About
CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Introduction
Most of the influenza vaccines currently approved and available in the United States are produced by the propagation of influenza viruses in eggs1234567. 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 status8. 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 allergy9. 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 recipient11. 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
| 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
| 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
References in this table: 121314151617181920212223242526
| 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;232:60-6227. 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
References in this table: 234567891011222428293031323334353637
| 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;232:60-6227. 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
References in this table: 383940
| 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;232:60-6227. 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
| 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;232:60-6227. 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
| 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;232:60-6227. 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
| 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;232:60-6227. 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 season41. 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
| 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;232:60-6227. 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
| 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;232:60-6227. 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
| 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;232:60-6227. 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
| 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)
References in this table: 121314151617181920212223242526343839
| 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)
References in this table: 222428293031323335363741
| 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
| 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
| 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
| 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
References in this table: 1721293041
| Author Publication year |
Vaccine | N egg allergic | N with severe allergy/ anaphylaxis to egg | Events |
|---|---|---|---|---|
| Esposito 2008 (17) | Seasonal virosomal | 44 | 11 |
|
| James 1998 (21) | Seasonal inactivated | 83 | 27 |
|
| Forsdahl 2012 (29) | Monovalent inactivated | 80 | 19 |
|
| Gagnon 2010-1 (30) | Monovalent inactivated | 830 | - |
|
| Gagnon 2010-2 (30) | Monovalent inactivated | 3640 | - |
|
| Schuler 2011 (41) | Monovalent inactivated | 62 | - |
|
*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
References in this table: 16172129303439
| 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 |
|
| Esposito 2008 (17) | Seasonal inactivated vaccine | 44 | 11 |
|
| James 1998 (21) | Seasonal inactivated vaccine | 83 | 27 |
|
| Forsdahl 2012 (29) | Monovalent inactivated | 80 | 19 |
|
| Gagnon 2010-1 (30) | Monovalent inactivated | 830 | - |
|
| Gagnon 2010-2 (30) | Monovalent inactivated | 3640 | - |
|
| Turner 2015a (39) | Seasonal live attenuated | 282 | 115 |
|
| Turner 2015b (34) | Seasonal live attenuated | 779 | 270 |
|
*Unclear whether these events occurred in persons with severe allergy/anaphylaxis to egg.
Appendix 3: Literature Search Strategy
Literature through October 26, 2021
| 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 |
View the complete list of GRADE evidence tables
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