ACIP Evidence to Recommendations (EtR) Framework: Safety of Influenza Vaccines for Persons with Egg Allergy

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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.

Interventions: Receipt of any influenza vaccine.

Comparisons: Placebo, non-egg based influenza vaccine, non-influenza control vaccine, no vaccine, no comparator.

Outcomes:

Death (Critical)

Anaphylaxis (Critical)

Allergic reaction symptoms requiring hospitalization (Critical)

Allergic reaction symptoms requiring outpatient or emergency department medical attention, including instances treated with medications (Important)

Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria (Important)

Background:

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.  Since the 2018-19 influenza season, ACIP has recommended that persons with egg allergy of any severity may receive any licensed, recommended, and age-appropriate influenza vaccine (inactivated influenza vaccine, recombinant influenza vaccine, or live attenuated influenza vaccine) that is otherwise appropriate for their 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).  Additional 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 all vaccines (11).

The policy change under consideration in this discussion was whether to no longer recommend additional safety measures for persons with egg allergy of any severity, beyond what is recommended for any persons presenting for influenza vaccination.  The specific proposed intervention referenced in the tables that follow was to no longer make a recommendation regarding vaccination setting for those with a history of severe allergic reaction to egg.

Public Health Problem

Problem
Criteria Work Group Judgements Evidence Additional Information
Is the problem of public health importance? Yes

Discussion focused on the importance of influenza vaccination for this population.

  • Egg allergy effects 1-3% of children by age 3 years (12, 13).
  • Development of tolerance to egg with increasing age is common. In one series, development of tolerance was estimated to be 4% by age 4 years, 12% by 6 years, 37% by 10 years, and 68% by 16 years (14).  Egg allergy is therefore more likely to affect younger children, who are at increased risk of severe influenza illness compared with older children.
  • Egg allergy also frequently co-exists with asthma, a condition which is associated with increased risk of severe influenza illness (15).
  • A smaller proportion of Work Group members indicated “Probably yes”; one indicated “No”.
  • Current recommendations might be a real or perceived barrier to vaccination for some (e.g., by fostering safety concerns or providing a reason to decline vaccination).
  • While any barriers might be ameliorated by the availability of one egg-free vaccine for persons aged ≥6 months, there is only one such vaccine approved for children under age 18 years, compared with 4 egg-based vaccines that are approved for this age group.

Benefits and Harms

Benefits and Harms
Criteria Work Group Judgements Evidence Additional Information
How substantial are the undesirable anticipated effects? Small
  • A systematic review of literature pertaining to safety of influenza vaccines for persons with egg allergy yielded 28 reports describing 31 studies which were included in GRADE (16).
  • There were no reported occurrences of the Critical outcomes of death, anaphylaxis, or hospitalization.
  • Among persons with egg allergy of all severities, frequencies of reported instances of Important outcomes were low overall.
    • Frequencies of reactions requiring outpatient or emergency department medical attention were 0.2% for seasonal IIV, 1.5% for monovalent IIV, and 0% for seasonal LAIV.
    • Frequencies of reactions which involved cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria were 0.3% for seasonal IIV, 0.6% for monovalent IIV, and 0.9% for seasonal LAIV.
  • Among those with a history of severe allergy or anaphylaxis to egg (where such data were available), there were no reported occurrences of the Critical or Important outcomes.
    • However, data specifically for persons with a history of severe egg allergy were limited.
  • A slightly smaller proportion of Work Group members indicated “Minimal”, a few indicated “Moderate” or “Varies”.
  • Limitations of the data reviewed include:
    • Data were limited to observational studies with no comparator groups meeting criteria.
    • Data specifically for those with severe egg allergy was limited.
    • Some data were available only from abstracts.
    • Level of detail in which reactions were described varied among reports.
    • Post-vaccination observation time varied among reports.
    • Vaccine ovalbumin content not known in many instances, and where known difficult to compare with current vaccines (as in most current egg-based influenza vaccine package inserts it is reported as an upper threshold (1-4, 7), and for two it is not reported (5, 6)).
What is the overall certainty of the evidence of effects? Very low See GRADE tables (16). Certainty of evidence for each of the three vaccine types (seasonal IIV, monovalent IIV, and seasonal LAIV) was downgraded for methodological quality, imprecision, and indirectness when egg allergy of all severities was considered.  For data referring to persons with a history of severe allergy or anaphylaxis to egg, certainty of evidence was downgraded for methodological quality and imprecision (16).

Values

Values
Criteria Work Group Judgements Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Don’t know
  • No direct evidence.
  • Smaller proportions of Work Group members indicated “Yes”, “Probably yes”, “Probably no”, and ”Varies”.
Is there important uncertainty about or variability in how much people value the main outcomes? Probably not important uncertainty or variability
  • No direct evidence.
  • A smaller proportion of Work Group members indicated “Probably important uncertainty or variability”; one indicated “No important uncertainty or variability”.

Acceptability

Acceptability
Criteria Work Group Judgements Evidence Additional Information
Is the intervention acceptable to key stakeholders? Probably yes
  • No direct evidence.
  • A smaller proportion of Work Group members indicated “Yes”.
  • A consideration possibly favoring acceptability is that several US professional societies (AAP, AAAAI, ACAAI) already recommend no special measures (screening, observation periods, selection of specific vaccines, specific vaccination settings) for those with egg allergy (9, 10).
  • As of the 2022-23 influenza season, package inserts still carry a contraindication for severe hypersensitivity reaction to any vaccine components (which include egg for egg-based vaccines), which might be a source of confusion for providers and consumers.  However, ACIP has previously recommended that any influenza vaccine otherwise appropriate for the recipients age and health status can be used for persons with egg allergy of any severity.

Resource Use

Resource Use
Criteria Work Group Judgements Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes
  • No direct evidence.
  • No economic evaluation was conducted given small size of target population and insufficient data to inform key assumptions. Moreover, the primary emphasis of this assessment was safety rather than cost.
  • Centers for Medicaid and Medicare Services (CMS) payment allowances (17) and Vaccines for Children (VFC) program private sector prices (18) are lower for egg based influenza vaccines than for equivalent non-egg based presentations.
  • A smaller proportion of Work Group members indicated “Probably yes”.
  • The proposed change does not include a recommendation to use a particular influenza vaccine or type of vaccine (either egg based or non-egg based vaccines would be appropriate).
  • However, the change could lead to greater use of egg-based vaccines in this population.
    • This could be associated with more efficient allocation of resources if there is no increase in adverse events.
    • Alternatively, costs could increase if there is an increase in reactions requiring medical attention.

Equity

Equity
Criteria Work Group Judgements Evidence Additional Information
What would be the impact on equity? Probably increased
  • No direct evidence.
  • Indirect lines of evidence include a study indicating that Black, Hispanic, and American Indian/Alaska Native children ≤4 years of age have higher influenza-associated hospitalization and ICU admission rates than White children (19), and that Black children were disproportionately represented among children with egg allergy in one series (15).
  • Smaller proportions of Work Group members indicated “Probably reduced”, “Probably no impact”, “Don’t know”, and “Varies”.

Feasibility

Feasibility
Criteria Work Group Judgements Evidence Additional Information
Is the intervention feasible to implement? Yes No direct evidence.
  • A smaller proportion of Work Group members indicated “Probably yes”.
  • Considerations favoring feasibility include that the proposed change is a simplification of the previous recommendations (i.e., the recommendations for egg allergy would be uniform for all persons with egg allergy, and the same as for any recipient of any vaccine). The change also does not recommend specific vaccines be used or change current recommendations for emergency equipment and resources.
  • A consideration against feasibility is that vaccination settings which are not already prepared to manage severe allergic reactions will need to address these needs. However, all settings are already recommended to be prepared for severe allergic reactions when administering any vaccine to any recipient.

Balance of consequences

The majority of the Work Group members responded that desirable consequences clearly outweigh undesirable consequences in most settings.  A smaller proportion responded that desirable consequences probably outweigh undesirable consequences in most settings.

Work Group Judgement of Sufficiency of Information:

The Work Group feels there is sufficient evidence to move forward with a recommendation.

ACIP Recommendation:

ACIP recommends that all persons ages ≥6 months with egg allergy should receive influenza vaccine.  Any influenza vaccine (egg based or non-egg based) that is otherwise appropriate for the recipients age and health status can be used.

References

  1. Afluria Quadrivalent [Package Insert]. Parkville, Victoria, Australia: Seqirus; 2023.
  2. Flumist Quadrivalent [Package Insert]. Gaithersburg, MD: MedImmune; 2023.
  3. Fluarix Quadrivalent [Package Insert]. Dresden, Germany: GlaxoSmithKline; 2023.
  4. FluLaval Quadrivalent [Package Insert]. Quebec City, QC, Canada: ID Biomedical Corporation of Quebec; 2023.
  5. Fluzone Quadrivalent [Package Insert]. Swiftwater, PA: Sanofi Pasteur; 2023.
  6. Fluzone High-Dose Quadrivalent [Package Insert]. Swiftwater, PA: Sanofi Pasteur; 2023.
  7. Fluad Quadrivalent [Package Insert]. Holly Springs, NC: Seqirus; 2023.
  8. Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices-United States, 2018-19 Influenza Season. MMWR Recomm Rep. 2018 Aug 24;67(3):1-20.
  9. American Academy of Pediatrics, Committee on Infectious Diseases. Recommendations for Prevention and Control of Influenza in Children, 2016-2017. Pediatrics. 2016;138(4):e20162527.
  10. Greenhawt M, Turner PJ, Kelso JM. Administration of influenza vaccines to egg allergic recipients: A practice parameter update 2017. Ann Allergy Asthma Immunol. 2018 Jan;120(1):49-52.
  11. Kroger A, Bahta L, Long S, Sanchez P. General best practice guidelines for immunization. Available at : https://www.cdc.gov/vaccines/hcp/acip-recs/general-recs/index.html.  Accessed March 10, 2023.
  12. Eggesbo M, Botten G, Halvorsen R, Magnus P. The prevalence of allergy to egg: a population-based study in young children. Allergy. 2001 May;56(5):403-11.
  13. Erlewyn-Lajeunesse M, Brathwaite N, Lucas JS, Warner JO. Recommendations for the administration of influenza vaccine in children allergic to egg. BMJ. 2009 Sep 15;339:b3680.
  14. Savage JH, Matsui EC, Skripak JM, Wood RA. The natural history of egg allergy. J Allergy Clin Immunol. 2007 Dec;120(6):1413-7.
  15. Samady W, Warren C, Wang J, Das R, Gupta RS. Egg Allergy in US Children. J Allergy Clin Immunol Pract. 2020 Oct;8(9):3066-73 e6.
  16. Advisory Committee on Immunization Practices. GRADE: Safety of Influenza Vaccines for Persons with Egg Allergy.  Available at: https://www.cdc.gov/vaccines/acip/recs/grade/influenza-egg-allergy.html.
  17. U.S. Center for Medicare and Medicaid Services. Seasonal Influenza Vaccines Pricing, 2022-23. Available at https://www.cms.gov/Medicare/Medicare-Fee-for-Service-Part-B-Drugs/McrPartBDrugAvgSalesPrice/VaccinesPricing.  Accessed July 4, 2023.
  18. U.S. Centers for Disease Control and Prevention. CDC Vaccine Price List. Available at https://www.cdc.gov/vaccines/programs/vfc/awardees/vaccine-management/price-list/index.html.  Accessed July 4, 2023.
  19. O’Halloran AC, Holstein R, Cummings C, Daily Kirley P, Alden NB, Yousey-Hindes K, et al. Rates of Influenza-Associated Hospitalization, Intensive Care Unit Admission, and In-Hospital Death by Race and Ethnicity in the United States From 2009 to 2019. JAMA Netw Open. 2021 Aug 2;4(8):e2121880.
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