in people living in highly endemic areas. A study from Brazil showed that, among 459 people with laboratory-confirmed yellow fever who reported previous vaccination, 432 (94%) had yellow fever 10 or more years after vaccination. This suggests secondary vaccine failure due to waning immunity, although primary vaccine failure (poor initial immune response) may have contributed.⁶²

Few studies have assessed the duration of immunity in groups who do not respond optimally to primary yellow fever vaccination. A cohort study measured levels of yellow fever neutralising antibodies in people with and without HIV. Within 1–10 years after vaccination, 23% of people with HIV lost protective antibody levels. In comparison, 12% of people without HIV lost protective antibody levels.²⁰

A booster dose of yellow fever vaccine can produce protective levels of yellow fever neutralising antibodies in people whose response to the primary vaccine dose was low or negative.^63,64

Transport according to National vaccine storage guidelines: Strive for 5.⁶⁵ Store at +2°C to +8°C. Do not freeze. Protect from light.

Stamaril must be reconstituted. Add the entire contents of the diluent syringe to the vial and shake until the powder completely dissolves. Use reconstituted vaccine within 1 hour.

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

State and territory public health authorities can provide advice about the public health management of yellow fever, including management of cases and their contacts.

The product information for Stamaril states that pregnancy is a contraindication to receiving the vaccine. The Australian Technical Advisory Group on Immunisation recommends that pregnant women can receive the vaccine if they cannot avoid travelling to an area with a risk of yellow fever virus transmission.

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