Yellow Fever Vaccine

Prevention of Disease Caused by Yellow Fever Virus

Yellow fever vaccine is used for the prevention of disease caused by yellow fever virus in adults, adolescents, and children 9 months of age or older residing or traveling in areas of Africa or South America where yellow fever is endemic or officially reported or where an International Certificate of Vaccination or Prophylaxis against yellow fever is required as a condition for entry.100, 106, 115 Vaccination against yellow fever virus also is recommended in adults, adolescents, and children 9 months of age and older traveling outside the urban areas of countries that do not officially report the disease, but that lie within the yellow fever endemic zone.100, 106, 115 In addition, yellow fever vaccine is used in laboratory personnel who might be exposed by direct or indirect contact or by aerosols to virulent yellow fever virus or to concentrated preparations of the yellow fever vaccine strain.100, 106

Yellow fever virus is a Flavivirus 100, 105, 106, 115 closely related to Dengue, Japanese encephalitis virus, St. Louis encephalitis viruses, and West Nile virus (WNV).100, 105 It has been estimated that there are 200,000 cases of yellow fever and 30,000 fatalities related to the disease reported annually worldwide.100, 101 Yellow fever virus is an arbovirus that is transmitted to humans through the bite of infected mosquitoes (principally Aedes or Haemagogus species) that acquired the virus by biting infected humans or nonhuman primates (monkeys).100, 101, 106, 115 Disease caused by yellow fever virus ranges from a mild, nonspecific febrile illness to severe disease with jaundice, hemorrhagic symptoms, and eventually shock and multisystem organ failure;100, 104, 115 the case fatality rate for severe disease caused by yellow fever virus is 20-50%.100, 104 Because there are no specific treatments available, prevention through vaccination with yellow fever vaccine is necessary to reduce morbidity and mortality associated with yellow fever virus infection.100, 104, 115 During 1970-2015, there were 10 cases of yellow fever reported in unvaccinated American and European travelers who traveled to yellow fever endemic zones and 8 of these travelers died.115

Travelers

Yellow fever virus is endemic and intermittently epidemic in sub-Saharan Africa and tropical South America.100, 101, 115 The risk for a traveler of acquiring yellow fever depends on several factors, including vaccination status, use of personal protective measures against mosquito bites, travel locations, season, duration of exposure, occupational and recreational activities while traveling, and the local rate of yellow fever virus transmission at the time of travel.100, 101, 104, 115

Countries in sub-Saharan Africa with a risk of yellow fever virus transmission include Angola, Benin, Burkina Faso, Burundi, Cameroon, Central African Republic, Chad, Congo (Republic of the Cote d'Ivoire), Democratic Republic of the Congo, Equatorial Guinea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Liberia, Mali, Mauritania, Niger, Nigeria, Senegal, Sierra Leone, South Sudan, Sudan, Togo, and Uganda.115 The majority of yellow fever outbreaks in Africa have occurred in West Africa and, during these outbreaks, up to 30% of the population was infected with yellow fever virus and 3-4% of the population developed clinical disease.100 The risk for yellow fever virus infection in rural West Africa is seasonal and is highest during the end of the rainy season through the beginning of the dry season (usually July to October), but the virus may be episodically transmitted by mosquitos even during the dry season in both rural and densely settled urban areas.100, 115

Countries in Central and South America with a risk of yellow fever virus transmission include Argentina, Bolivia, Brazil, Colombia, Ecuador, French Guiana, Guyana, Panama, Paraguay, Peru, Suriname, Trinidad and Tobago, and Venezuela.115 In South America, transmission of yellow fever virus occurs predominantly in sparsely populated forested areas rather than in urban areas.100 During the last 20 years, Peru and Bolivia have had the highest cumulative incidence of yellow fever in South America.100 However, the endemic areas of yellow fever within Brazil have been expanding in recent years and there have been an increasing number of confirmed cases of yellow fever virus infection in Brazil and in other countries in South America.100 The risk for yellow fever virus infection in South America is highest during the rainy season (January to May)100, 115 and yellow fever activity peaks in February and March.115

For US travelers, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) and the US Centers for Disease Control and Prevention (CDC) recommend primary immunization with yellow fever vaccine in adults, adolescents, and children 9 months of age or older who will be traveling to or living in areas at risk for yellow fever virus transmission in Africa and South America.100, 115 However, because yellow fever vaccine has been associated with serious adverse effects, decisions regarding the use of yellow fever vaccine should involve careful consideration of the individual's overall risk for travel-associated yellow fever, the high mortality rate reported for disease caused by yellow fever virus, international regulations regarding yellow fever vaccination for countries on the travel itinerary, and all precautions and contraindications for administration of the vaccine.100, 115

ACIP states that primary immunization with a single dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers; however, ACIP states that revaccination with yellow fever vaccine is recommended for certain travelers who will be visiting countries with a risk of yellow fever virus transmission (e.g., women who received primary immunization during pregnancy, individuals who received a hematopoietic stem cell transplant after receiving primary immunization, individuals who had human immunodeficiency virus [HIV] infection when they received their last dose of yellow fever vaccine).104 ACIP also states that revaccination (booster dose) may be given to travelers who received their last dose of yellow fever vaccine at least 10 years previously and who will be in higher-risk settings based on location, season, activities, and duration of travel.104 This includes travelers who plan to spend prolonged periods in endemic areas or those traveling to highly endemic areas (e.g., rural West Africa during peak transmission season) or to areas with an ongoing outbreak of yellow fever.104

In addition to vaccination, travelers should take precautions to avoid exposure to mosquitoes since this reduces the risk for yellow fever and other mosquito-borne infectious diseases.100, 115 Although yellow fever transmission is unusual in urban areas and only occurs during an epidemic, travelers to rural areas of Africa and South America may be exposed to mosquitoes transmitting the disease and other mosquito-borne diseases.115 Travelers to yellow fever virus areas should be advised of the importance of taking measures to reduce contact with mosquitoes (e.g., staying in air-conditioned or well-screened quarters, wearing long-sleeved shirts and long pants to cover most of the body, using appropriate insect repellents, using mosquito nets between dusk and dawn).100, 115 If travelers are staying in a rural area with limited facilities, they should bring mosquito nets and aerosol insecticides or mosquito coils.115

The most recent information regarding geographic areas associated with risk of yellow fever, information on mosquito avoidance and protective measures against mosquito bites, and additional information on yellow fever vaccination is available from CDC at [Web] and [Web].100, 115

International Regulations Regarding Vaccination Against Yellow Fever

To prevent importation and indigenous transmission of yellow fever virus, international health regulations (IHR) of the World Health Organization (WHO) allow countries to require proof of yellow fever vaccination documented on a validated International Certificate of Vaccination or Prophylaxis (ICVP) as a condition of entry for travelers arriving from infected areas or from countries with infected areas, even if only in transit.100, 115 Some countries require evidence of vaccination against yellow fever from all entering travelers, including those traveling directly from the US.100, 115 Travelers who have a specific contraindication to yellow fever vaccine and who cannot avoid travel to a country requiring vaccination should obtain a medical waiver before embarking on travel.100, 115 Requirements regarding ICVPs may be strictly enforced and travelers arriving without a valid ICVP or medical waiver may be quarantined for up to 6 days, denied entry, or possibly vaccinated or revaccinated at the point of entry.100, 115

For the purposes of international travel, yellow fever vaccines produced worldwide must be approved by WHO and administered at an approved yellow fever vaccination center.115 In the US, yellow fever vaccine is supplied to and can be administered only at certain sites that are authorized to issue valid ICVPs.100, 106, 115 Local or state public health departments are responsible for designating nonfederal yellow fever vaccination centers.100, 115 Vaccinees should receive a completed ICVP that is signed and validated with the official uniform stamp of the yellow fever vaccination center where the vaccine was given.100, 106, 115 These certificates are valid for 10 years beginning 10 days after vaccination with yellow fever vaccine.100, 106, 115 As of July 2016, WHO no longer requires revaccination (booster dose) of yellow fever vaccine every 10 years and states that a completed ICVP is considered valid for the lifetime of the vaccinee.115 However, it is uncertain when or if all countries with entry requirements for yellow fever vaccination will adopt this change.115

If international travel regulations are the only reason to vaccinate a traveler with a contraindication to yellow fever vaccine, the medical contraindications to vaccination section of the ICVP should be filled out and signed by the clinician.100, 115 In addition, a letter clearly stating the traveler's contraindication (e.g., hypersensitivity to egg or chicken protein, altered immunocompetence, pregnancy) should be written on letterhead stationery and stamped with the official uniform stamp of the yellow fever vaccination center.100, 115 Issuance of a medical waiver does not guarantee its acceptance by the destination country.100, 115 To improve the likelihood that the waiver will be accepted, it is helpful for the traveler to also obtain specific and authoritative advice and documentation from the country or countries to be visited (e.g., by contacting their embassies or consulates).115 Waivers of requirements obtained from embassies or consulates should be documented by appropriate letters and retained for presentation with the ICVP.115

Information on country-specific requirements for yellow fever vaccination for travelers and information on regulations regarding ICVPs and medical waivers is available from CDC at [Web].115

Laboratory Personnel

Laboratory personnel who might be exposed to virulent yellow fever virus or to concentrated preparations of the yellow fever vaccine virus strain by direct or indirect contact or by aerosols should receive primary immunization with yellow fever vaccine.100, 106

ACIP states that laboratory workers who routinely handle wild-type yellow fever virus and are at continued high risk of exposure to the virus should be tested for yellow fever virus-specific neutralizing antibody titers at least every 10 years after primary immunization to determine whether revaccination (booster dose) of the vaccine is indicated.104 These experts state that laboratory workers who are unable to have neutralizing antibody titers measured should receive a dose of yellow fever vaccine every 10 years if they remain at risk.104

Dosage and Administration ⬆ ⬇

Reconstitution and Administration

Yellow fever vaccine is administered by subcutaneous injection.106

Yellow fever vaccine should not be administered IM.100 However, if the vaccine is inadvertently given IM, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that the immunologic response to the vaccine probably will be unaffected and a repeat dose given by subcutaneous injection is unnecessary.100

Yellow fever vaccine is reconstituted by using only the 0.9% sodium chloride diluent supplied by the manufacturer.106 The appropriate volume of diluent specified on the label of lyophilized yellow fever vaccine should be drawn into a syringe and slowly added to the vaccine vial.106 The vial should be allowed to stand for 1-2 minutes and then carefully swirled until a uniform suspension is obtained.106 Vigorous shaking should be avoided since this tends to cause foaming of the suspension.106

Reconstituted yellow fever vaccine should appear as a slightly pink-brown suspension and should not be used if it is discolored or contains extraneous particulate matter.106

Yellow fever vaccine must be administered subcutaneously within 1 hour following reconstitution (see Chemistry and Stability: Stability).106 The vial and any unused portion of reconstituted vaccine must be disposed of properly (e.g., sterilized, disposed of as medical waste).106

When multiple parenteral vaccines are administered during a single health-care visit, each vaccine should be given with a different syringe and at different injection sites.134 Injection sites should be separated by at least 1 inch (if anatomically feasible) to allow appropriate attribution of any local adverse effects that may occur.134

Prior to administration of yellow fever vaccine, the patient should be evaluated for a history of sensitivity to egg or chicken protein and sensitivity testing should be performed if indicated.106 (See Dosage and Administration: Sensitivity Testing and Desensitization.)

Following administration of yellow fever vaccine, vaccinees should be observed for at least 15 minutes for signs and symptoms of allergic reaction to the vaccine.100 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Syncope (vasovagal or vasodepressor reaction; fainting) may occur following vaccination;105, 134 such reactions occur most frequently in adolescents and young adults.105, 134 Syncope and secondary injuries may be averted if vaccinees sit or lie down during and for 15 minutes after vaccination.105, 134 If syncope occurs, the patient should be observed until symptoms resolve.105, 134

In the US, yellow fever vaccine can only be administered at certain sites authorized to issue a valid International Certificate of Vaccination or Prophylaxis (ICVP).100, 106, 115 (See Restricted Distribution under Preparations.)

Subcutaneous Administration

Prior to administering a dose, the vial of reconstituted yellow fever vaccine should be carefully swirled until a uniform suspension is obtained;106 vigorous shaking should be avoided.106

Subcutaneous injections should be made at a 45° angle134 using a 5/8 to 3/4 inch, 23- to 25-gauge needle.106, 134

Subcutaneous injections usually should be made into the upper-outer triceps area in adults, adolescents, and children 12 months of age or older or into the anterolateral thigh in infants younger than 12 months of age.134

Dosage

Prevention of Disease Caused by Yellow Fever Virus

Adults, Adolescents, and Children 9 Months of Age or Older

For primary immunization in adults, adolescents, and children 9 months of age or older, yellow fever vaccine is administered as a single 0.5-mL dose.100, 106 The vaccine dose should be administered at least 10 days prior to potential exposure to yellow fever virus.100, 106, 115

The manufacturer states that revaccination with a single 0.5-mL dose of yellow fever vaccine is recommended every 10 years in individuals at risk of exposure to yellow fever virus.106

The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that revaccination is no longer considered necessary for most US travelers who previously received primary immunization with yellow fever vaccine.104 However, ACIP states that women who were pregnant when they received primary immunization should receive one additional dose of yellow fever vaccine before their next travel that puts them at risk for exposure to yellow fever virus.104 ACIP also states that individuals who received a hematopoietic stem cell transplant after receiving yellow fever vaccine and who are now sufficiently immunocompetent should be revaccinated before their next travel that puts them at risk for exposure to yellow fever virus.104 In addition, ACIP recommends that individuals who had human immunodeficiency virus (HIV) infection when they received their last dose of yellow fever vaccine should receive a dose of the vaccine every 10 years if they continue to be at risk for exposure to yellow fever virus.104 These experts state that a booster dose of yellow fever vaccine may be given to travelers who received their last dose at least 10 years previously and who will be in higher-risk settings based on location, season, activities, and duration of travel (e.g., travelers who plan to spend prolonged periods in endemic areas, travelers to highly endemic areas such as rural West Africa during peak transmission seasons, travelers to areas with an ongoing outbreak).104

The World Health Organization (WHO) states that revaccination (booster dose) of yellow fever vaccine every 10 years is no longer considered necessary.115 Although WHO states that an International Certificate of Vaccination or Prophylaxis (ICVP) is considered valid for the lifetime of the vaccinee, it is uncertain when or if all countries with entry requirements for yellow fever vaccination will adopt this change.115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

Laboratory Personnel

For primary immunization in laboratory personnel who might be exposed to virulent yellow fever virus or to concentrated preparations of the yellow fever vaccine virus strain, yellow fever vaccine is administered as a single 0.5-mL dose.106

To determine whether revaccination (booster dose) of yellow fever vaccine is indicated in laboratory workers at continued high risk of exposure, ACIP states that yellow fever virus-specific neutralizing antibody titers should be measured at least every 10 years after primary immunization.104 If neutralizing antibody titers cannot be measured,104 ACIP states that a dose of yellow fever vaccine should be administered every 10 years as long as the laboratory worker remains at risk.104

Sensitivity Testing and Desensitization

Because of the risk of a severe hypersensitivity reaction (e.g., anaphylaxis) if yellow fever vaccine is administered to an individual hypersensitive to eggs or chicken protein, a scratch and an intradermal skin test is recommended prior to administration of the vaccine in anyone suspected of being sensitive to eggs.106 Epinephrine should be available during such testing in case an immediate sensitivity reaction occurs.106

Sensitivity Testing

For the scratch test, a 1:10 dilution of yellow fever vaccine in 0.9% sodium chloride should be used.106 A drop of the 1:10 dilution should be put on a superficial scratch, prick, or puncture on the volar surface of the forearm and positive (histamine) and negative (0.9% sodium chloride) controls should be used.106 The scratch test is read after 15-20 minutes.106 A positive reaction consists of a wheal that is 3 mm larger than that of the 0.9% sodium chloride negative control, usually with surrounding erythema.106 The histamine control must be positive for valid interpretation.106 If the scratch test is negative, an intradermal test should be performed.106

For the intradermal skin test, 0.02 mL of a 1:100 dilution of yellow fever vaccine in 0.9% sodium chloride injection is given intradermally on the volar surface of the forearm.106 Positive and negative control intradermal tests should be performed concurrently at separate sites.106 A positive intradermal skin test reaction consists of a wheal that is 5 mm or larger in diameter than the negative control with surrounding erythema.106

Desensitization

If vaccination with yellow fever vaccine is considered essential in an individual with a history of severe egg sensitivity and positive sensitivity test, desensitization can be considered.100, 106, 115 However, desensitization should only be performed under the direct supervision of a clinician experienced in the management of anaphylaxis and with necessary emergency equipment immediately available.100, 106, 115

The procedure for desensitization recommended by the manufacturer consists of subcutaneous injection of the following increasing doses of yellow fever vaccine at 15- to 20-minute intervals: 0.05 mL of a 1:10 dilution, 0.05 mL of undiluted vaccine, 0.1 mL of undiluted vaccine, 0.15 mL of undiluted vaccine, 0.2 mL of undiluted vaccine.106

Cautions ⬆ ⬇

Adverse reactions to yellow fever vaccine generally are mild and infrequent and occur within 5-14 days following administration of the vaccine.100, 106, 115 Low-grade fever, mild headache, myalgia, malaise, or other minor symptoms have been reported in individuals receiving the vaccine.100, 106, 115 Local effects at the injection site, including edema, hypersensitivity, erythema, pain, swelling, or mass, also have been reported with yellow fever vaccine.100, 106

In uncontrolled clinical studies from 1953-1994 that evaluated yellow fever vaccine in adults and infants residing in Europe or in yellow fever endemic areas, self-limited and mild local adverse effects (erythema, pain) and systemic adverse effects (headache and/or fever) were reported in less than 5% of vaccinees and occurred 5-7 days after vaccination.106 It has been reported that approximately 1% of vaccinees curtail regular activities secondary to adverse effects related to yellow fever vaccine.100, 115

In a randomized clinical study in the US in 2001 that evaluated the yellow fever vaccine currently available in the US (YF-VAX^®) and a different yellow fever vaccine prepared using the 17D-204 strain of yellow fever virus in 725 adults, approximately 72% of those who received the US vaccine had adverse reactions, principally mild to moderate injection site reactions.106 Rash occurred in approximately 3% of vaccine recipients and urticaria occurred rarely.106 Systemic reactions (headache, myalgia, malaise, asthenia) occurred in 10-30% of those who received the US vaccine; these reactions were usually mild in severity and were reported during the first few days after vaccination.106 Adverse events were less frequent in the 1.7% of vaccinees who had preexisting immunity to yellow fever virus, compared to those who had no previous exposure to the virus.106

Rarely, yellow fever vaccine has been associated with serious adverse reactions, including sensitivity reactions, yellow fever vaccine-associated neurotropic disease, and yellow fever vaccine-associated viscerotropic disease.100, 106, 108, 115 Because of reports of these serious effects, postmarketing surveillance for adverse events associated with yellow fever vaccine was enhanced beginning in 2001 to include soliciting reports from health-care providers at certified yellow fever vaccination clinics and review of all cases of febrile illness reported to the Vaccine Adverse Event Reporting System (VAERS) that were temporally associated with yellow fever vaccine.108 A low-level viremia caused by the yellow fever vaccine virus (17D strain) may occur 3-7 days after administration of the vaccine and persist for 1-3 days.100 It has been suggested that yellow fever vaccine-associated neurotropic and viscerotropic disease might represent an aberrant host response to the yellow fever vaccine virus rather than intrinsic virulence of the vaccine virus or reversion of vaccine virus to wild-type virus.106, 108 Because of reports of severe adverse effects, yellow fever vaccine should be administered only to individuals truly at risk for exposure to yellow fever.100, 106, 115 (See Cautions: Precautions and Contraindications.)

Sensitivity Reactions

Anaphylaxis and other immediate hypersensitivity reactions manifested as rash, urticaria, and/or respiratory symptoms (e.g., asthma, dyspnea, bronchospasm, pharyngeal edema) have been reported rarely following administration of yellow fever vaccine.100, 106

Although hypersensitivity reactions have been reported principally in individuals with a history of egg allergy,100, 106 anaphylaxis has been reported in individuals with no history of reactions to the components of yellow fever vaccine.100 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Vaccine-associated Neurotropic Disease

Yellow fever vaccine-associated neurotropic disease (YEL-AND; formerly known as postvaccinal encephalitis) has been reported rarely following administration of yellow fever vaccine.100, 106, 108, 115

Yellow fever vaccine-associated neurologic disease is potentially fatal and may include meningoencephalitis (neurotropic disease), Guillain-Barré syndrome (GBS), acute disseminated encephalomyelitis, and, rarely, cranial nerve palsies.100, 115

Historically, YEL-AND was reported principally in children younger than 9 months of a 100, 106 however, cases have now been reported in all age groups.115 Almost all cases of YEL-AND reported to date worldwide have occurred after primary immunization;104, 115 this adverse effect has been reported only rarely following revaccination (booster dose).104 Immunosuppression is a known risk factor for YEL-AND.106, 115

The US Centers for Disease Control and Prevention (CDC) estimates that the incidence of YEL-AND in vaccine recipients in the US is 0.8 cases per 100,000 doses administered and the incidence is higher (2.2 cases per 100,000 doses) in vaccinees 60 years of age or older.115 In documented US cases of YEL-AND, the onset of illness was 2-56 days after vaccination.115

During 2001-2002, there were 4 reports of probable YEL-AND reported in the US among adult recipients of yellow fever vaccine with onset of illness 4-23 days after vaccination and clinical evidence suggesting that the 17D-derived yellow fever vaccine virus was the probable cause of the illness.108 These 4 adults experienced onset of illness soon after the vaccine was administered, had high CSF levels of yellow fever-specific IgM antibody, and no other causes of neurologic disease were identified.108 Although isolation of vaccine-associated virus in these patients was negative or not performed and the presence of IgM antibody in the CSF could be attributed to serum antibody from recent immunization possibly crossing an inflamed blood-brain barrier, this is unlikely because of the large size of IgM.108

Vaccine-associated Viscerotropic Disease

Yellow fever vaccine-associated viscerotropic disease (YEL-AVD; previously known as febrile multiple organ system failure) has been reported rarely in individuals who received various yellow fever vaccines.100, 106, 108, 110, 115, 120

YEL-AVD resembles fulminant yellow fever caused by wild-type yellow fever virus.100, 106 Case analysis indicates that this serious adverse reaction probably occurs as a clinical spectrum of disease, varying in severity from moderate illness with focal organ dysfunction to fatal disease with overt multiple organ system failure and death.115, 120 All cases of YEL-AVD reported to date worldwide have occurred after primary immunization;100, 115 laboratory-confirmed cases have not been reported to date following revaccination (booster dose).100, 115

CDC estimates that the incidence of YEL-AVD in vaccine recipients in the US is 0.3 cases per 100,000 doses; the incidence is estimated to be higher (1.2 cases per 100,000 doses) in vaccinees 60 years of age or older and may be even higher in those 70 years of age or older.115 In US cases, the median time from administration of yellow fever vaccine to onset of symptoms of YEL-AVD has been 4 days (range: 1-18 days) and the case fatality rate associated with this serious adverse reaction has been approximately 46%.115

There were 4 cases of YEL-AVD reported in the US during 1996-1998; all 4 cases involved older adults (63-79 years of age) and 3 were fatal.106, 110 The 4 patients required intensive care after they experienced fever, hypotension, respiratory failure, elevated liver enzymes, hyperbilirubinemia, lymphocytopenia, and thrombocytopenia; 3 developed renal failure that required hemodialysis.110, 115 Symptoms were evident 2-5 days after administration of yellow fever vaccine and began with a nonspecific febrile syndrome with fatigue, myalgia, and headache that progressed rapidly to severe illness; the 3 fatalities occurred 8-30 days after vaccination.106, 110 Yellow fever virus resembling the vaccine virus was isolated from the serum of 2 patients and the CSF of 1 patient.110

During 2001-2002, there were 2 reports of probable YEL-AVD reported in the US among adult recipients of the vaccine (a 25-year old with onset of illness 1 day after vaccination and a 70-year old with onset of illness 5 days after vaccination).108 A fatality related to YEL-AVD occurred in the US in 2014 when yellow fever vaccine was administered to a woman with undiagnosed thymoma.120

Of 7 cases of YEL-AVD reported internationally during 1996-2001, 6 patients died from multiple organ system failure.106 In an Australian case and 2 Brazilian cases that were fatal 8-11 days after vaccination, histopathologic changes in the liver included midzonal necrosis, microvesicular fatty change, and Councilman bodies, which are characteristic of wild-type yellow fever.106 Vaccine-type yellow fever virus was isolated from blood and autopsy material (i.e., brain, liver, kidney, spleen, lung, skeletal muscle, skin) from these patients.106

As of February 2010, a total of 57 cases of YEL-AVD had been reported to CDC from 14 countries (Australia, Belgium, Brazil, China, Colombia, Ecuador, France, Germany, Japan, Peru, Spain, Switzerland, United Kingdom, US); these cases occurred in association with yellow fever vaccines from several different manufacturers that were prepared using the different substrains of yellow fever virus.100 The case fatality rate for these patients was 65%.100 The median time from vaccination with yellow fever vaccine until onset of symptoms was 3 days (range: 1-8 days) and the median time from vaccination until death was 10 days (range: 7-30 days).100

Risk factors for YEL-AVD include older age and history of thymus disease associated with abnormal immune cell function (e.g., myasthenia gravis, thymoma) or thymectomy.100, 106 There is no conclusive evidence to date that this adverse effect is caused by a reversion to increased virulence in the vaccine virus.100

Precautions and Contraindications

Prior to administration of yellow fever vaccine, all known precautions should be taken to prevent adverse reactions, including a review of the patient's immunization history, current health status, medical history, and history regarding possible sensitivity to the vaccine, similar vaccines, or vaccine components.106

Yellow fever vaccine is contraindicated in individuals with a history of acute hypersensitivity to eggs, egg products, or chicken protein and in individuals hypersensitive to any ingredient in the formulation, including gelatin.106 (See Sensitivity Reactions under Cautions: Precautions and Contraindications.)

Yellow fever vaccine is contraindicated in individuals with immunosuppression (e.g., leukemia, lymphoma, thymus disease, generalized malignancy, gamma globulin deficiency, acquired immunodeficiency syndrome [AIDS] or other manifestations of human immunodeficiency virus [HIV] infection).106 (See Individuals with Altered Immunocompetence under Cautions: Precautions and Contraindications.) The vaccine also is contraindicated in individuals receiving immunosuppressive therapy.106 (See Drug Interactions: Immunosuppressive and Immunomodulatory Agents.)

Yellow fever vaccine is contraindicated in children younger than 9 months of age106 (see Cautions: Pediatric Precautions) and in nursing women, particularly when nursing infants are younger than 9 months of age (see Lactation under Cautions: Pregnancy and Lactation).106 The vaccine also is contraindicated in individuals with acute or febrile illness.106 (See Acute Illness under Cautions: Precautions and Contraindications.)

The patient and/or the patient's parent or guardian should be informed of the benefits and risks of vaccination with yellow fever vaccine and should be provided with a copy of the appropriate Vaccine Information Statement (available at CDC website at [Web]).106, 112 Patients and/or the patient's parent or guardian should be instructed to report any severe or unusual adverse reactions that occur up to 30 days after vaccination to their healthcare provider.106 Clinicians or individuals can report any adverse reactions that occur following vaccination to VAERS at 800-822-7967 or [Web].100, 106 Adverse reactions to the vaccine also should be reported to the manufacturer at 800-822-2463.106

Sensitivity Reactions

Because yellow fever vaccine is produced in chick embryos, the vaccine is contraindicated in individuals with a history of acute hypersensitivity to eggs, egg products, or chicken protein since anaphylaxis may occur.100, 106 Less severe or localized manifestations of allergy to eggs or to feathers are not considered contraindications to yellow fever vaccine.106 A history for evidence of sensitivity to egg or chicken protein should be obtained prior to administration of yellow fever vaccine.106 Asking individuals whether they can eat eggs without adverse effects is a reasonable method to screen for those who may be at risk from receiving yellow fever vaccine since individuals who are able to eat eggs or egg products generally can receive the vaccine safely.100, 106, 134

If administration of yellow fever vaccine is considered necessary in an individual with a possible history of acute hypersensitivity to eggs or egg products, a skin test for hypersensitivity should be performed prior to administration of the vaccine.100, 115 Less severe or localized manifestations of allergy to eggs or to feathers usually do not warrant skin testing with the vaccine.106 If vaccination is considered essential despite a positive skin test, use of desensitization can be considered.106 (See Dosage and Administration: Sensitivity Testing and Desensitization.)

If international travel regulations are the only reason to vaccinate an individual hypersensitive to egg or chicken protein, efforts should be made to obtain a medical waiver.115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

The possibility of a hypersensitivity reaction to gelatin, which is present in yellow fever vaccine as a stabilizer, should be considered.106 The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that vaccines containing gelatin as a stabilizer should be used with extreme caution in individuals who have had an anaphylactic reaction to gelatin or gelatin-containing products.134

Epinephrine should be available for immediate treatment if an anaphylactic or other serious allergic reaction occurs following administration of yellow fever vaccine.100, 106

Vaccinees should be observed for at least 15 minutes following administration of yellow fever vaccine.100 In addition, vaccinees should be advised of the signs and symptoms of an allergic reaction (e.g., urticaria, angioedema, rash, dyspnea, bronchospasm, pharyngeal edema, wheezing, throat tightness) and advised to immediately contact a clinician if any symptoms of an allergic reaction develop following vaccination.100

Vaccine-associated Neurotropic and Viscerotropic Disease

Because enhanced surveillance for serious adverse effects in recipients of yellow fever vaccine has identified cases consistent with YEL-AND and YEL-AVD, yellow fever vaccine should be administered only to individuals truly at risk for exposure to yellow fever.100, 106, 115 In addition, clinicians are encouraged to report any patients with symptoms suggestive of viscerotropic or neurotropic illness following administration of yellow fever vaccine to VAERS at 800-822-7967 or [Web].106

Individuals with Altered Immunocompetence

Because yellow fever vaccine contains live, attenuated virus, viral replication and development of infection with the vaccine virus may be potentiated by altered immune status and the risk of encephalitis or other serious adverse effects may be increased in immunocompromised individuals.100, 106, 134, 155

Yellow fever vaccine is contraindicated in individuals with severe underlying disease (e.g., leukemia, lymphoma, thymic disease, generalized malignancy), gammaglobulin deficiency (e.g., agammaglobulinemia, hypogammaglobulinemia, dysgammaglobulinemia), immunosuppression secondary to AIDS or other manifestations of HIV infection, or those receiving immunosuppressive or immunomodulatory therapy (e.g., alkylating agents, antimetabolites, corticosteroids, interleukin-1 blocking agents, monoclonal antibodies targeting immune cells, tumor necrosis factor alpha [TNF-α] inhibitors, radiation).100, 106, 115 (See Drug Interactions: Immunosuppressive and Immunomodulatory Agents.)

There is evidence suggesting that thymic dysfunction is an independent risk factor for development of YEL-AVD, and clinicians should ask about a history of thymus disorder (e.g., myasthenia gravis, thymoma, prior thymectomy) prior to administration of yellow fever vaccine because the vaccine is contraindicated in such individuals.106 However, ACIP and CDC state that the vaccine can be used in individuals who have undergone incidental surgical removal of their thymus or have had direct radiation therapy in the distant past since there is no evidence of immune dysfunction or increased risk of yellow fever vaccine-associated serious adverse effects in such individuals.100, 115

Individuals with altered immunocompetence should postpone or avoid travel to yellow fever endemic areas.106 If travel to such areas cannot be avoided, individuals with altered immunocompetence should be advised of the risk, instructed in methods for avoiding bites by vector mosquitoes, and provided with a medical waiver letter to use with the required International Certificate of Vaccine or Prophylaxis (ICVP) to fulfill international health regulations.100, 106, 115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

The manufacturer, ACIP, and CDC state that family members of immunosuppressed or HIV-infected individuals who themselves have no contraindications for yellow fever vaccine may receive the vaccine.100, 106, 115

HIV-infected Individuals

ACIP and CDC state that yellow fever vaccine is contraindicated in HIV-infected individuals with AIDS or other clinical manifestations of HIV, including those with severe immunosuppression (i.e., CD4⁺ T-cell count less than 200/mm³ in adults and children 6 years of age or older or CD4⁺ T-cell percentage less than 15% in children younger than 6 years of age).100, 115 This recommendation is based on a theoretical increase in the risk for encephalitis in this population.100, 115

If travel to an area where yellow fever is endemic cannot be avoided, symptomatic HIV-infected individuals and those with severe immunosuppression should be advised of the risk, instructed in methods for avoiding bites by vector mosquitoes, and provided with a medical waiver letter to use with the required ICVP to fulfill international health regulations.100, 115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

The manufacturer, ACIP, CDC, and other experts state that asymptomatic HIV infection and moderate immunosuppression (i.e., CD4⁺ T-cell count 200-499/mm³ in adults and children 6 years of age or older or CD4⁺ T-cell percentage of 15-24% in children younger than 6 years of age) is a precaution for use of yellow fever vaccine.100, 115, 155 Only limited data are available regarding the safety and efficacy of the vaccine in such individuals.100, 115 If yellow fever vaccine is used in individuals with asymptomatic HIV infection, they should be monitored closely for possible adverse effects.100, 106, 115 In addition, seroconversion rates may be lower in HIV-infected individuals (see Pharmacology: Response to Yellow Fever Vaccine), 100, 103, 106, 115, 116 and it has been suggested that consideration should be given to measuring the neutralizing antibody response to the vaccine in such individuals to document that a protective antibody response occurs prior to travel.106, 115 Appropriate state health departments or the CDC (970-221-6400) should be contacted for information on serologic testing.100, 115

ACIP states that individuals with asymptomatic HIV infection and no evidence of immunosuppression (i.e., CD4⁺ T-cell count 500/mm³ or greater in adults and children 6 years of age or older or CD4⁺ T-cell percentage 25% or greater in children younger than 6 years of age) can receive yellow fever vaccine if indicated based on the destination-specific risk for exposure to yellow fever virus.100, 115, 155

Acute Illness

The decision whether to administer or delay administration of yellow fever vaccine in an individual with a current or recent febrile illness depends largely on the severity and etiology of the illness.134

The manufacturer states that vaccination should be postponed in individuals with acute or febrile disease, but that disease with low-grade fever is not usually a reason to postpone vaccination.106

ACIP states that vaccination of individuals with moderate or severe acute illness (with or without fever) generally should be deferred until they have recovered to avoid superimposing adverse effects of the vaccine on the underlying illness or to avoid mistakenly concluding that a manifestation of the underlying illness resulted from vaccination.134

Chronic Illness

Yellow fever vaccine is contraindicated in individuals with chronic illness associated with altered immunocompetence.100, 105, 106, 115, 134 (See Individuals with Altered Immunocompetence under Cautions: Precautions and Contraindications.)

Data are limited regarding possible increased incidence of adverse effects or decreased vaccine efficacy if yellow fever vaccine is administered to patients with other chronic medical conditions (e.g., diabetes mellitus, renal disease, hepatitis C virus [HCV] infection or other liver disease).115 Use of the vaccine in such patients should be considered with caution, taking into account the patient's general level of immune competence, disease severity and duration, and comorbidities.115

Transmission of Vaccine Virus

Yellow fever vaccine contains live, attenuated yellow fever virus.106 Low-level viremia caused by the yellow fever vaccine virus (17D-204 strain) may occur 3-7 days after administration of the vaccine and persist for 1-3 days.100 This level of viremia is high enough for the vaccine virus to be transmitted through blood products.100

Transfusion-related transmission of yellow fever vaccine virus has been documented in a few individuals who received blood products that were collected from individuals who received yellow fever vaccine 4 days before their blood donation.100 ACIP states that vaccinees should be advised to defer blood donation for 2 weeks after receiving yellow fever vaccine.100

There has been at least 1 case of intrauterine transmission of yellow fever vaccine virus from mother to child during pregnancy.100, 115 (See Pregnancy under Cautions: Pregnancy and Lactation.)

There is evidence that yellow fever vaccine virus can be transmitted via milk to nursing infants.100, 122, 123 (See Lactation under Cautions: Pregnancy and Lactation.)

Limitations of Vaccine Effectiveness

Yellow fever vaccine may not protect all vaccine recipients against yellow fever virus.106

There is some evidence that a small percentage of immunologically normal individuals who fail to develop an immune response to initial vaccination with yellow fever vaccine may do so following revaccination.106

Duration of Immunity

The duration of protection and need for revaccination or additional (booster) doses after primary immunization with yellow fever vaccine has not been fully determined.102, 103, 104, 106 Following primary immunization with a single dose of yellow fever vaccine in healthy individuals, 80-100% of vaccinees develop protective levels of yellow fever virus neutralizing antibodies within 10 days and there is some evidence that this immunity may persist for at least 30-35 years and possibly for life.100, 101, 103, 106

Revaccination (booster dose) of yellow fever vaccine boosts levels of yellow fever virus-specific neutralizing antibody,100, 106 and there is some evidence that the degree of this increase is inversely correlated with the preexisting level of antibody.100

The manufacturer states that revaccination with yellow fever vaccine is recommended every 10 years in individuals at risk of exposure to yellow fever virus.106

ACIP states that a single primary dose of yellow fever vaccine provides long-lasting protection and is adequate for most travelers.104 However, because data are not available on vaccine efficacy or protective antibody titers (i.e., seroprotection) related to long-term immunogenicity after vaccination with yellow fever vaccine, ACIP recommends that certain individuals who may have had a less robust or less sustained immune response to the vaccine, certain travelers who will be in higher-risk settings, and laboratory personnel at continued high risk of exposure to yellow fever virus should receive revaccination (booster dose) of yellow fever vaccine.104 (See Prevention of Disease Caused by Yellow Fever Virus under Dosage and Administration: Dosage.)

The World Health Organization (WHO) states that a single primary dose of yellow fever vaccine provides sustained immunity and lifelong protection against disease caused by yellow fever virus and that revaccination (booster dose) every 10 years is no longer considered necessary.115 Although international health regulations no longer require revaccination (booster dose) of yellow fever vaccine and WHO states that an ICVP is considered valid for the lifetime of the vaccinee, it is uncertain when or if all countries with entry requirements for yellow fever vaccination will adopt this change.115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

Improper Storage and Handling

Improper storage or handling of vaccines may reduce vaccine potency resulting in reduced or inadequate immune responses in vaccinees.134

Yellow fever vaccine is heat sensitive and potency is substantially reduced if stored at room temperature.106 This information is important for countries or areas where there is an inadequate cold chain and where there is potential for inadvertent exposure to abnormal temperatures during shipping and/or storage of the vaccine.106

All vaccines should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.134 (See Chemistry and Stability: Stability.)

Vaccine that has been mishandled or has not been stored at the recommended temperature should not be administered.134 If there are concerns about mishandling, the manufacturer or state or local immunization or health departments should be contacted for guidance on whether the vaccine is usable.134

Pediatric Precautions

The manufacturer states that yellow fever vaccine is contraindicated in infants younger than 9 months of age.106 This contraindication is based on the increased risk of YEL-AND in this age group (see Cautions: Vaccine-associated Neurotropic Disease).106 The rate of YEL-AND has been reported to be 50-400 cases per 100,000 doses in infants younger than 6 months of age, but the risk is believed to be substantially lower by 9 months of age.100, 115 The mechanism of increased neurovirulence in infants is not known, but may be related to immaturity of the blood-brain barrier, higher or more prolonged viremia, or immaturity of the immune system.100, 115

ACIP, CDC, and the American Academy of Pediatrics (AAP) state that yellow fever vaccine is contraindicated in infants younger than 6 months of a 100, 105, 115 however, these experts state that the vaccine may be considered and used with caution if necessary in infants 6-8 months of age†.100, 105, 115 Individuals who plan to travel with infants younger than 9 months of age to areas where yellow fever is endemic or epidemic should postpone or avoid such travel whenever possible.100, 106, 115 If travel to such areas is unavoidable, a decision regarding whether to vaccinate infants 6-8 months of age† should be based on the relative risk of exposure to yellow fever virus and the risk for serious adverse effects following administration of yellow fever vaccine.100, 105, 115

Geriatric Precautions

Postmarketing surveillance data of adverse effects reported to VAERS from 1990-1998 and from 2000-2006 suggest that adults 60 years of age or older may be at increased risk for serious adverse effects after receiving yellow fever vaccine compared with younger adults.100, 106 Some data indicate that the rate of adverse systemic effects occurring following vaccination with yellow fever vaccine was 2.5 times higher in adults 65-74 years of age compared with those 25-44 years of age.106

The manufacturer states that use of yellow fever vaccine in adults older than 65 years of age should be limited to those individuals traveling to or residing in known yellow fever endemic or epidemic areas.106

ACIP and CDC state that yellow fever vaccine should be used with caution in adults 60 years of age or older, especially in those receiving their first dose of the vaccine.100, 115

If travel is unavoidable, a decision regarding whether to vaccinate a geriatric individual 60 years of age or older should be based on the risks and benefits of the vaccine in the context of the destination-specific risk for exposure to yellow fever virus.100, 115 The health status of the geriatric individual should be evaluated prior to vaccination and such individuals should be carefully monitored for adverse effects for 10 days after vaccination.106

Mutagenicity and Carcinogenicity

The mutagenic and carcinogenic potential of yellow fever vaccine have not been evaluated.106

Pregnancy and Lactation

Pregnancy

Yellow fever vaccine should be used during pregnancy only when clearly needed.106

It is not known whether yellow fever vaccine can cause fetal harm when administered to pregnant women.106 Animal reproduction studies have not been performed with yellow fever vaccine.106

Limited data indicate that when the vaccine is administered during pregnancy, yellow fever vaccine virus can cross the placenta and infect the developing fetus;100, 106 however, the potential risk of adverse effects due to such congenital infection is not known.115 In several international studies (Nigeria, Trinidad, Brazil) where pregnant women received yellow fever vaccine containing the 17D-204 strain of vaccine virus, there was no evidence of an increased incidence of spontaneous abortions and no increased incidence of adverse effects in the women or their infants.106

Live, attenuated virus vaccines administered during pregnancy pose a theoretical risk to the fetus and such vaccines generally are contraindicated during pregnancy, unless the disease to be prevented poses a greater risk to the pregnant woman or fetus than the vaccine.105, 134 The sequelae of yellow fever infection are not altered by pregnancy and efforts should be made to postpone travel to areas with a substantial risk of exposure to yellow fever until after delivery when the vaccine can be administered.105, 115

If travel to high-risk areas is unavoidable during pregnancy and the risks of the vaccine are felt to outweigh the risks of exposure to yellow fever virus, pregnant women should be advised of the risk, instructed in methods for avoiding bites by vector mosquitoes, and provided with a medical waiver letter to use with the required ICVP to fulfill international health regulations.100, 105, 115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

If travel to high-risk areas is unavoidable and the risks of exposure to yellow fever virus are felt to outweigh the risks of the vaccine, ACIP, CDC, and AAP state that yellow fever vaccine can be administered during pregnancy (e.g., if travel to high-risk area is unavoidable during pregnancy and a high level of protection against mosquito exposure is not feasible).100, 105, 115

If a pregnant woman receives yellow fever vaccine, her infant should be monitored closely for evidence of congenital infection and other possible vaccine adverse effects.115 In addition, because some data indicate that the seroconversion rate after vaccination with yellow fever vaccine may be lower in pregnant women compared with other healthy adults (see Pharmacology: Response to Yellow Fever Vaccine), consideration should be given to performing serologic testing to document seroconversion after vaccination.100, 115 Appropriate state health departments or the CDC (970-221-6400) should be contacted for information on serologic testing.115

Although specific data are not available, ACIP and CDC state that women who receive yellow fever vaccine and are planning to become pregnant should wait at least 4 weeks after vaccination before conceiving.100, 115

Lactation

The manufacturer states that yellow fever vaccine is contraindicated in nursing mothers, especially if the breast-fed infant is younger than 9 months of age.106

ACIP and CDC state that yellow fever vaccine should be avoided in nursing women whenever possible; however, if travel to an area where yellow fever virus is endemic cannot be avoided or postponed, yellow fever vaccine can be used with caution.100, 115

There is evidence that yellow fever vaccine virus can be transmitted via milk from nursing mothers to their infants.100, 122, 123 In one reported case, a nursing mother in Brazil received a dose of yellow fever vaccine (prepared using the 17DD strain of yellow fever virus) at 15 days postpartum and her infant, who was exclusively breast-fed, was hospitalized 8 days later with seizures and possible meningoencephalitis.123 Yellow fever vaccine virus, identical to the 17DD vaccine strain, was detected in the infant's CSF and yellow fever-specific immunoglobulin M (IgM) antibodies were present in the infant's serum and CSF, indicating transmission and infection with yellow fever vaccine virus.123

Drug Interactions ⬆ ⬇

Chloroquine

Yellow fever vaccine has been administered concurrently with chloroquine.106 Although chloroquine inhibits replication of yellow fever virus in vitro, the drug does not appear to adversely affect antibody response to yellow fever vaccine in individuals receiving antimalarial prophylaxis.100

Immune Globulins and Blood Products

The US Public Health Service Advisory Committee on Immunization Practices (ACIP), US Centers for Disease Control and Prevention (CDC), and American Academy of Pediatrics (AAP) state that yellow fever vaccine may be administered concurrently with (at a different site) or any time before or after immune globulin or specific immune globulin (hyperimmune globulin) preparations (e.g., IGIM, IGIV, hepatitis B immune globulin [HBIG], rabies immune globulin [RIG], varicella zoster immune globulin [VZIG]).105, 134 Data indicate that immune globulin does not interfere with the immune response to yellow fever vaccine.100, 105, 106, 111, 115 In a randomized, double-blind, placebo-controlled study in previously unvaccinated healthy adults 18-40 years of age without a history of travel or residence in areas where yellow fever is endemic, concurrent administration of a single dose of immune globulin (0.06 mL/kg given IM at a different site) and a single dose of yellow fever vaccine did not affect seroconversion rates (all vaccinees in both treatment groups seroconverted by day 14 after vaccination) and did not affect postvaccination viremia or adverse effects associated with the vaccine.111

ACIP states that yellow fever vaccine may be administered concurrently with (at a different site) or at any time before or after blood products (e.g., whole blood, packed red blood cells, plasma) because blood products available in the US are unlikely to contain a substantial amount of antibody to yellow fever vaccine virus.134 However, because there is evidence that yellow fever vaccine virus can be transmitted via blood products collected from individuals who received yellow fever vaccine a few days before their blood donation (see Transmission of Vaccine Virus under Cautions: Precautions and Contraindications), 100 ACIP states that vaccinees should be advised to defer blood donation for 2 weeks after receiving yellow fever vaccine.100

Immunosuppressive and Immunomodulatory Agents

Individuals receiving immunosuppressive or immunomodulatory therapy (e.g., alkylating agents, antimetabolites, corticosteroids, interleukin-1 blocking agents, monoclonal antibodies targeting immune cells, tumor necrosis factor alpha [TNF-α] inhibitors, radiation) may have decreased or suboptimal antibody response to yellow fever vaccine and may be at increased risk of adverse effects reported with the vaccine (e.g., encephalitis).100, 106, 114, 115, 134

Yellow fever vaccine is contraindicated in individuals receiving immunosuppressive or immunomodulatory therapy.100, 106, 115 Vaccination with yellow fever vaccine and travel to yellow fever endemic areas should be deferred until the immunosuppressive or immunomodulatory therapy is discontinued and immune function has improved.100, 115 If travel to such areas cannot be avoided, individuals receiving immunosuppressive or immunomodulatory therapy should be advised of the risk, instructed in methods for avoiding bites by vector mosquitoes, and provided with a medical waiver letter to use with the required International Certificate of Vaccine or Prophylaxis (ICVP) to fulfill international health regulations.100, 115 (See International Regulations Regarding Vaccination Against Yellow Fever under Prevention of Disease Caused by Yellow Fever Virus: Travelers, in Uses.)

The manufacturer states that intra-articular, bursal, or tendon injections of prednisone or other corticosteroids should not constitute an increased hazard to recipients of yellow fever vaccine.106 ACIP states that short-term (less than 2 weeks), low- to moderate-dose (less than 20 mg of prednisone daily or equivalent) systemic corticosteroid therapy; long-term, alternate-day treatment with short-acting systemic corticosteroid therapy; maintenance physiologic doses (replacement therapy); topical (e.g., cutaneous, ophthalmic) or inhaled corticosteroid therapy; or intra-articular, bursal, or tendon injections with corticosteroids should not be immunosuppressive and do not usually contraindicate vaccination with live virus vaccines.100, 134 Although the immunosuppressive effects of corticosteroids can vary, these experts state that a dose equivalent to either 2 mg/kg or greater or a total daily dosage of 20 mg or greater of prednisone or equivalent in individuals weighing more than 10 kg when administered for 2 weeks or longer is considered sufficiently immunosuppressive to contraindicate use of live attenuated vaccines.100, 134 ACIP states that vaccination with live virus vaccines should be deferred for at least 1 month after high-dose systemically-absorbed corticosteroid therapy that has been administered for 14 days or longer is discontinued.134

ACIP states that individuals with leukemia in remission who have not received chemotherapy for at least 3 months may receive live viral vaccines.134

Vaccines

Only limited data are available regarding concurrent administration of yellow fever vaccine and other vaccines.106 Decisions to administer yellow fever vaccine concurrently with other vaccines should be made based on information regarding possible interference with immune responses to the vaccines and should take into consideration the convenience to the traveler in completing the desired vaccinations before travel.100, 106

If yellow fever vaccine is administered concurrently with other vaccines, each parenteral vaccine should be administered using a different syringe and different injection site.106

Inactivated Vaccines and Toxoids

ACIP states that there is no evidence that inactivated vaccines interfere with the immune response to live vaccines; therefore, inactivated vaccines, recombinant vaccines, polysaccharide vaccines, or toxoids can be administered concurrently with or at any time before or after yellow fever vaccine.100, 134 The manufacturer of yellow fever vaccine states that, when data are not available to support concurrent administration, the other vaccine should be administered 4 weeks after yellow fever vaccine.106

Yellow fever vaccine has been administered concurrently with BCG vaccine,100 hepatitis A vaccine,100, 106 hepatitis B vaccine,100, 106, 134 influenza vaccine,100 meningococcal polysaccharide vaccine,100, 106 poliovirus vaccine inactivated (IPV),100 or smallpox vaccine100 without reported interference with the immune response and without an increase in adverse effects.100

Yellow fever vaccine has been administered concurrently at a different site with parenteral typhoid vaccine Vi capsular polysaccharide (Typhim Vi^®) with or without concomitant hepatitis A vaccine (Vaqta^®) without any apparent decrease in the immune response or increase in adverse effects.109 Yellow fever vaccine also has been administered concomitantly with parenteral typhoid vaccine Vi capsular polysaccharide with or without meningococcal (groups A, C, Y and W-135) oligosaccharide diphtheria CRM₁₉₇ conjugate vaccine (MenACWY-CRM; Menveo^®) without any apparent decrease in the immune response to any of the vaccine antigens or an increase in adverse effects.121

Yellow fever vaccine has been administered concomitantly (at a different site) with diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP; no longer commercially available in the US).106

Data are not available regarding concurrent administration and possible interference between yellow fever vaccine and human papillomavirus (HPV) vaccine, Japanese encephalitis virus vaccine, or rabies vaccine.100, 106 When data are not available to support concurrent administration, the manufacturer of yellow fever vaccine states that the vaccines should be administered 4 weeks apart.106

Live Vaccines

There are theoretical concerns that the immune response to one parenteral live virus vaccine might be impaired if given within 28-30 days (i.e., 4 weeks) of another parenteral live virus vaccine (e.g., measles, mumps, rubella, varicella, yellow fever).134 ACIP states that yellow fever vaccine should be administered either concurrently with or at least 30 days (4 weeks) apart from other live vaccines.100, 134 The manufacturer of yellow fever vaccine states that, when data are not available to support concurrent administration, the other vaccine should be administered 4 weeks after yellow fever vaccine.106

Yellow fever vaccine has been administered with or within 1-27 days of measles virus vaccine live (no longer commercially available in the US as a monovalent vaccine) without an increase in adverse effects or interference with the immune response to the vaccines.100, 134 In a study in children 12-23 months of age in Brazil, yellow fever vaccine was administered either concurrently with (at a different site) or 30 days after measles, mumps, and rubella virus vaccine live (MMR).117 Results indicated that antibody responses to the measles antigen were similar when yellow fever vaccine was administered concurrently or 30 days later (98 or 99%, respectively), but that seroconversion rates to the mumps, rubella, and yellow fever antigens were lower when the vaccines were administered concomitantly (90, 67, or 70%, respectively) compared with 30 days apart (97, 71, or 88%, respectively).117

Data are not available regarding concurrent administration of varicella virus vaccine live and yellow fever vaccine.100

Concurrent administration of typhoid vaccine live oral and yellow fever vaccine does not interfere with the immune response to the typhoid antigen.113 ACIP states that typhoid vaccine live oral may be administered concurrently with or at any interval before or after yellow fever vaccine.100

Other Information ⬆ ⬇

Tuberculin Skin Test

Although the effect of yellow fever vaccine, if any, on tuberculin testing has not been determined,100, 134 another live virus vaccine (measles virus vaccine live; no longer commercially available in the US as a monovalent vaccine) has been reported to temporarily suppress tuberculin skin sensitivity.134

The US Public Health Service Advisory Committee on Immunization Practices (ACIP) states that a tuberculin skin test can be given during the same health-care visit as yellow fever vaccine;100, 134 if not given simultaneously, the tuberculin test should be delayed for at least 4 weeks after the vaccine dose.100, 134 However, vaccination with the yellow fever vaccine should not be delayed based only on a theoretical concern about a possible interaction with tuberculin skin testing.134

Pharmacology

Yellow fever vaccine is used to stimulate active immunity to yellow fever virus infection by inducing production of yellow fever virus-specific neutralizing antibodies.106 (See Uses: Prevention of Disease Caused by Yellow Fever Virus.)

Yellow Fever Virus and Infection

Yellow fever is an acute viral illness caused by the yellow fever virus, a Flavivirus .100, 105, 106, 115 Yellow fever virus is transmitted to humans by mosquito vectors.100, 105, 106, 115 Yellow fever virus occurs in sub-Saharan Africa and South America where it is endemic and intermittently epidemic.106, 115

Infection with yellow fever virus can result in a subclinical illness and influenza-like syndrome, or may progress to an overwhelming pansystemic disease with hepatic and renal failure and hemorrhage caused by platelet and clotting abnormalities.100, 106, 115 Yellow fever has an abrupt onset after an incubation period of 3-6 days.100, 106 Symptoms usually include fever, prostration, headache, photophobia, lumbosacral pain, extremity pain (especially knee joints), epigastric pain, anorexia, and vomiting.106 Humans infected with yellow fever virus experience the highest levels of viremia and can transmit the virus to mosquitoes shortly before onset of fever and for the first 3-6 days of illness.100, 101, 115 The World Health Organization (WHO) estimates that about 200,000 cases of yellow fever occur annually worldwide.100 The case fatality rate varies widely, but is typically 20-50% for severe disease.104, 106, 115

Response to Yellow Fever Vaccine

Vaccination with yellow fever vaccine containing live, attenuated strains of the 17D strain of yellow fever virus is predicted to produce an immune response similar to that induced by infection with wild-type yellow fever virus.106 Following administration of yellow fever vaccine, initial infection with the vaccine virus occurs in the cells in the dermis or other subcutaneous tissues near the injection site.106 Subsequently, replication and limited spread of the virus leads to the processing and presentation of viral antigens to the immune system, similar to what would occur during infection with wild-type yellow fever virus.106 The humoral immune response to the structural proteins of the vaccine virus can be detected by formation of specific antibodies that are detected as neutralizing antibodies in assays that measure the ability of serum to reduce plaque formation in tissue culture cells.106

The minimum titer of anti-yellow fever neutralizing antibodies conferring protection against yellow fever has not been definitely established to date.100, 106 WHO considers a log₁₀ neutralization index of 0.7 or greater measured by plaque reduction assay to be indicative of an adequate response to yellow fever vaccine and this was the level used to define seroconversion in clinical trials of the vaccine.106

Immunity to yellow fever generally develops within about 10 days following primary immunization with a single subcutaneous dose of yellow fever vaccine and may persist for at least 30-35 years and possibly for life.100, 106 In US studies using the currently available yellow fever vaccine containing the 17D-204 strain of yellow fever virus, the seroconversion rate in adults was 80-100%.100, 106 In 2 clinical studies that used vaccine containing the 17D-204 strain, 90% of vaccinees seroconverted within 10 days after vaccination and 100% seroconverted within 14 days.106 In early studies evaluating yellow fever vaccine, there was no evidence of age-related differences in the immune response to the vaccine;103, 106 however, additional study is needed since some more recent studies suggest that children have a lower immune response than adults and that the difference in seroconversion rates is most pronounced in children 9-36 months of age.103 There is some evidence that immunocompetent individuals who do not seroconvert after an initial dose of yellow fever vaccine may do so following revaccination.100, 106

The immunologic response to yellow fever vaccine may be reduced in individuals with human immunodeficiency virus (HIV) infection and there is some evidence that the seroconversion rate in HIV-infected individuals is reduced in those with lower CD4⁺ T-cell counts and higher plasma HIV RNA levels.100, 103, 106, 115, 116 Other immunocompromised individuals also may have a reduced immune response to yellow fever vaccine.106

The seroconversion rate after vaccination in pregnant women may be reduced compared with that in other healthy women, especially when the vaccine is given late in pregnancy.100, 103, 106 In a study involving 101 Nigerian women (88% in the third trimester of pregnancy), the seroconversion rate was approximately 39% in pregnant women compared with approximately 82% in a control group of nonpregnant women.106

Chemistry and Stability

Chemistry

Yellow fever vaccine is a lyophilized preparation of live, attenuated organisms of the 17D-204 strain of yellow fever virus.106 The vaccine is prepared by culturing the 17D-204 strain of live yellow fever virus in living chick embryos that are free of avian leukosis virus (AVL).106 A suspension is prepared, processed, freeze-dried, and hermetically sealed under nitrogen.106 Commercially available yellow fever vaccine meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration and the World Health Organization (WHO).106

Each 0.5-mL of yellow fever vaccine contains not less than 4.74 log₁₀ plaque-forming units (PFU) throughout the life of the product.106 Yellow fever vaccine contains sorbitol and gelatin as a stabilizer.106 The vaccine does not contain thimerosal or any other preservative.106

Following reconstitution with the 0.9% sodium chloride diluent supplied by the manufacturer, yellow fever vaccine is a slightly pink-brown suspension.106

Stability

Lyophilized yellow fever vaccine should be stored at 2-8°C prior to reconstitution and should not be frozen.106

Yellow fever vaccine is heat sensitive and potency is substantially reduced if the lyophilized vaccine is stored at room temperature.106 The manufacturer states that the half-life of yellow fever vaccine is approximately 14 days if stored at 35-37°C and only 3-4 days if stored at 45-47°C.106 This information is important for countries or areas where there is an inadequate cold chain and where there is potential for inadvertent exposure to abnormal temperatures during shipping and/or storage of the vaccine.106

Because yellow fever vaccine and the diluent supplied by the manufacturer do not contain preservatives, the vaccine should be used within 1 hour following reconstitution.106

section name header

Introduction ⬇

AHFS Class:

Generic Name(s):

Uses ⬆ ⬇

Dosage and Administration ⬆ ⬇

Cautions ⬆ ⬇

Drug Interactions ⬆ ⬇

Other Information ⬆ ⬇

Preparations ⬆ ⬇

Yellow Fever Vaccine

Copyright ⬆ ⬇

References ⬆