Safe Administration of Flu Vaccine to Egg Allergic Children (SAFE)

Multi-Centered, Randomized, Placebo-Controlled Trial of the Safety of Influenza Vaccine in Egg Allergic Children With a History of Anaphylaxis or Severe Allergy to Egg

Historically, providing influenza vaccination of egg allergic children and young adults (EAC) with a history of anaphylaxis to egg, or other severe symptoms of an allergic reaction to egg (e.g., severe hives, swelling, or asthma), has been contra-indicated, though vaccination of children with less severe egg allergy has been shown to be safe. Though many children with severe egg allergy, including anaphylaxis, have received past influenza vaccination anecdotally, very few data exist to show this procedure is safe. The investigators propose a double blind, placebo-controlled randomized, prospective multi-centered study to a) demonstrate seasonal trivalent influenza vaccine (TIV) can be safely given in a single dose (as opposed to through 2-step graded dosing of 10% then 90% of the vaccine dose) to EAC despite history of anaphylaxis or previous severe allergic reaction to egg; and b) provide further evidence that adverse outcomes are not related to ovalbumin (egg) content in TIV. Study participants must have a documented history of a severe egg allergy, substantiated by both a history of clinical reactivity AND either a positive skin test or ImmunoCAP/RAST test greater than 0.7 kUA/L. Participants will be randomized to receive either a 2-step graded challenge or a single dose given after a small placebo dose of saline (to mimic the graded challenge). If required, all participants will receive a booster vaccination as a single dose.

Seasonal Trivalent Influenza Vaccine (TIV) is grown in embryonated chicken eggs, and since it contains residual egg protein (ovalbumin), providing TIV to egg allergic children (EAC) could potentially provoke allergic reactivity. Because of this possibility, historically caution has been advised in providing TIV to these children, and the vaccine has been withheld in certain individuals, though for many it has been safely administered after vaccine skin testing and stepwise administration. In the 2009 American Academy of Pediatrics Red Book (and previous editions), a history of severe allergic reactivity to egg is a contraindication to receiving TIV, though it is acknowledged that less severely egg allergic kids have safely received TIV if precautions had been taken. In the past year, several studies have emerged that demonstrate that most, if not all, EAC can safely be vaccinated with both TIV ad the H1N1 vaccine. A recent 5 year review of TIV administration in EAC ages 6 mo-36 mo, showed safe administration to 135 EAC after TIV skin testing, including 14 subjects with a history of anaphylaxis to egg. Another large, retrospective study of non-anaphylactic EAC showed TIV could be successfully administered using a 2-step protocol without skin testing to TIV. In a single center H1N1 vaccine study last fall, 105 EAC received either a full vaccine dose if skin tests were negative, or a 2-step graded challenge if the tests were positive, including 25 subjects with a history of anaphylaxis. No allergic reactions resulted, regardless of the results of skin testing, the method of administration, ovalbumin content of the vaccine, or use of a different booster lot without pre-testing. In a sister-study, 68 H1N1 participants prospectively received TIV safely without graded challenge, including 13 EAC with a history of egg anaphylaxis. A large prospective, Canadian multi-centered study, using an adjuvanted H1N1 preparation containing 0.03μg/mL of ovalbumin, was safely given to 72 individuals with either a history of severe cardiopulmonary reactivity to egg or a history of poorly controlled asthma (this group was not further broken down), via 2-step graded challenge. Thus, these studies suggest it is safe for EAC with a history of anaphylaxis to receive TIV and H1N1 without pre-testing, suggest that use of a 2-step graded challenge may be unnecessary, and show some evidence that past egg allergy severity may not be an important factor in vaccine tolerance. Recent guidelines published by the AAAAI suggest a flexible approach is reasonable, and that EAC can receive TIV without prior skin testing through either a single dose or a 2-step approach. This double blind, randomized, placebo-controlled, multi-centered study aims to investigate the safety of TIV given to EAC with a history of a severe past reaction or anaphylaxis to egg, and aims to show that a single dose route of administration is safe and sufficient. Participants with new or established severe egg allergy (see eligibility criteria) will be randomized to receive either a 2-step (10%, followed by 30 min. observation, then residual 90%) graded challenge or a single dose of TIV given 30 minutes after a placebo dose of normal saline is administered (to approximate the graded challenge). Vaccine tolerance will be analyzed and compared to ovalbumin content of the vaccine lots, as well as to baseline characteristics of the participant's egg allergy and allergic history. Secondary outcomes originally posted on the www.clinicaltrials.gov website were hypotheses which were aims of complex data analysis but were not in and of themselves actual outcome measures. Therefore these have been deleted from the record

This arm will receive TIV as 2 doses, the first of which will be normal saline administered at approximately 10% of the total age appropriate dose volume, followed 30 minutes later by the full age appropriate dose. For children receiving a 0.25ml dose, a 20%/80% split will be used for ease of administration in drawing up the dose.

Subjects in this arm will receive TIV by standard 10%/90% 2-step graded challenge split of the age appropriate dose, separated by 30 minutes. For children receiving a 0.25ml dose, a 20%/80% split will be used for ease of administration in drawing up the dose.

Age appropriate dose of seasonal Trivalent Influenza Vaccine (TIV), either 0.25mL under age 3 or 0.5mL over the age of 3.

After randomization, group 1 will receive a 10%/90% (or 20%/80% for 0.25ml) graded challenge of the age appropriate TIV dose, separated by 30 minutes for observation. Group 2 will receive a first dose consisting of normal saline at a volume equal to 10% of their age appropriate dose, and the second dose will consist of their full age appropriate dose as the "90%" equivalent, also separated by 30 minutes of observation. For children receiving a 0.25ml dose, a 20%/80% split will be used for ease of administration in drawing up the dose. All parties will report any adverse reactions occurring in the next 48 hours after vaccination that were not observed at the time of in office observation.

Rates of co-morbid allergic disease, size and magnitude of egg skin and ImmunoCAP tests, presence of other food allergy, and tolerance of "baked egg" will be assessed through a screening questionnaire and chart review, and compared between the groups to assess for any significant differences that may predict TIV tolerance.

Inclusion Criteria: Ages 6 months-24 years, seen in the UMHS Allergy Clinics (and similar academic Allergy clinics of collaborating sites) in the last 24 months with a discharge diagnosis code of v15.03 indicating an of egg allergy, AND with correlated history including the following: Egg allergy as defined by: Positive egg challenge; OR strong history suggestive of clinical allergy within 4 hours of ingestion AND egg-specific IgE above 0.70 kUA/L OR wheal 3mm > control (or 2+ score if wheal size not available). Anaphylaxis after egg ingestion, defined by: Patients with a verified history (by chart review) of their single most severe reaction to egg resulting in the following, per NIAID/FAAN 2006 criteria:5 i) Acute onset of an illness with involvement of the skin/mucosal tissue (e.g., generalized hives, pruritus or flushing, swollen lips-tongue-uvula) AND EITHER respiratory compromise (e.g., dyspnea, wheezing/bronchospasm, stridor, reduced peek expiratory flow) OR reduced blood pressure or associated symptoms (eg, hypotonia or syncope); OR ii) Two or more of the following after exposure to an allergen: involvement of the skin/mucosal tissue (e.g., urticaria, itching/flushing, swollen lips/tongue/uvula); respiratory compromise (e.g., dyspnea, wheezing/bronchospasm, stridor, reduced peak expiratory flow); reduced blood pressure or associated symptoms (e.g., hypotonia or syncope); or persistent gastrointestinal symptoms (e.g., crampy abdominal pain or vomiting); OR iii) Hypotension after exposure to known allergen for that patient c) A severe allergic reaction will be defined by a history of development of severe hives, angioedema, or allergic asthma attributable to egg allergy. Subject must fulfill criteria for both egg allergy and for either anaphylaxis or a severe allergic reaction (both attributable to egg) to be included in the study, i.e. both (a) and either (b) or (c). Ability to remain off antihistamines for at least 5 days prior to the study visit, for skin testing. For children, the ability to remain in the exam room for the duration of the testing visit. Previous history of TIV of H1N1 vaccination is neither inclusive nor exclusive for the study. Exclusion Criteria: Does not fulfill requirements for both egg allergy AND anaphylaxis or severe allergic reaction. Prolonged use of immunosuppressive medication, including high dose corticosteroids > 6 months, as well as other immunosuppressive agents. Prior history of egg allergy, now outgrown and tolerating egg ingestion. Eosinophilic esophagitis. Cardiac disease. Known malignancy under treatment. Pregnant women.

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