Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Safety of Influenza Vaccines for Persons with Egg Allergy

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Introduction

Most of the influenza vaccines currently approved and available in the United States are produced by the propagation of influenza viruses in eggs (1-7).  These vaccines therefore can contain small quantities of egg proteins.  As of the 2022-23 influenza season, ACIP has recommended annual influenza vaccination for all persons aged 6 months and older with egg allergy, regardless of severity of previous allergic reactions to egg and with any licensed influenza vaccine that is otherwise appropriate for the recipient’s age and health status (8).  For those with a history of severe allergic reaction to egg (defined as any symptom other than hives), an additional recommendation has been made that such individuals be vaccinated in a medical setting, supervised by a provider who is able to recognize and manage a severe allergic reaction.  This recommendation differs from those of the American Academy of Pediatrics, which since the 2016-17 influenza season has recommended that no measures beyond those recommended for any recipient of any vaccine are needed for persons with egg allergy (9).  Such measures are also not recommended by the Joint Task Force of the American Academy of Allergy, Asthma and Immunology (AAAAI) and the American College of Allergy, Asthma and Immunology (ACAAI) (10).  Additionally, vaccination providers are recommended to be prepared for the possibility of severe allergic reactions when administering any vaccine to any recipient (11). The current review was performed to assess whether the safety of influenza vaccines for persons with egg allergy favors routine vaccination of this population without additional measures, regardless of severity of previous allergic reactions to egg.

Methods

A systematic literature review using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was performed to assess published evidence concerning the safety of influenza vaccines for persons with egg allergy.  Medline, Embase, PsycInfo, CINAHL, NTIS, Scopus, Cochrane Library, and ClinicalTrials.gov were searched from inception through October 26, 2021.  Report types included were those describing randomized controlled trials, observational studies, case reports, case series, safety surveillance system reports (including Vaccine Adverse Event Reporting System and other safety surveillance system reports).  Abstracts for which no associated papers were found were included.   Animal studies, duplicate reports, clinical trial registry summaries, and review articles were excluded.  Clinical trial registry summaries and bibliographies of relevant review articles were reviewed in order to help identify additional eligible reports.  Data included were those evaluating egg-based vaccines only, administered to egg-allergic individuals either by full-dose (single-step) administration protocol (in which the whole dose volume is administered in one step) or a split-dose protocol (in which the required dose volume is administered in two steps, most commonly 10% of the dose followed by an observation period, with the remaining 90% of the dose volume administered if no adverse effects are observed).  In instances where vaccine was not specified, determination of vaccine type was attempted where it was possible to make a reasonable assumption based upon the location and influenza season in which the study was conducted and vaccine administration method used. Data with unknown vaccine type, unspecified/unclear administration protocol, graded (≥3 steps) dosing, and/or unknown denominator were excluded.  GRADE assessment was performed with stratification based on vaccine type (seasonal inactivated influenza vaccine, monovalent H1N1pdm09 inactivated influenza vaccine, or live attenuated influenza vaccine) and severity of egg allergy (e.g., egg allergy of all severities vs those with a history of severe allergy/anaphylaxis to egg).

Table 1: Policy Questions and PICO

Table 1: Policy Questions and PICO
Policy question Does available evidence concerning safety of influenza vaccines in persons with a history of egg allergy favor routine vaccination without additional safety measures, regardless of severity of previous allergic reaction to egg?
Population Persons of any age with a history of allergy to eggs, or who have had an allergic reaction to influenza vaccine believed to be secondary to egg allergy.
Intervention Receipt of any influenza vaccine.
Comparison Placebo, nonegg-based influenza vaccine, non-influenza control vaccine, no vaccine, no comparator.
Outcomes§ Critical:

Death

Anaphylaxis meeting Brighton criteria Levels 1-3*

Anaphylaxis otherwise classified*

Allergic reaction symptoms requiring hospitalization

Important:

Allergic reaction symptoms requiring outpatient or emergency department medical attention†

Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*These outcomes are combined in the evidence profile tables.
†Includes instances described as being treated with medications, without specific mention of transfer to a different care setting.
§ Reactions occurring up to four hours post-vaccination.

Table 2: Outcomes and Rankings

 

Table 2: Outcomes and Rankings
Outcome§ Importance Included in evidence profile
Death Critical Yes
Anaphylaxis meeting Brighton criteria Levels 1-3* Critical Yes
Anaphylaxis otherwise classified* Critical Yes
Allergic reaction symptoms requiring hospitalization Critical Yes
Allergic reaction symptoms requiring outpatient or emergency department medical attention† Important Yes
Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria Important Yes
*These outcomes are combined in the evidence profile tables.
†Includes instances described as being treated with medications without mention of transfer to a different care setting.
§Reactions occurring up to four hours post-vaccination.

Table 3. Summary of Studies Reporting Occurrences of Outcomes of Interest

Table 3a: Seasonal Inactivated Influenza Vaccines

Table 3a: Seasonal Inactivated Influenza Vaccines
Author
Publication year		 Age N intervention Comparator Events by outcome Methodological quality concern*
Anvari 2011 (12) Not specified 86 None None Unclear
Chung 2010 (13) Skin test group: Average 6.2
(95%CI 5.1-7.2) yrs
Non-skin test group: Average 3.9
(95%CI 3.3-4.5) yrs		 171 None None Moderate
Comeau 2016† (14) Not specified 88 None None Unclear
Des Roches 2012-1 (15) <2 yrs: 27
2-4 yrs: 83
5-11 yrs: 82
>12 yrs: 37		 230 None None Low
Des Roches 2012-2 (15) <2 yrs: 29
2-4 yrs: 53
5-11 yrs: 51
>12 yrs: 4		 137 None None Unclear
Erlewyn-Lajeunesse 2010† (16) Not specified 16 doses§ None Cardiovascular, respiratory, angioedema, or generalized urticaria: 1 Unclear
Esposito 2008 (17) 6.03 +/- 3.33 yrs 44 Non-allergic group Outpatient or emergency department medical attention: 1
Cardiovascular, respiratory, angioedema, or generalized urticaria: 1		 Low
Greenhawt 2012-1 (18) Median 11-12 mos 31 Comparison of full- vs. split-dose (combined in this review) None Low
Greenhawt 2012-2 (18) Median 12 mos at diagnosis 112 None None Low
Hotte 2008† (19) Not provided 164 doses§ None None Unclear
Howe 2011 (20) Not specified 69 Non-allergic group None Unclear
James 1998 (21) Median 3 (1-46) yrs 83 Non-allergic group Outpatient or emergency department medical attention: 2
Cardiovascular, respiratory, angioedema, or generalized urticaria: 3		 Low
Leo 2010† (22) Not provided 31 None None Unclear
Park 2008† (23) Mean 36.1 +/- 19.9 (11 to 105 mos) 33 None None Unclear
Paschall 2011† (24) Mean 3.8 yrs 65 doses§ None None Unclear
Shimizu 2016 (25) Median 15
(IQR 13-20) mos		 17 None None Low
Thanik 2010† (26) Not specified 214 doses§ None None Unclear

*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60-62 (27). Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.
†Abstract only.
§ Number of individuals unclear.

Table 3b: Monovalent H1N1pdm09 Inactivated Influenza Vaccines

Table 3b: Monovalent H1N1pdm09 Inactivated Influenza Vaccines
Author
Publication year		 Age N intervention Comparator Events by outcome Methodological quality concern*
Didenko 2010 (28) median 4 (2-11) yrs 6 None None Moderate
Forsdahl 2012 (29) Mean 6.25 yrs
(10 mos-16.5 yrs)		 80 None Outpatient or emergency department medical attention: 1
Cardiovascular, respiratory, angioedema, or generalized urticaria: 1		 Moderate
Gagnon 2010-1 (30) 173 <2 yrs
280 2-4 yrs
277 5-11 yrs
100 ≥12 yrs		 830 Non-allergic group Outpatient or emergency department medical attention: 4
Cardiovascular, respiratory, angioedema, or generalized urticaria: 6		 Low
Gagnon 2010-2 (30) Not specified 3640 None Outpatient or emergency department medical attention: 68
Cardiovascular, respiratory, angioedema, or generalized urticaria: 26		 Unclear
Greenhawt 2010 (31) Mean 5.5 (range 0.4-20.4) yrs 105 Non-allergic group None Low
Leo 2010† (22) Not specified 50 None None Unclear
Paschall 2011† (24) Mean 3.8 yrs 66 None None Unclear
Pien 2010 (32) Mean 3.7 +/- 3.0 yrs 59 None None Moderate
Pitt 2011 (33) Mean 5.6 (1-27) yrs 59 None None Moderate
Schuler 2011 (34) Mean 4.5 yrs
(10 mos-16 yrs)		 62 None Outpatient or emergency department medical attention: 4 Moderate
Siret-Alatrista 2010 (35) Unclear 53 None None Unclear
Spiegel 2010† (36) Range 1-56 yrs 150 None None Unclear
Upton 2012 (37) 3-5 yrs:12
6-9 yrs:24
10-13 yrs:28
14+ yrs:10		 75 None None Moderate

*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60-62 (27).  Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.
†Abstract only.

Table 3c: Seasonal Live Attenuated Influenza Vaccine

Table 3c: Seasonal Live Attenuated Influenza Vaccine
Author
Publication year		 Age N intervention Comparator Events by outcome Methodological quality concern*
Des Roches 2015 (38) 2-16 yrs 68 Non-allergic group None Low
Turner 2015a (39) Median 4.9 yrs
(2-17 yrs)		 282 None Cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria: 6 Low
Turner 2015b (40) Median 5.3 yrs
(2-18 yrs)		 779 None Cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria: 4 Low

*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60-62 (27). Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting

Table 4: GRADE Evidence Profile Tables

Table 4a: Seasonal inactivated influenza vaccine administered full or split dose, egg allergy of all severities.

Table 4a—Seasonal inactivated influenza vaccine administered full or split dose, egg allergy of all severities.
Certainty assessment Impact Certainty Importance
№ of studies Study design Methodological
Quality*		 Inconsistency Indirectness Imprecision Other considerations
1. Death
17 observational studies seriousa not serious seriousb seriousc none 0/1591 (0%) Very low CRITICAL
2. Anaphylaxis
17 observational studies seriousa not serious seriousb seriousc none 0/1591 (0%) Very low CRITICAL
3. Allergic reaction symptoms requiring hospitalization
17 observational studies seriousa not serious seriousb seriousc none 0/1591 (0%) Very low CRITICAL
4. Allergic reaction symptoms requiring outpatient or emergency department medical attention (includes instances treated with medications)
17 observational studies seriousa not serious seriousb seriousc none 3/1591 (0.2%) Very low IMPORTANT
5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
17 observational studies seriousa not serious seriousb seriousc none 5/1591 (0.3%) Very low MPORTANT

*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60-62 (27).  Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.

Explanations
a. All are cohort studies without comparator interventions, with the exception of one randomized study which compared administration of full dose vs split dose. Because full-dose and split- dose administration are treated as equivalent in this assessment, this study is treated here as a cohort study. Ten of 17 are of unclear methodological quality. Seven of 17 are abstracts.
b. Includes 322/1591 (20%) persons with a history of severe allergy/anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision should be assumed.

Table 4b: Seasonal inactivated influenza vaccine administered full or split dose, persons with a history of severe allergy/anaphylaxis to egg

Table 4b: Seasonal inactivated influenza vaccine administered full or split dose, persons with a history of severe allergy/anaphylaxis to egg
Certainty assessment Impact Certainty Importance
№ of studies Study design Methodological
Quality*		 Inconsistency Indirectness Imprecision Other considerations
1. Death
10a observational studies seriousb not serious not serious seriousc none 0/322 (0%) Very low CRITICAL
2. Anaphylaxis
10a observational studies seriousb not serious not serious seriousc none 0/322 (0%) Very low CRITICAL
3. Allergic reaction symptoms requiring hospitalization
10a observational studies seriousb not serious not serious seriousc none 0/322 (0%) Very low CRITICAL
4. Allergic reaction symptoms requiring outpatient or emergency department medical attention (includes instances treated with medications)
9a observational studies seriousb not serious not serious seriousc none 0/295 (0%) d Very low IMPORTANT
5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized hives
8a observational studies seriousb not serious not serious seriousc none 0/291 (0%) e Very low IMPORTANT

*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60-62 (27). Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.

Explanations
a. Includes only studies which explicitly mentioned inclusion of persons with severe allergy/anaphylaxis to egg for whom outcomes can be discerned.
b. All are cohort studies without comparator intervention groups, including administration via either full dose or split-dose (2-step) protocols. Four of 10 are of unclear methodological quality. Two of 10 are abstracts.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision should be assumed.
d. One study including (n=27) removed from denominator which reported events, but unclear whether they occurred in persons with severe allergy/anaphylaxis to egg.
e. Two studies (n=31) removed from denominator which reported events, but unclear whether they occurred in persons with severe allergy/anaphylaxis to egg.

Table 4c: Monovalent inactivated influenza vaccine administered full or split dose, egg allergy of all severities.

Table 4c—Monovalent inactivated influenza vaccine administered full or split dose, egg allergy of all severities
Certainty assessment Impact Certainty Importance
№ of studies Study design Methodological
Quality*		 Inconsistency Indirectness Imprecision Other considerations
1. Death
13 observational studies very seriousa not serious seriousb seriousc none 0/5235 (0%) Very low CRITICAL
2. Anaphylaxis
13 observational studies very seriousa not serious seriousb seriousc none 0/5235 (0%) d Very low CRITICAL
3. Allergic reaction symptoms requiring hospitalization
13 observational studies very seriousa not serious seriousb seriousc none 0/5235 (0%) Very low CRITICAL
4. Allergic reaction symptoms requiring outpatient or emergency department medical attention (includes instances treated with medications)
13 observational studies very seriousa not serious seriousb seriousc none 77/5235 (1.5%) Very low IMPORTANT
5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
13 observational studies seriousa not serious seriousb seriousc none 33/5235 (0.6%) Very low IMPORTANT

*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60-62 (27).  Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.

Explanations
a. All were cohort studies without comparator intervention groups, including administration via either full dose or split-dose (2-step) protocols. Five of 13 are of unclear methodological quality. Three of 13 are abstracts.
b. Includes 66/5235 (1.3%) persons with a history of severe allergy/anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions without confidence intervals. However, some degree of imprecision should be assumed.
d. One instance of Brighton Level 1 anaphylaxis in a person with “possible egg allergy” was reported in a Vaccine Adverse Event Reporting System (VAERS) surveillance summary from the 2009-10 influenza season (41). This instance is not included in GRADE as no denominator of persons or doses administered is available. However, it was reported that 127,075,320 doses of monovalent influenza vaccine were distributed in the United States for the season.

Table 4d: Monovalent inactivated influenza vaccine administered full or split dose, persons with a history of severe/allergy anaphylaxis to egg.

Table 4d—Monovalent inactivated influenza vaccine administered full or split dose, persons with a history of severe/allergy anaphylaxis to egg
Certainty assessment Impact Certainty Importance
№ of studies Study design Methodological
Quality*		 Inconsistency Indirectness Imprecision Other considerations
1. Death
3 observational studies very seriousb not serious not serious seriousc none 0/66 (0%) Very low CRITICAL
2. Anaphylaxis
3 observational studies very seriousb not serious not serious seriousc none 0/66 (0%) Very low CRITICAL
3. Allergic reaction symptoms requiring hospitalization
3 observational studies very seriousb not serious not serious seriousc none 0/66 (0%) Very low CRITICAL
4. Allergic reaction symptoms requiring outpatient or emergency department medical attention (includes instances treated with medications)
3 observational studies very seriousb not serious not serious seriousc none 0/66 (0%) Very low IMPORTANT
5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
3 observational studies very seriousb not serious not serious seriousc none 0/66 (0%) Very low IMPORTANT

*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60-62 (27). Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.

Explanations
a. Includes only studies which explicitly mentioned inclusion of persons with severe allergy/anaphylaxis to egg for whom outcomes can be discerned.
b. Cohort studies without comparator intervention groups, including administration via either full dose or split-dose (2-step) protocols.
c. Cannot assess imprecision as these are proportions without confidence intervals. However, some degree of imprecision should be assumed.

Table 4e: Live attenuated influenza vaccine, egg allergy of all severities

Table 4e: Live attenuated influenza vaccine, egg allergy of all severities
Certainty assessment Impact Certainty Importance
№ of studies Study design Methodological
Quality*		 Inconsistency Indirectness Imprecision Other considerations
1. Death
3 observational studies seriousa not serious seriousb seriousc none 0/1129 (0%) Very low CRITICAL
2. Anaphylaxis
3 observational studies seriousa not serious seriousb seriousc none 0/1129 (0%) Very low CRITICAL
3. Allergic reaction symptoms requiring hospitalization
3 observational studies seriousa not serious seriousb seriousc none 0/1129 (0%) Very low CRITICAL
4. Allergic reaction symptoms requiring outpatient or emergency department medical attention (includes instances treated with medications
3 observational studies seriousa not serious seriousb seriousc none 0/1129 (0%) Very low IMPORTANT
5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
3 observational studies seriousa not serious seriousb seriousc none 10/1129 (0.9%) Very low IMPORTANT

*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60-62 (27). Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.

Explanations
a. All are cohort studies without a comparison intervention, including administration via either full dose or split-dose (2-step) protocols.
b. Includes 412/1129 (36%) persons with a history of severe allergy/anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions without no confidence intervals. However, some degree of imprecision should be assumed

Table 4f: Live attenuated influenza vaccine, persons with a history of severe allergy/anaphylaxis to egg

Table 4f: Live attenuated influenza vaccine, persons with a history of severe allergy/anaphylaxis to egg
Certainty assessment Impact Certainty Importance
№ of studies Study design Methodological
Quality*		 Inconsistency Indirectness Imprecision Other considerations
1. Death
3a observational studies seriousb not serious not serious seriousc none 0/412 (0%) Very low CRITICAL
. Anaphylaxis
3a observational studies seriousb not serious not serious seriousc none 0/412 (0%) Very low CRITICAL
3. Allergic reaction symptoms requiring hospitalization
3a observational studies seriousb not serious not serious seriousc none 0/412 (0%) Very low CRITICAL
4. Allergic reaction symptoms requiring outpatient or emergency department medical attention (includes instances treated with medications)
3a observational studies seriousb not serious not serious seriousc none 0/412 (0%) Very low IMPORTANT
5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
1a observational studies seriousb not serious not serious very seriousd none 0/27 (0%)e Very low IMPORTANT

*Adapted from Murad MH et al, Methodological quality and synthesis of case series and case reports, BMJ Evid Based Med 2018;23(2):60-62 (27). Domains assessed included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose-response effect), and Reporting.

Explanations
a. Includes only studies which explicitly mentioned inclusion of persons with severe allergy/anaphylaxis to egg for whom outcomes can be discerned.
b. All are cohort studies with no comparison groups, including administration via either full dose or split-dose (2-step) protocols.
c. Cannot assess imprecision as these are proportions without confidence intervals. However, some degree of imprecision should be assumed.
d. Cannot assess imprecision as these are proportions without confidence intervals. However, some degree of imprecision should be assumed. Very low denominator count.
e. Two studies (n=385) removed from denominator which reported events, but unclear whether they occurred in persons with severe allergy/anaphylaxis to egg.

Table 5. Summary of Evidence for Outcomes of Interest

Table 5. Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty*
Death Critical Yes Very low
Anaphylaxis meeting Brighton criteria Levels 1-3 Critical Yes Very low
Anaphylaxis otherwise classified Critical Yes Very low
Allergic reaction symptoms requiring hospitalization Critical Yes Very low
Allergic reaction symptoms requiring outpatient or emergency department medical attention Important Yes Very low
Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria Important Yes Very low

*Certainty was assessed as Very low for every outcome for each of the three vaccine types (seasonal inactivated, monovalent inactivated, and live attenuated).

Summary

Overall across vaccine types, frequency of adverse events was low, with no occurrences of the predefined critical outcomes among studies for which denominators were available. Important outcomes such as reaction symptoms requiring outpatient or emergency department medical attention (the majority being instances in which medications were given, without explicit mention of transfer to another clinical setting; Appendix 2) and reactions including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria were uncommon.

Limitations:

  • All studies were observational without comparison groups, with the exception of one randomized study comparing full- and split- dosing for which these two groups were combined and the study treated as a cohort study.
  • For eight studies, data were available only from abstracts, which contain limited information.
  • Some studies employed skin testing with egg proteins and/or vaccine prior to decision to vaccinate, or to guide selection of administration protocol. This might introduce selection bias.
  • There was variability in level of detail in which reactions were described.
  • Observation time post-vaccination varied (under 4 hours for most studies; generally 30 min to 2 hours), and time elapsed post-vaccination not often reported for reactions that occurred after the recipient left the vaccination setting.
  • Data specifically for persons with severe allergy/anaphylaxis to egg were limited. Not all studies specified that persons with severe egg allergy/anaphylaxis were included.  Not all studies which included such persons reported reactions specifically for this subgroup.

Appendix 1: Studies Included in Review of Evidence

Appendix 1 Table A: Seasonal influenza vaccines (N=20)

Appendix 1 Table A: Seasonal influenza vaccines (N=20)
Author and publication year Study design Country Season(s) Age N of egg allergic persons Intervention vaccine Comparator Funding source
Anvari 2011 (12) Cohort United States 2010-11 Not provided 86 Seasonal inactivated vaccine No comparator group Unclear
Chung 2010 (13) Retrospective cohort United States 2002-03 through 2008-09 Skin test group: Average 6.2 yrs
(95%CI 5.1-7.2 yrs)
Non-skin test group: Average 3.9 yrs
(95%CI 3.3-4.5 yrs)		 171 Seasonal inactivated vaccine No comparator group Housestaff research and education
fund.
Comeau 2016† (14) Cohort Australia 2012-2016 Not provided.
Based at a children’s hospital.		 88
26 (30%) with anaphylaxis to egg		 Seasonal inactivated vaccine No comparator group Unclear
Des Roches 2012 (15) Prospective cohort Canada 2010-11 and 2011-12 <2 yrs: 27
2-4 yrs: 83
5-11 yrs: 82
>12 yrs: 37		 230
101 (44%) with a history of severe allergy to egg.		 Seasonal inactivated vaccine No comparator group Canadian government
Des Roches 2012 (15) Retrospective
cohort		 Canada 2008-09
and
2009-10		 <2 yrs: 29
2-4 yrs: 53
5-11 yrs: 51
>12 yrs: 4		 137
227 doses
31 (23%) with a history of severe egg allergy		 Seasonal inactivated vaccine No comparator group Canadian government
Des Roches 2015 (38) Prospective cohort Canada 2013-14 2-16 yrs (total sample; egg allergic and non-egg allergic groups) 68 with egg allergy
27 (40%) with a history of anaphylaxis to egg		 Seasonal live attenuated vaccine Non-allergic comparator group Unclear
Erlewyn-Lajeunesse 2010† (16) Retrospective cohort United Kingdom 2009-10 Children; ages not specified 16 doses
4/15 (27%) to persons with known anaphylaxis to egg		 Seasonal inactivated vaccine No comparator group Unclear
Esposito 2008 (17) Prospective cohort Italy 2007-08 6.03 +/- 3.33 yrs for egg-allergic 44
11 (27%) severely egg-allergic: 9 having had mild-to moderate anaphylaxis and 2 severe anaphylaxis)		 Seasonal virosomal vaccine No comparator intervention
Comparison group of 44 without egg allergy		 Italian government
Greenhawt 2012 (18) Randomized controlled trial United States 2010-11
and
2011-12		 Median 11 mos at diagnosis in split- dose group; 12 mos at diagnosis in full-dose group 31
14* (45%) with a history of anaphylaxis to egg		 Seasonal inactivated vaccine Comparison of split dose vs full dose (these groups are combined) ACAAI; National Center for Research Resources
Greenhawt 2012 (18) Retrospective cohort United States 2010-11
and
2011-12		 Median 12 mos at diagnosis 112
87* (78% per abstract) had experienced anaphylaxis to egg.		 Seasonal inactivated vaccine No comparator group ACAAI; National Center for Research Resources
Hotte 2008† (19) Retrospective cohort Canada 2000 through 2006 Not provided.
Conducted at a children’s hospital.		 115
173 doses, 95% of which were full- or split-dose.		 Seasonal inactivated vaccine No comparator group Unclear
Howe 2011 (20) Prospective cohort United States 2009-10 Children; ages not provided 69 egg-allergic.
13 (19%) with documented anaphylaxis to egg		 Seasonal inactivated vaccine No comparator intervention.
Comparison group of 14 non egg-allergic.		 Unclear
James 1998 (21) Prospective cohort United States 1994 through 1997 Median 3 yrs, range 1-46 yrs 83
27 (33%) with history of anaphylaxis to egg.		 Seasonal inactivated vaccine No comparator intervention
Comparator group of 124 non egg-allergic		 AAAAI
Leo 2010† (22) Cohort Canada 2009-10 Not provided. 31 Seasonal inactivated vaccine No comparator group Unclear
Park 2008† (23) Retrospective cohort United States 2006 Mean 36.1 +/- 19.9 mos
(range 11 to 105 mos)		 33 of whom received vaccine via single dose. Seasonal inactivated vaccine No comparator group Unclear
Paschall 2011† (24) Retrospective cohort United States 2009-10 Mean 3.8 yrs 65 doses Seasonal influenza vaccine No comparator group Unclear
Shimizu 2016 (25) Cohort Japan 2013 Median 15 mos
(IQR 13-20 mos)		 17
8 (47%) with history of anaphylaxis to egg.		 Seasonal inactivated vaccine No comparator group Unclear
Thanik 2010† (26) Retrospective cohort United States 2007-08
and
2008-09		 Pediatric patients, ages not specified. 214 doses Seasonal inactivated vaccine No comparator group Unclear
Turner 2015 (39) Prospective cohort United Kingdom 2013-14 Median 4.9 yrs
(range 2-17 yrs)		 282 children
115 (41%) with prior anaphylaxis to egg; however, those who required invasive ventilation for an egg reaction were excluded).		 Seasonal LAIV No comparator group UK Government
Turner 2015 (34) Prospective cohort United Kingdom 2014-15 Median 5.3 yrs
(range 2-18 yrs)		 779
270 (34.7%) with prior anaphylaxis to egg; however, those who required invasive ventilation for a reaction to egg were excluded		 Seasonal LAIV No comparator group UK Government

*Numbers not provided but are calculated from percentages provided.
†Abstract only.

Appendix 1 Table B: Monovalent H1N1pdm09 influenza vaccines (N=13)

Table B: Monovalent H1N1pdm09 influenza vaccines (N=13)
Author and publication year Study design Country Season(s) Age N of egg allergic persons Intervention vaccine Comparator Funding source
Didenko 2010 (28) Cohort Brazil 2009 Median 4 yrs (range 2-37) yrs
For those who received full or split dose, median 4 (range 2-11 yrs		 6 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Forsdahl 2012 (29) Retrospective cohort Norway 2009-10 Mean 6.25 yrs
(Range 10 mos-16.5 yrs)		 80
19 (24%) had serious reaction to egg (anaphylaxis or cardiovascular reaction)		 Monovalent H1N1pdm09 vaccine No comparator group No study sponsor and author received no funding.
Gagnon
2010 (30)		 Prospective cohort Canada 2009-10 173 <2 yrs
280 2-4 yrs
277 5-11 yrs
100 ≥12 yrs		 830 Monovalent H1N1pdm09 vaccine Comparator group of non allergic. Canadian government
Gagnon
2010 (30)
PMID: 20579720		 Prospective cohort Canada 2009-10 Not specified 3640 Monovalent H1N1pdm09 vaccine No comparator group Canadian Government
Greenhawt 2010 (31) Prospective cohort United States 2009-10 Mean 5.5
(range 0.4-20.4) yrs		 105
25 (24%) with a history of anaphylaxis to egg		 Monovalent H1N1pdm09 vaccine No comparator intervention
Comparator group of non-allergic		 Unclear
Leo 2010* (22) Cohort Canada 2009-10 Not provided 50 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Paschall 2011* (24) Retrospective cohort United States 2009-10 Mean 366.8 yrs 66 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Pien 2010 (32) Cohort United States 2009-10 <10 yrs
Mean 3.7 yr +/- 3.0 yrs		 59 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Pitt 2011 (33) Cohort Canada 2009-10 Mean 5.6 yrs, range 1-27 yrs 59 Monovalent H1N1pdm09 vaccine No comparator intervention
Comparator group of non-allergic		 Unclear
Schuler 2011 (41) Prospective
cohort		 Canada  2009-10 Mean 4.5 yrs, range 10 mos-16 yrs 62 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Siret-Alatrista 2010* (35) Cohort France  2009-10 Unclear 53 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Spiegel 2010* (36) Retrospective cohort United States 2009-10 Range 1-56 yrs 150 Monovalent H1N1pdm09 vaccine No comparator group Unclear
Upton 2012 (37) Prospective cohort Canada 2009-10 3-5 yrs:12
6-9 yrs:24
10-13 yrs:28
14+ yrs:10		 75
22 (29%) with prior anaphylaxis to egg (24 with anaphylaxis history vaccinated; unclear whether they include two vaccinated via 5-step protocol).		 Monovalent H1N1pdm09 vaccine No comparator group Unclear

*Abstract only.

Appendix 2: Event Descriptions by Outcome

Appendix 2 Table A: Death

Appendix 2 Table A: Death
Author
Publication year		 Vaccine N egg allergic N with severe allergy/ anaphylaxis to egg Events
No studies reported this outcome.

Appendix 2 Table B: Anaphylaxis

Appendix 2 Table B: Anaphylaxis
Author
Publication year		 Vaccine N egg allergic N with severe allergy/ anaphylaxis to egg Events
No studies reported this outcome.

Appendix 2 Table C: Hospitalization

Appendix 2 Table C: Hospitalization
Author
Publication year		 Vaccine N egg allergic N with severe allergy/ anaphylaxis to egg Events
No studies reported this outcome.

Appendix 2 Table D: Outpatient/Emergency Care

Appendix 2 Table D: Outpatient/Emergency Care
Author
Publication year		 Vaccine N egg allergic N with severe allergy/ anaphylaxis to egg Events
Esposito 2008 (17) Seasonal virosomal 44 11
  • 1 instance bronchospasm in mildly allergic recipient, received bronchodilator and steroid.
James 1998 (21) Seasonal inactivated 83 27
  • 1 instance (>1 hour post-vaccination) emesis, mild cough, wheeze; received nebulizer treatment.*
  • 1 instance (>1 hour post-vaccination) erythema at injection site; received hydroxizine.*
Forsdahl 2012 (29) Monovalent inactivated 80 19
  • 1 instance wheal on lip, diffuse rash, and loose stools; recipient previously unexposed to egg but had a positive serum specific IgE; received antihistamine.
Gagnon 2010-1 (30) Monovalent inactivated 830 –
  • 1 instance wheeze; received bronchodilator.
  • 1 instance hives; received antihistamine.
  • 1 instance ocular pruritis; received antihistamine.
  • 1 instance angioedema; received antihistamine.
Gagnon 2010-2 (30) Monovalent inactivated 3640 –
  • 1 instance mouth/throat tingling and dyspnea 10-15 min post-vaccination; received epinephrine, observed in emergency department.
  • 1 instance wheezing 30 min post-vaccination; received epinephrine and bronchodilator, observed.
  • 66 instances skin and respiratory symptoms; received antihistamine:
    • 42 instances skin involvement
    • 17 instances throat tingling/tightening
    • 7 instances cough (4 also received bronchodilator)
Schuler 2011 (41) Monovalent inactivated 62 –
  • 1 hyporesponsive episode; sent to emergency department.
  • 2 instances hives; received antihistamine.
  • 1 instance erythema/itching of face; received antihistamine.

*Unclear whether these events occurred in persons with severe allergy/anaphylaxis to egg.

Appendix 2 Table E: Cardiovascular Symptoms, Respiratory Symptoms, Angioedema, or Generalized Urticaria

Appendix 2 Table E: Cardiovascular Symptoms, Respiratory Symptoms, Angioedema, or Generalized Urticaria
Author
Publication year		 Vaccine N egg allergic N with severe allergy/ anaphylaxis to egg Events
Erlewyn-Lajeunesse 2010 (16) Seasonal inactivated vaccine 16 doses 4
  • 1 instance subjective wheeze*
Esposito 2008 (17) Seasonal inactivated vaccine 44 11
  • 1 instance bronchospasm in mildly allergic recipient, received bronchodilator and steroid.
James 1998 (21) Seasonal inactivated vaccine 83 27
  • 1 instance mild throat itching, cough, and wheeze.*
  • 1 instance (>1 hour post-vaccination) emesis, mild cough, wheeze treated with nebulizer.*
  • 1 instance mild URI symptoms.*
Forsdahl 2012 (29) Monovalent inactivated 80 19
  • 1 instance sneezing without bronchospasm; recipient previously unexposed to egg but had a positive serum specific IgE.
Gagnon 2010-1 (30) Monovalent inactivated 830 –
  • 1 instance sensation of throat closure
  • 1 instance hoarse voice
  • 1 instance angioedema
  • 1 instance bilateral wheeze
  • 2 instances generalized urticaria
Gagnon 2010-2 (30) Monovalent inactivated 3640 –
  • 1 instance mouth/throat tingling and dyspnea 10-15 min post-vaccination; received epinephrine, observed in emergency department, recovered.
  • 1 instance wheezing 30 min post-vaccination; received epinephrine and bronchodilator, observed 4 hours, recovered.
  • 17 instances throat tingling/tightening
  • 7 instances cough (4 also received bronchodilator)
Turner 2015a (39) Seasonal live attenuated 282 115
  • 6 instances rhinitis within 2 hours post-vaccination.*
Turner 2015b (34) Seasonal live attenuated 779 270
  • 4 instances rhinitis within 2 hours post-vaccination.*

*Unclear whether these events occurred in persons with severe allergy/anaphylaxis to egg.

Appendix 3: Literature Search Strategy

Literature through October 26, 2021

Appendix 3: Literature Search Strategy
Database Strategy
Medline
(OVID)
1946-		 (Egg* ADJ5 (allerg* OR sensitivit* OR hypersensitivit* OR anaphylaxis))
AND
((influenza OR flu OR laiv) ADJ5 vaccin*)
Embase
(OVID)
1947-		 (Egg* ADJ5 (allerg* OR sensitivit* OR hypersensitivit* OR anaphylaxis))
AND
((influenza OR flu OR laiv) ADJ5 vaccin*)
PsycInfo
(OVID)
1967-		 (Egg* ADJ5 (allerg* OR sensitivit* OR hypersensitivit* OR anaphylaxis))
AND
((influenza OR flu OR laiv) ADJ5 vaccin*)
CINAHL
(Ebsco)		 (Egg* N5 (allerg* OR sensitivit* OR hypersensitivit* OR anaphylaxis))
AND
((influenza OR flu OR laiv) N5 vaccin*)
NTIS (Egg* N5 (allerg* OR sensitivit* OR hypersensitivit* OR anaphylaxis))
AND
((influenza OR flu OR laiv) N5 vaccin*)
Scopus TITLE-ABS-KEY((Egg* W/5 allerg*) OR (Egg* W/5 sensitivit*) OR (Egg* W/5 hypersensitivit*) OR (Egg* W/5 anaphylaxis)) AND TITLE-ABS-KEY((influenza W/5 vaccin*) OR (flu W/5 vaccin*) OR (laiv W/5 vaccin*))
Cochrane Library ((Egg* NEAR/5 allerg*) OR (Egg* NEAR/5 sensitivit*) OR (Egg* NEAR/5 hypersensitivit*) OR (Egg* NEAR/5 anaphylaxis)):ti,ab
AND
((influenza NEAR/5 vaccin*) OR (flu NEAR/5 vaccin*) OR (laiv NEAR/5 vaccin*)):ti,ab
Clinicaltrials.gov Egg Allergy OR egg sensitivity OR egg hypersensitivity
AND
Influenza OR flu OR vaccine OR vaccination

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