What information is available regarding yellow fever vaccine administration in patients with egg allergy?

Introduction
Yellow fever is caused by the yellow fever virus, which is endemic to parts of sub-Saharan Africa and tropical South America.1 The virus is transmitted through mosquito bites, with reservoirs in both nonhuman primates and humans. There are 3 primary transmission cycles that can result in human disease: the sylvatic (jungle) cycle, the intermediate (savannah) cycle, and the urban cycle. In the sylvatic cycle, yellow fever is transmitted from monkeys to humans via mosquito bite; this most commonly occurs when humans enter the jungle for recreational or occupational reasons. In the intermediate cycle, the virus is transmitted to humans from monkeys or other humans via tree hole-breeding Aedes mosquitos in jungle border areas. In the urban cycle, the virus is transmitted between humans via peridomestic mosquitos (mainly Aedes aegypti). Yellow fever disease is most commonly acquired through the sylvatic or intermediate transmission cycles, though urban transmission does occur periodically in Africa and sporadically in the Americas.

The risk of contracting yellow fever during travel depends on destination-specific and travel-associated factors.1 Certain countries have been identified by the World Health Organization (WHO) as countries where risk for yellow fever transmission exists; the risk of exposure may be limited to certain regions within some countries.1,2 Transmission of yellow fever can also be seasonal, depending on the region.1 For example, risk for yellow fever in West Africa is increased at the end of the rainy season and at the beginning of the dry season (usually July through October); in South America, the risk is usually highest during the rainy season (January through May). Travelling to a region where an active yellow fever outbreak is occurring may increase the risk of infection, but there is always a risk to travelers in endemic areas regardless of the number of reported human cases.

Yellow fever virus infection is often asymptomatic; however, it can lead to serious symptoms and/or death in some patients.1,3 The typical incubation period for the virus is 3 to 6 days; initial symptoms are usually non-specific and may include fever, chills, muscle pain, headache, loss of appetite, and nausea/vomiting. Symptoms resolve after 3 to 4 days in most patients, but approximately 12% will enter a second, more toxic phase within 24 to 48 hours of initial symptom remission. These patients develop severe symptoms such as jaundice, abdominal pain, and bleeding from the mouth, nose, eyes, or stomach. The fatality rate for severe yellow fever is estimated at 30% to 60%.1

Since there are no specific treatments for yellow fever beyond usual supportive care measures, prevention of the disease is vital to reduce morbidity and mortality.1 Prevention of mosquito bites can help stop the spread of the virus; mosquito bites can be avoided with the use of insect repellants as well as clothing that minimizes skin exposure (e.g., long-sleeved shirts, long pants, hats, closed shoes).1,4 Vaccination against yellow fever is also recommended or required for people living in or traveling to certain countries.1

Yellow Fever Vaccine Characteristics and Use
The Centers for Disease Control and Prevention (CDC) and the Advisory Committee on Immunization Practices (ACIP) recommend yellow fever vaccination for people aged ≥9 months who are traveling to or living in areas at risk for yellow fever virus transmission in South America and Africa.5 There is only one yellow fever vaccine (YF-VAX) currently licensed for use in the United States.1 A similar vaccine (Stamaril) is commonly used outside the United States; the primary difference between YF-VAX and Stamaril is the absence of gelatin in the Stamaril formulation.1,6 Other vaccines, including some that utilize different sub-strains of yellow fever virus, are also available in some countries.7 All yellow fever vaccines are produced in embryonated chicken eggs.

The YF-VAX vaccine is a live attenuated vaccine that utilizes the 17D-204 strain of the yellow fever virus; the formulation of YF-VAX contains sorbitol and gelatin.8,9 It is typically administered as a single subcutaneous injection of 0.5 mL.5,8 Booster doses are not necessary in most patients; however, ACIP recommends additional doses of the vaccine in patients who were initially vaccinated while pregnant, patients who received a hematopoietic stem cell transplant after their initial yellow fever vaccination (if they are immunocompetent enough to be safely revaccinated), and patients who were infected with HIV when they received their last dose of the vaccine.1,10 Booster doses can also be considered in travelers who received their last dose of yellow fever vaccine at least 10 years previously if they will be in a higher-risk setting based on season, location, activities, and duration of travel.

The YF-VAX vaccine carries a risk of significant adverse events, including hypersensitivity reactions, yellow fever vaccine-associated neurologic disease, and yellow fever vaccine-associated viscerotropic disease; in order to minimize the risk of adverse events with the vaccine, there are a number of contraindications and precautions to its use.1 The vaccine is contraindicated in patients aged <6 months, patients with an allergy to any vaccine component, and immunosuppressed patients (e.g., patients with symptomatic HIV infection, CD4 lymphocyte count <200 cell/mL, primary immunodeficiency, malignancy, or thymus disorder associated with abnormal immune cell function; transplant patients; patients receiving immunomodulatory or immunosuppressive therapies). It should be used with caution in patients aged 6 to 8 months, patients aged ≥60 years, pregnant or breastfeeding patients, and patients with asymptomatic HIV infection with CD4 lymphocyte counts 200 to 499 cells/mL.

Yellow Fever Vaccination in Patients with Egg Allergy
The VF-VAX vaccine is generally thought to contain higher amounts of ovalbumin (an egg protein) than the influenza vaccine, which also utilizes embryonated chicken eggs in its production process.11 While it has been established that influenza vaccines can be administered to egg-allergic patients without additional safety precautions, the safety of administering yellow fever vaccines to such patients remains less clear.11,12 As mentioned above, the YF-VAX vaccine is contraindicated in patients with an allergy to any vaccine component; according to the manufacturer and the CDC, this includes patients with a history of acute hypersensitivity reactions to chicken proteins, eggs, or egg products, since the virus used in the vaccine is propagated in chicken embryos.1,8 The manufacturer states that less severe or localized manifestations of allergy to eggs or to feathers are not contraindications to vaccine administration, and do not usually warrant skin testing.8 Additionally, the manufacturer notes that patients who can eat eggs or egg products can generally receive the vaccine. For patients with a questionable history of allergy to a vaccine component, the CDC states that skin testing and (if necessary) desensitization can be performed under physician supervision if vaccination is deemed necessary.1 Desensitization typically follows the 5-step graduated dose administration protocol recommended by the manufacturer.8

Several observational studies have examined the safety of yellow fever vaccines in patients with egg allergy, include patients with a history of anaphylaxis to eggs (see Table).13-17 In the largest and most recent of these studies, skin prick testing and intradermal testing were not found to reliably predict allergic reactions to the vaccine in egg-allergic patients.13,14 The majority of egg-allergic patients in these studies tolerated the yellow fever vaccine administered as a single dose (ie, without any sort of graded administration/desensitization protocol).13-15 When hypersensitivity reactions were reported, they were generally mild local or skin reactions that resolved with administration of an antihistamine.14,15 It remains unclear whether a history of anaphylaxis to eggs increases a patient’s risk of hypersensitivity to the yellow fever vaccine; one study reported no significant association between the two variables, but the confidence interval for this finding was wide.14 Authors of another study recommended that patients with a history of anaphylaxis to eggs be evaluated by an allergist prior to vaccination, as the only patients who reacted to the vaccine in their study had a history of anaphylaxis to eggs.15 An important limitation of these studies is that they were primarily conducted in South America, where other versions of the yellow fever vaccine are widely used.13-15,17 It is possible that the manufacturing processes for these vaccines may differ slightly from those used to produce the U.S. version, leading to differences in the level of egg proteins/allergens present.

Table. Observational studies examining yellow fever vaccine administration in patients with egg allergy.13-17
Study design and durationSubjectsInterventionsResultsConclusions
Ramirez-Giraldo 202513

MC, retrospective observational study conducted in Columbia

Study period: January 2014 to November 2023		N=171 patients with egg allergy and positive egg skin prick test or serum IgE test

Mean age at yellow fever vaccination: 20.7 months

All patients experienced their first egg-related reaction prior to 1 year of age (mean age, 6 months)

Previous reactions to eggs included skin reactions (67.8%), anaphylaxis (23.9%), respiratory reaction (3.5%), gastrointestinal reaction (2.9%), or other (1.7%)		Yellow fever vaccine (product not specified)

All patients underwent skin prick testing and intradermal testing with the vaccine prior to administration; 5 patients had a positive skin prick test and 21 had a positive intradermal test		No hypersensitivity reaction was reported in any patient

Among the patients with a positive skin prick or intradermal test with the vaccine (n=26), 10 received the vaccine as a single dose and 11 in a divided dose; none of these patients demonstrated a reaction.

History of egg anaphylaxis was not associated with a positive yellow fever vaccine allergy test (OR, 1.7; 95% CI, 0.63 to 4.56; p=0.2)

Number of previous egg reactions was not associated with a positive yellow fever vaccine allergy test (OR, 2.7; 95% CI, 0.95 to 7.9; p=0.06)		Yellow fever vaccine can be safely administered to most patients with egg allergy; skin prick/intradermal testing with the vaccine does not help predict whether a patient with egg allergy will experience a reaction to the vaccine.
Tanos Lopes 202314

SC cross-sectional study conducted in Brazil

Study period: February 2018 to January 2020		N=435 children with history or suspicion of egg allergy

Median age: 12 months

Patients were classified as “probably nonallergic” (if they had no confirmed history of an immediate reaction, no sensitization to egg protein based on serum IgE measured in the past 6 months, and they were able to eat eggs or egg products without symptoms) or “probably allergic” (if they had a medical history of immediate reaction and evidence of sensitization to egg protein based on serum IgE measured in the past 6 months)

51.7% of patients were classified as “probably allergic”, and 32.8% had a history of anaphylaxis		Yellow fever vaccine (product not specified)

Patients who were “probably nonallergic” and patients who were “probably allergic” with no history of anaphylaxis received the vaccine in a single dose

Patients who were “probably allergic” with a history of anaphylactic reactions underwent skin prick testing with the vaccine prior to administration; patients with a positive skin prick test received the vaccine in 2 equally divided doses with 30 minutes between doses		Most patients (95.2%) did not demonstrate a reaction to the vaccine

Of the 21 patients who reacted to the vaccine, 10 experienced a local reaction, 10 experienced a mild skin reaction distant from the vaccine site, and 1 developed a possible anaphylactic reaction requiring epinephrine; 11 of these patients were classified as “probably nonallergic” to eggs at baseline

Among those who reacted to the vaccine, only 2 had positive skin prick test results with the vaccine, and 7 had negative skin prick test results (including the patient who experienced anaphylaxis); 12 did not undergo skin prick testing prior to administration because they did not have a history of anaphylactic reactions

Reactions to the vaccine were not predicted by probable egg allergy (OR, 1.41; 95% CI, 0.41 to 4.92; p=0.78), egg anaphylaxis (OR, 2.20; 95% CI, 0.90 to 5.38; p=0.12), or positive vaccine skin prick test result (OR, 1.29; 95% CI, 0.25 to 6.73; p=0.67)		The yellow fever vaccine can be safely administered in a single dose to children with a confirmed or suspected egg allergy without prior vaccine skin testing; however, it should always be administered in a facility equipped to manage any potential adverse reactions, and patients with a history of anaphylactic reactions to egg should be observed for 60 minutes following administration.
Garcia-Paba 202315

SC, retrospective, cross-sectional study conducted in Columbia

Study period:
January 2017 to December 2019		N=71 patients with a confirmed IgE-mediated egg allergy

Median age at vaccination: 20 months

Egg allergy was confirmed by suggestive history (urticaria, angioedema, eczema, gastrointestinal symptoms, and/or respiratory symptoms 2 hours after egg consumption within the past 6 months) and positive skin prick test and/or specific IgE, OR by positive oral food challenge within the past 6 months

24 patients (33.8%) had a history of anaphylaxis to eggs		Yellow fever vaccine (Stamaril)

All patients underwent skin prick testing with the vaccine, and patients with a history of severe egg anaphylaxis also underwent intradermal testing with the vaccine

If skin prick testing and intradermal testing were negative, the vaccine was administered in one dose; if either test was positive, the vaccine was administered in 2 or 3 graded doses with a 30-minute interval between each dose		All patients had negative skin-prick tests; 5 patients had a history of severe anaphylaxis with eggs and had additional intradermal testing performed (2 patients in this group had a positive intradermal test)

The vaccine was administered in 1 dose to 69 patients (including 3 patients with a history of severe egg anaphylaxis and negative intradermal test); of these, 68 patients had no reaction to the vaccine and 1 patient with a history of moderate egg anaphylaxis developed urticaria 10 minutes after administration (this was treated with an antihistamine)

The 2 patients with positive intradermal tests received the vaccine in 2 (n=1) or 3 (n=1) graded doses; the patient who received 2 graded doses had no reaction to the vaccine; the patient who received 3 graded doses had urticaria 5 minutes after the intradermal test, but tolerated the vaccine

No patients without a history of egg anaphylaxis reacted to the vaccine		It may be safe to administer the yellow fever vaccine as a single dose in patients with egg allergy who do not have a history of egg anaphylaxis; patients with a history of egg anaphylaxis should be evaluated by an allergist prior to vaccination.
Bedard 202116

Retrospective study

Study period: June 1998 to November 2019		N=24 pediatric patients with confirmed egg allergy or sensitization who received a yellow fever vaccine

Egg allergy was defined by a clinical history of reaction after egg ingestion and a positive confirmation test (eg, skin prick test, IgE); egg sensitization was defined by a positive confirmation test in patients who had never introduced eggs into their diet		Yellow fever vaccine (product not specified)

All patients underwent intradermal testing with the vaccine; among the patients with negative intradermal tests (n=4), 2 received the vaccine in 1 step and 2 received the vaccine in 5 steps; among the patients with positive intradermal tests (n=20), 12 received the vaccine in 1 step, 1 received the vaccine in 3 steps, and 7 received the vaccine in 5 steps		No allergic reactions were reported in any patient, despite the fact that 83% had positive intradermal skin tests

2 patients with egg white-specific IgE >100 kUA/L and 1 patient with a history of egg anaphylaxis tolerated the vaccine in 1 step		The yellow fever vaccine may be safe to administer in 1 step in egg-allergic patients; further studies in larger cohorts are required to confirm this finding.
Gerhardt 202017

Prospective, SC study conducted in Brazil

Study period: January 2018 to September 2019		N=58 patients with a history of egg allergy confirmed by positive oral food challenge within 6 months of vaccination, anaphylactic reaction to egg protein within 6 months of vaccination, or IgE-mediated reaction to egg reported within 2 months of vaccination and a positive IgE and/or skin prick test

Most patients (72.4%) had a positive oral food challenge, and 15 patients experienced anaphylaxis during their oral food challenge; 9 additional patients had a history of egg anaphylaxis within the previous 6 months

Median age at diagnosis: 2.3 years		Yellow fever vaccine (Brazilian manufacturer)

All patients underwent skin prick testing with the vaccine prior to administration; patients with negative skin prick tests went on to receive intradermal testing with the vaccine; if both tests were negative, the yellow fever vaccine was administered in a single dose; patients who had a positive skin prick or intradermal test received the vaccine in 5 graded doses		Skin prick testing was negative in all patients; intradermal testing was positive in 10 patients and negative in 48 patients

All patients with negative intradermal tests received the vaccine as a single dose with no reactions reported

The 10 patients with positive intradermal tests received the vaccine in a graded manner; of these, 6 patients had hypersensitivity reactions to the vaccine

Of the 24 patients with history of anaphylaxis to eggs, only 4 presented with reactions to the vaccine, and all reactions were mild (hives or a red welt at the injection site)		Patients with egg allergy may safely receive the yellow fever vaccine if an appropriate protocol is used for skin testing.
Abbreviations: CI=confidence interval; MC=multicenter; OR=odds ratio; SC=single-center.

Conclusion
The yellow fever vaccine is produced in embryonated chicken eggs and therefore, may contain residual amounts of chicken and/or egg proteins. Current guidance from the CDC and the manufacturer states that the vaccine is contraindicated in patients with a history of acute hypersensitivity reactions to chicken proteins, eggs, or egg products. Less severe or localized manifestations of egg or feather allergy are not contraindications to vaccine administration, and do not usually warrant skin testing. Additionally, patients who can eat eggs or egg products can generally receive the vaccine. Individuals with a history of hypersensitivity who require vaccination may undergo skin testing and, if necessary, desensitization. However, recent data seem to indicate that skin testing has limited utility in determining which egg-allergic patients may react to the vaccine. Overall, the vaccine appears to be well-tolerated in egg-allergic patients, including those with a history of anaphylaxis to eggs. Most patients with egg allergy may be able to receive the yellow fever vaccine as a single dose, without the need for a graduated administration protocol; however, caution is still warranted in patients with a history of anaphylaxis to eggs, and more data with the U.S. version of the vaccine are needed.

References

  1. Gershman M, Staples JE. Yellow fever: CDC Yellow Book 2024. Centers for Disease Control and Prevention. Updated January 31, 2025. Accessed March 21, 2025. https://wwwnc.cdc.gov/travel/yellowbook/2024/infections-diseases/yellow-fever
  2. Countries with risk of yellow fever transmission and countries requiring yellow fever vaccination (November 2022). World Health Organization. Published November 18, 2022. Accessed March 21, 2025. https://www.who.int/publications/m/item/countries-with-risk-of-yellow-fever-transmission-and-countries-requiring-yellow-fever-vaccination-(november-2022)
  3. Yellow fever. World Health Organization. Published May 31, 2023. Accessed March 21, 2025. https://www.who.int/news-room/fact-sheets/detail/yellow-fever
  4. Mutebi JP, Gimnig J. Mosquitoes, ticks & other arthropods: CDC Yellow Book 2024. Centers for Disease Control and Prevention. Updated January 31, 2025. Accessed March 21, 2025. https://wwwnc.cdc.gov/travel/yellowbook/2024/environmental-hazards-risks/mosquitoes-ticks-and-other-arthropods
  5. Staples JE, Gershman M, Fischer M; Centers for Disease Control and Prevention (CDC). Yellow fever vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2010 Jul 30;59(RR-7):1-27.
  6. Stamaril. Package insert. Sanofi Pasteur; 2018.
  7. Hansen CA, Barrett ADT. The present and future of yellow fever vaccines. Pharmaceuticals (Basel). 2021;14(9):891. doi: 10.3390/ph14090891
  8. YF-VAX. Package insert. Sanofi Pasteur; 2020.
  9. Yellow fever vaccine. Centers for Disease Control and Prevention. Updated May 15, 2024. Accessed March 21, 2025. https://www.cdc.gov/yellow-fever/vaccine/index.html
  10. Staples JE, Bocchini JA Jr, Rubin L, Fischer M; Centers for Disease Control and Prevention (CDC). Yellow fever vaccine booster doses: recommendations of the Advisory Committee on Immunization Practices, 2015. MMWR Morb Mortal Wkly Rep. 2015 Jun 19;64(23):647-50.
  11. Smith D, Wong P, Gomez R, White K. Ovalbumin content in the yellow fever vaccine. J Allergy Clin Immunol Pract. 2015;3(5):794-5. doi: 10.1016/j.jaip.2015.03.011
  12. Greenhawt M, Turner PJ, Kelso JM. Administration of influenza vaccines to egg allergic recipients: a practice parameter update 2017. Ann Allergy Asthma Immunol. 2018;120(1):49-52. doi: 10.1016/j.anai.2017.10.020
  13. Ramírez-Giraldo RH, Giraldo-Avila PA, Calle AM, Santamaria LC, Sánchez J. No yellow fever vaccine reactions in IgE-mediated egg allergic patients. Int Arch Allergy Immunol. 2025;186(1):52-58. doi: 10.1159/000539505
  14. Tanos Lopes FT, Maia de Castro Romanelli R, Isabela de Oliveira L, Abrantes MM, Rocha W. Safe administration of yellow fever vaccine in patients with suspected egg allergy. J Allergy Clin Immunol Glob. 2023;2(3):100089. doi: 10.1016/j.jacig.2023.100089
  15. García-Paba MB, Aparicio C, Rodríguez M, Moreno S, García E. Frequency of allergic reactions in egg allergic patients after receiving the yellow fever vaccine. Allergol Immunopathol (Madr). 2023;51(4):139-147. doi: 10.15586/aei.v51i4.850
  16. Bédard MA, Graham F, Paradis L, Samaan K, Bégin P, Des Roches A. Single-dose yellow fever vaccination is well tolerated in egg-allergic children despite positive intradermal test to the vaccine. J Allergy Clin Immunol Pract. 2021;9(11):4170-4172.e1. doi: 10.1016/j.jaip.2021.06.050
  17. Gerhardt CMB, Castro APBM, Pastorino AC, et al. Safety of yellow fever vaccine administration in confirmed egg-allergic patients. Vaccine. 2020;38(42):6539-6544. doi: 10.1016/j.vaccine.2020.08.020

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

April 2025

The information presented is current as of March 14, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.