Safe Administration of Flu Vaccine to Egg Allergic Children

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

Inclusion Criteria:

1. 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:

1. 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).

2. 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.

2. 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).

3. Ability to remain off antihistamines for at least 5 days prior to the study visit, for
skin testing.

4. For children, the ability to remain in the exam room for the duration of the testing
visit.

5. Previous history of TIV of H1N1 vaccination is neither inclusive nor exclusive for the
study.

Exclusion Criteria:

1. Does not fulfill requirements for both egg allergy AND anaphylaxis or severe allergic
reaction.

2. Prolonged use of immunosuppressive medication, including high dose corticosteroids > 6
months, as well as other immunosuppressive agents.

3. Prior history of egg allergy, now outgrown and tolerating egg ingestion.

4. Eosinophilic esophagitis.

5. Cardiac disease.

6. Known malignancy under treatment.

7. Pregnant women.