Influenza vaccines, commonly known as trivalent injectable influenza vaccine (TIV), are grown on embryonated chicken eggs. For several decades, there has been concern that residual egg protein (ovalbumin) may provoke an allergic reaction in an egg-allergic individual (EAI).1 As recently as the 2009, the Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) and the American Academy of Pediatrics’ (AAP) Committee on Infectious Diseases (Red Book committee) advised that “children with known severe allergic reactions (eg, hives, angioedema, allergic asthma, or systemic anaphylaxis) to chicken or egg proteins should not receive trivalent injectable influenza vaccine.”2 Thus, it was commonplace to withhold TIV in EAIs, or only administer it in an allergist’s office after a series of risk-reducing steps such as having negative vaccine skin test and using stepwise vaccine administration involving only low ovalbumin containing TIV.3,4
With the outbreak of the 2009 H1N1 influenza pandemic, a flurry of new research has re-addressed the safety of TIV in EAIs. The results strongly suggest that both the H1N1 and TIV vaccines are safe, and that the risk-reducing measures are unnecessary.5–12 Based on these data, the 2011 guidelines from the CDC’s Advisory Committee on Immunization Practices (ACIP) were updated and no longer recommended withholding TIV from EAIs.13 EAIs with “only hives” after egg ingestion were advised to receive TIV at their primary care physician, provided they could be observed for 30 minutes afterward. The more severe EAIs could still receive TIV, but referral to an allergist was advised for administration.13,14
To date, there is published data regarding 4,315 patients who have safely received 4,872 total doses of TIV, including 656 EAIs with severe egg allergy (including anaphylaxis to egg) who safely received 740 doses of TIV.12,15 Thus, ample data exist that support the safety of providing TIV to EAIs in the primary care setting. This review article will trace the evolution of this practice.
Influenza Vaccination in Food-Allergic Children
Approximately 294,128 hospitalizations annually are attributable to influenza A, including 21,156 occurring in children 5 years of age or younger.16 Approximately 8% of US children are food allergic, including approximately 2% with egg allergy.17 As many as 33% of food-allergic children also have comorbid asthma.18 Withholding TIV in these EAIs places these children at significant risk for influenza-related morbidity.14,19 The benefits of influenza vaccination in asthmatic patients are well-documented and strongly supported by a recent Cochrane review.20
The CDC and World Health Organization (WHO) recommend all children younger than age 5 years receive annual TIV.13,19
Since the 1940s, data suggested some risk to EAIs posed by the ovalbumin contained in TIV.21,22 A small 1952 study documented two systemic reactions to TIV in five patients, all of whom had positive vaccine skin tests.23 Nine studies conducted prior to 1998 demonstrated that a moderate percentage of EAIs would have positive prick or intradermal skin tests to either full-strength or dilute TIV. However, in five small studies investigating vaccine tolerance in this population, only nine of 50 EAIs vaccinated between 1952 and 1992 manifested symptoms (12%).12 A 1976 CDC surveillance of TIV-related reaction noted 11 cases of anaphylaxis, of which none were in EAIs populations.24
Fatality attributed to the vaccine in EAIs has been rarely reported, with one known case in 1969.25 From 1990 to 2005, four deaths attributed to anaphylaxis from TIV were reported, though it is not known if these occurred in EAIs.26 During this time, there was wide variability in the known egg content of the vaccine, which ranged from undetectable to as high as 45 mcg/mL. The egg content depended both on the manufacturer and year.27 Based on these data, the Red Book has always issued a contraindication to EAIs receiving TIV.2
In 1988, James et al5 conducted a landmark study pertaining to TIV safety in EAIs. In a 3-year, multicenter randomized controlled trial, 83 egg-allergic children (including 27 severely EAIs), and 124 control patients were vaccinated to TIV. All patients, including controls, underwent prick skin testing to full strength vaccine and received TIV as a two-step graded challenge consisting of 10% of the age appropriate dose, followed by the residual 90% after 30 minutes of observation for symptom development. Skin testing was positive in four EAIs and one control; eight of 83 EAIs developed mild and localized symptoms (just two patients received treatment) versus four of 123 controls with similar symptoms (one patient was treated).
There were no reactions among those with positive skin tests. The TIV ovalbumin content was measured and ranged between 0.02 mcg/L and 1.2 mcg/mL. It was concluded that EAIs could be safely by a two-step graded process, and that using vaccine with ovalbumin content of less than 1.2 mcg/mL was safe.5
This study provided a basis for a cautious approach for the allergist to vaccinate EAIs, using a two-step graded process and a vaccine with less than 1.2 mcg/mL ovalbumin.3 However, through 2009, the Red Book on immunization practices still recommended that EAIs generally should not receive TIV.2 During this time, a handful of other studies in addition to James et al5
evaluated an additional 618 patients in the US, Canada, and Europe, which noted 19 mild or local reactions in published data.12
Pandemic and Renewed Research Interest
The onset of the 2009 H1N1 pandemic spurned several groups to re-evaluate the safety of both the H1N1 and TIV vaccines in EAIs, given the well-established benefits and a strong desire from many of these patients to receive both vaccines.
The Risk of H1N1 Influenza Vaccine
Two 2009 studies directly addressed H1N1 influenza vaccine safety. Gagnon et al6 performed a prospective multicenter trial conducted in Canada using an adjuvanted H1N1 influenza A vaccine (pH1N1) containing approximately 0.3 mcg/mL ovalbumin, without vaccine skin testing. They successfully vaccinated 850 EAIs with physician confirmed allergy and 393 control patients. Among the 850 EAIs, 72 had either a history of severe cardiovascular/respiratory symptoms attributable to egg or poorly controlled asthma and were vaccinated with a two-step graded challenge.
The remaining 758 EAIs received a single dose. There were 3% who developed mild symptoms within a 1-hour observation period, and an additional 13.7% reporting mild gastrointestinal symptoms or rhinitis at 24 hours after vaccination, compared with 14.7% in the control group. Based on this success, a separate group of 3,640 patients with self-reported egg allergy were vaccinated using the same protocol, with 69 patients (2%) developing symptoms consistent with an allergic reaction, including two patients requiring epinephrine (without fulfilling criteria for anaphylaxis).
This was the first study to demonstrate the safety of a single-dose approach, and that vaccine skin testing was unnecessary.6 This group released safety data pertaining to specific allergic symptoms provoked by the pH1N1 vaccine. Among 95 patients with a history of reactivity to the pH1N1 (including two EAIs), they noted that reactions to pH1N1 were rare and unlikely to be IgE-mediated.28
In the US, a controlled prospective study was conducted of 105 egg-allergic children and 19 non–egg-allergic controls.29 All patients, including controls, received skin testing. Control patients and EAIs with negative vaccine skin testing received a single-dose injection, and EAIs with positive skin testing (n = 44) received two-step graded challenge. Only minor symptoms were reported, and nobody with a positive H1N1 skin test developed symptoms.
Positive skin tests correlated with increasing vaccine ovalbumin content, suggesting an irritant effect. There were 25 EAIs with a history of anaphylaxis attributable to egg, all of whom were vaccinated without developing symptoms (including 13 with a positive skin test). Moreover, 94 EAIs tolerated a booster from a different vaccine lot. The vaccine ovalbumin level was less than 50 ng/mL.29,30
The Risk of Injectable Trivalent Influenza Vaccine
In 2009 and 2010, five studies investigated the safety of TIV in EAIs. Chung et al7 performed a retrospective review of 171 egg-allergic children without a history of severe reaction, all receiving a two-step protocol (similar to James et al5) without vaccine skin testing and concluded that that TIV was safe for non-anaphylactic egg-allergic children without vaccine skin testing. Ovalbumin content was not measured.
Webb et al10 conducted a retrospective study of 152 patients (34 with anaphylaxis to egg) receiving 292 vaccinations, in which all 95% of patients undergoing skin testing to undiluted vaccine tested negative, and tolerated a single-dose administration (5% underwent graded-dose challenge for a positive test and tolerated the vaccine). Owens and McGinnitie9 conducted a retrospective review of 64 EAIs receiving TIV containing up to 1.4 mcg/mL of ovalbumin, using a two-step graded challenge without vaccine skin testing, concluding that TIV with ovalbumin at less than 1.2 mcg/mL was well tolerated.
Howe et al8 conducted a 5-year retrospective review of 135 patients receiving TIV from 2004 to 2009, including 28 patients without vaccine skin testing and 14 with anaphylaxis to egg, noting that vaccine skin testing was not predictive of reactivity, and that single dose administration was well-tolerated.
Lastly, DesRoches et al12 published a large 5-year (2007–2011) retrospective series from five Canadian hospitals, as well as a prospective study from 2010 to 2012, describing a total of 367 patients who safely received 457 doses of TIV, including 132 patients (153 doses) with severe egg allergy, noting the vaccine was safe to administer without skin testing and was safe in severely EAIs.
The Risk of TIV in Severely Egg-Allergic Individuals
Most recent studies deliberately evaluated a subgroup of severely egg-allergic patients and showed this was safe. However, only two studies have specifically focused on this population. Fung et al11 described a case series of 56 children (119 vaccinations) children with a history of anaphylaxis to egg who received TIV. Vaccine skin testing was performed, and if positive, a stepwise desensitization was used for administering TIV: three or four steps in 2007, and a two-step graded challenge in 2008 and 2009). There were 15 participants with positive TIV skin tests (wheal > 3 mm), but only threee localized reactions were noted in the cohort (two had positive skin testing).11
Greenhawt et al15 performed a 2-year, multicenter, double-blind, randomized, placebo-controlled trial (RCT) in severely EAIs, and compared the safety of a single dose versus a two-step graded challenge. These data were supplemented by a retrospective phase investigating the same outcome.
In the RCT, 31 patients were randomly assigned to receive either a two-step graded challenge (n = 16) or a sham “10%” dose of saline, followed by 100% of the full, age-appropriate dose to simulate the “90%” residual of a graded challenge (n = 17). The retrospective phase evaluated open-label vaccination of TIV as a single vs. split-dose across the same centers. Among 143 total participants, three of 31 RCT patients reported symptoms, none of which were vaccine-related allergic reactions. No reactions occurred among the 112 retrospective patients (n = 25, two-step protocol; n = 87, single dose). Seventeen patients received TIV at their primary care provider’s office.15
Advice for the Pediatrician
Although the research summarized herein strongly indicates that providing TIV to any EAI is safe, provider implementation and comfort with new policy is not immediate. Within the allergy literature, there was a stepwise change in policy.4 The CDC and ACIP revised its recommendation in the summer of 2011, formally removing any language recommending that TIV be contraindicated in egg-allergic or chicken-allergic individuals. These groups recommended that EAIs with a history of developing only hives after egg ingestion could receive TIV at their primary care provider’s office if they so desired (see Figure 1).13 This guidance will have been re-visited at the June 2013 ACIP annual meeting and will likely change for the fall of 2013. (personal communication).
Figure 1. Recommendations regarding influenza vaccination for persons who report allergy to eggs from Advisory Committee on Immunization Practices, United States, 2012–13 influenza season. TIV = trivalent influenza vaccine. TIV = trivalent influenza vaccine. (Adapted from Grohskopf et al33
Evidence-Based Guide to FLU Vaccination and EAI
The following summary points can help to serve as an evidence-based guide to the upcoming influenza vaccination season:
Vaccine Skin Testing
Vaccine skin testing in egg-allergic patients is a poor indicator for predicting EAIs at risk for a reaction to TIV. Several studies have been safely conducted without the use of skin testing; thus, vaccine skin testing of EAIs is not recommended.10,14,29
Low Ovalbumin-Containing Vaccine
There are no data suggesting that an ovalbumin content of greater than 1.2 mcg/mL is not well-tolerated. In the past, ovalbumin levels were not always disclosed, though more recently, US vaccine makers have disclosed their ovalbumin content the summer before each flu season starts. All brands of TIV available in the US now contain less than 1 mcg/mL of ovalbumin. Given that it is unlikely future TIV will contain more than 1 mcg/mL ovalbumin, this issue is moot, and all available US TIV should be considered safe for EAIs. Cell-cultured TIV is now available for EAIs older than 18 years who desire this option; however, it is unnecessary.9,14,30,31
Safety of Single Dose
Both single and divided dose strategies have been studied; there is no difference in outcome, irrespective of baseline severe reactivity to egg. Therefore, a single dose is sufficient.10,14
TIV Safety for Severely Egg-Allergic Patients
In published studies dating back to 1998, 656 severely EAIs have safely received 740 doses of TIV (one patient was noted to be included in a 1977 study). These data from both the US and Canada span open-label and controlled trials, including one double-blind, placebo-controlled, multicenter study.11,12,15
Office-Based Vaccination and Observation of EAIs:
Figure 1 details the decision-making process for office-based EAI vaccination and observation. These recommendations may change for the 2013 season, however. In the office setting, EAIs should be observed for 30 minutes in a setting where a reaction could be assessed and treated (this is a Red Book recommendation for any vaccine).32 It is not recommended that EAIs receive TIV at a pharmacy or other nonmedical settings, specifically because these sites cannot provide the observation.2,13,14
EAIs and Live-Attenuated Influenza Vaccine
There are no data evaluating the safety of this vaccine in EAIs. Logically, this likely is safe, but again, until there are published studies evaluating this process, EAIs should only be provided TIV.14
Non–Egg-Allergic TIV Reactions
Reactions to TIV in non-EAIs are a distinct topic, and are well-described elsewhere. Patients with an apparent allergic reaction to any vaccine should be evaluated by an allergist.14
Providing TIV to an EAI is safe and no longer is contraindicated, according to the latest CDC/ACIP recommendations. This is backed by very convincing data from 10 recent studies that show significant allergic reactions to TIV are unlikely to occur in EAIs, and that the risk of reaction to the vaccine is no greater when compared with the general population. Risk-reducing strategies such as low-ovalbumin containing vaccine, vaccine skin testing, and providing graded dosing do not mitigate risk and are unnecessary. EAIs can safely enjoy the well-established benefits from annual TIV vaccination.
- O’Brien TC, Maloney CJ, Tauraso NM. Quantitation of residual host protein in chicken embryo-derived vaccines by radial immunodiffusion. Appl Microbiol. 1971;21(4):780–782.
- American Academy of Pediatrics. Influenza. In: Pickering LK, Kimberlin DW, Long SS (eds). Red Book: 2009 Report of the Committtee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:400–412.
- Zeiger RS. Current issues with influenza vaccination in egg allergy. J Allergy Clin Immunol. 2002;110(6):834–840.
- Greenhawt MJ, Li JT, Bernstein DI, et al. Administering influenza vaccine to egg allergic recipients: a focused practice parameter update. Ann Allergy Asthma Immunol. 2011;106(1):11–16.
- James JM, Zeiger RS, Lester MR, et al. Safe administration of influenza vaccine to patients with egg allergy. J Pediatr. 1998;133(5):624–628.
- Gagnon R, Primeau MN, Des Roches A, et al. Safe vaccination of patients with egg allergy with an adjuvanted pandemic H1N1 vaccine. J Allergy Clin Immunol. 2010;126(2):317–323.
- Chung EY, Huang L, Schneider L. Safety of influenza vaccine administration in egg-allergic patients. Pediatrics. 2010;125(5):e1024–1030.
- Howe LE, Conlon AS, Greenhawt MJ, Sanders GM. Safe administration of seasonal influenza vaccine to children with egg allergy of all severities. Ann Allergy Asthma Immunol. 2011;106(5):446–447.
- Owens G, MacGinnitie A. Higher-ovalbumin-content influenza vaccines are well tolerated in children with egg allergy. J Allergy Clin Immunol. 2011;127(1):264–265.
- Webb L, Petersen M, Boden S, et al. Single-dose influenza vaccination of patients with egg allergy in a multicenter study. J Allergy Clin Immunol. 2011;128(1):218–219.
- Fung I, Spergel JM. Administration of influenza vaccine to pediatric patients with egg-induced anaphylaxis. J Allergy Clin Immunol. 2012;129(4):1157–1159.
- Des Roches A, Paradis L, Gagnon R, et al. Egg-allergic patients can be safely vaccinated against influenza. J Allergy Clin Immunol. 2012;130(5):1213–1216.
- Marcucci F, Duse M, Frati F, Incorvaia C, Marseglia GL, La Rosa M. The future of sublingual immunotherapy. Int J Immunopathol Pharmacol. 2009;22(Suppl 4):31–33.
- Kelso JM, Greenhawt MJ, Li JT, et al. Adverse reactions to vaccines practice parameter 2012 update. J Allergy Clin Immunol. 2012;130(1):25–43.
- Greenhawt MJ, Spergel JM, Rank MA, et al. Safe administration of the seasonal trivalent influenza vaccine to children with severe egg allergy. Ann Allergy Asthma Immunol. 2012;109(6):426–430.
- Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292(11):1333–1340.
- Gupta RS, Springston EE, Warrier MR, et al. The prevalence, severity, and distribution of childhood food allergy in the United States. Pediatrics. 2011;128(1):e9–17.
- Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: report of the NIAID-sponsored expert panel. J Allergy Clin Immunol. 2010;126(6 Suppl):S1–58.
- Vaccines against influenza WHO position paper. Wkly Epidemiol Rec. 2012;87(47):461–476.
- Cates CJ, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev. 2013;2:CD000364.
- Ratner B, Untracht S. Allergy to virus and rickettsial vaccines; allergy to influenza A and B vaccine in children. J Am Med Assoc. 1946;132(15):899–905.
- Stull A. Allergenic and anaphylactogenic properties of vaccines prepared from embryonic tissues of developing chicks; a study to determine whether chick yolk sac vaccines contained sufficient egg proteins to cause severe systemic reactions if given to egg-sensitive individuals. Fed Proc. 1946;5(1 Pt 2):254.
- Ratner B, Untracht S, Hertzmark F. Allergy to viral and rickettsial vaccines. II. Allergic reactions encountered and further studies with refined influenza and mumps vaccines in allergic children. Am J Dis Child. 1952;83(5):608–617.
- Retailliau HF, Curtis AC, Storr G, Caesar G, Eddins DL, Hattwick MA. Illness after influenza vaccination reported through a nationwide surveillance system, 1976–1977. Am J Epidemiol. 1980;111(3):270–28.
- Bierman CW, Shapiro GG, Pierson WE, Taylor JW, Foy HM, Fox JP. Safety of influenza vaccination in allergic children. J Infect Dis. 1977;136(Suppl):S652–655.
- Burks AW, Jones SM, Boyce JA, et al. NIAID-sponsored 2010 guidelines for managing food allergy: applications in the pediatric population. Pediatrics. 2011;128(5):955–965.
- Davies R, Pepys J. Egg allergy, influenza vaccine, and immunoglobulin E antibody. J Allergy Clin Immunol. 1976;57(4):373–383.
- Rouleau I, De Serres G, Drolet JP, et al. Allergic symptoms after pandemic influenza vaccination rarely mediated by vaccine-specific IgE. J Allergy Clin Immunol. 2012;130(6):1423–1426.
- Greenhawt MJ, Chernin AS, Howe L, Li JT, Sanders G. The safety of the H1N1 influenza A vaccine in egg allergic individuals. Ann Allergy Asthma Immunol. 2010;105(5):387–393.
- Li JT, Rank MA, Squillace DL, Kita H. Ovalbumin content of influenza vaccines. J Allergy Clin Immunol. 2010;125(6):1412–1413.
- Waibel KH, Gomez R. Ovalbumin content in 2009 to 2010 seasonal and H1N1 monovalent influenza vaccines. J Allergy Clin Immunol. 2010;125(3):749–751, 751 e1.
- Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of egg allergy. J Allergy Clin Immunol. 2007;120(6):1413–1417.
- Grohskopf L, Uyeki T, Breesee J, Cox N. Prevention and control of influenza with vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP) — United States, 2012–13 Influenza Season. Morb Mortal Wkly Rep MMWR. 2012;61:613–618.