02 influenza grohskopf 508

National Center for Immunization & Respiratory Diseases
Influenza Vaccination of Persons with Egg Allergy:
Evidence to Recommendations Discussion and Work Group Considerations
Lenee H. Blanton
Lisa A. Grohskopf
Influenza Division, CDC/NCIRD
Advisory Committee on Immunization Practices
June 21, 2023
•Donna Hummell
•Karen Broder
•Pedro Moro
•Geta Aynalem
•Shashi Sharma
•Elaine Miller
•Andrew Leidner
•Rebecca Morgan
•Doug Campos -OutcaltAcknowledgements
2
Background
•Affects approximately 1 -3% of children by age 3 years.1,2
•Resolves for many during later childhood and adolescence .
–In one study,3
›4% developed tolerance by age 4 years,
›12% by age 6 years,
›37% by age 10 years,
›68% by age 16 years.
•Reactions range from mild to life -threatening.
•Diagnosis:
–Clear history of immediate allergic reaction to egg or egg -containing foods.2
–Skin prick testing (SPT) or estimation of egg -specific IgE levels.2Egg Allergy
1. Eggesbo M et al. Allergy 2001;56(5):403 -411
2. Erlewyn -Lajeunesse M et al. BMJ 2009;339:b3680.3. Savage JH et al. J Allergy Clin Immunol 2007;120(6):1413 -7.
4
Ovalbumin Content of U.S. Influenza Vaccines, 2022 -23
Vaccine (manufacturer) Approved age
indicationOvalbumin, mcg/dose*
(per package insert)
Egg-based
Afluria Quadrivalent (Seqirus) ≥6 mos <1
Fluarix Quadrivalent (GSK) ≥6 mos ≤0.05
FluLaval Quadrivalent (GSK) ≥6 mos ≤0.3
Fluzone Quadrivalent (Sanofi Pasteur) ≥6 mos Not stated
FluMist Quadrivalent (AstraZeneca) 2 through 49 yrs <0.024
Fluad Quadrivalent (Seqirus) ≥65 yrs ≤1
Fluzone High -Dose Quadrivalent (Sanofi Pasteur) ≥65 yrs Not stated
Egg-free
Flucelvax Quadrivalent (Seqirus) ≥6 mos Egg-free
Flublok Quadrivalent (Sanofi Pasteur) ≥18 yrs Egg-free
* 0.5 mL for injectable vaccines and 0.2 mL for LAIV 5
•Persons with a history of egg allergy of any severity should receive influenza vaccine.
•Any licensed, recommended influenza vaccine (i.e., any IIV4, RIV4, or LAIV4) that is
otherwise appropriate can be used.
•For persons with previous reactions to egg involving symptoms other than urticaria:
–“If a vaccine other than ccIIV4 or RIV4 is used, the selected vaccine should be
administered in an inpatient or outpatient medical setting, including but not
necessarily limited to hospitals, clinics, health departments, and physician
offices. Vaccine administration should be supervised by a health care provider
who is able to recognize and manage severe allergic reactions.”
•No specific observation period recommended.Current ACIP Recommendations1
1. CDC/ACIP . MMWR Recomm Rep 2022;71(No. RR -1):1–28. IIV4= quadrivalent inactivated influenza vaccine
LAIV4=quadrivalent live attenuated influenza vaccine
ccIIV4=quadrivalent cell culture based inactivated influenza vaccine
RIV4= quadrivalent recombinant influenza vaccine6
•American Academy of Pediatrics
–Since 2016 -17, no additional measures recommended for persons with egg allergy.1
–“Children with egg allergy can receive any influenza vaccine without any additional precautions
beyond those recommended for all vaccines.”2
–Measures related to use of specific vaccines, observation periods, or restricting vaccination to
specific medical settings not warranted and constitute a barrier to vaccination.3
–Not necessary to inquire about or screen for egg allergy prior to influenza vaccination.3
•Joint Task Force, AAAAI/ACAAI
–“No special precautions beyond those recommended for the administration of any vaccine to
any patient are necessary for administration of influenza vaccine to egg allergic individuals.”4Influenza Vaccines and Egg Allergy: Other Guidance
1. Recommendations for Prevention and Control of Influenza in Children, 2016 –2017 | Pediatrics | American Academy of Pediatrics (aa p.org)
2. Recommendations for Prevention and Control of Influenza in Children, 2022 –2023 | Pediatrics | American Academy of Pediatrics (aa p.org) .
3. AAP . Technical Report for the 2022 -23 Recommendations for the Prevention and Control of Influenza in Children, 2022 -23
4. Greenhawt M et al . Ann Allergy Asthma Immunol 2018;120:49 -52. 7
•From chapter titled “Preventing and Managing Adverse Reactions”:
–“Although allergic reactions are a common concern for vaccine providers, these
reactions are uncommon and anaphylaxis following vaccines is rare, occurring at
a rate of approximately one per million doses for many vaccines. Epinephrine
and equipment for managing an airway should be available for immediate use.”General Best Practices Guidelines for Immunization1
1. Kroger AT et al. https://www.cdc.gov/vaccines/hcp/acip -recs/general -recs/index.html
8
•Vaccine skin testing prior to vaccination.1,2
–Skin prick and/or intradermal testing with dilution of vaccine
–If positive, vaccination deferred or administered via alternative dosing protocol
•Graded administration of vaccine.3
–Incrementally increasing volumes, often in 5 to 6 steps; sometimes with dilutions in early steps
–E.g., 0.05 mL of 1:100 dilution →0.05 mL of 1:10 dilution →0.05 mL→0.1 mL→0.15 mL→0.2 mL,
with observation periods after each dose (e.g., 15 minutes).
•Split dosing of vaccine.4
–Most commonly 10% of dose volume →observation period →remaining 90% of dose volume,
often with additional observation after final dose.Past Approaches to Influenza Vaccination of Persons with
Egg Allergy (Not Currently Recommended)
1. Bierman CW et al. J Infect Dis 1977;136:S652 -S655.
2. Miller JR et al. J Allergy Clin Immunol 1983;71:568 -173.3. Murphy KR et al. J Pediatr 1985;106(6):931 -933.
4. James JM et al. J Pediatr 1998;133:624 -628.
9
•Whether t o no longer recommend additional safety measures for
persons with egg allergy of any severity, beyond what is recommended
forany other persons presenting for influenza vaccination.
–In the discussion that follows, the proposed intervention is to no longer make
the recommendation regarding vaccination setting for those with a history of
severe allergic reaction to egg.Policy Question
1
0
EtR Domain 1: Public Health Importance
•Egg allergy more common in younger children, and often co -exists with asthma:
–In a cross -sectional survey of 38,408 children,1
›Egg allergy prevalence was 0.9% overall; 1.3% for those  <5 yrs.
›Asthma prevalence higher with egg allergy (46.5%) with other 8 most common food allergies (33.2%).
•Younger children and people with asthma are at increased risk of severe influenza
illness.Is Vaccination of Egg -Allergic Persons an Issue of Public
Health Importance?
1.Samady W, Warren C, Wang J, et al.  Egg allergy in US children. J Allergy Clin Immunol Pract. 2020;8(9):3066 -73. 12
Public Health Importance: WG Considerations
•Current recommendations might be
a real or perceived barrier to
vaccination (e.g., by promoting
hesitancy based on safety concerns,
or providing a reason to decline
vaccination).
-No data specifically examining or
confirming that current
recommendations are a barrier found,
but existence of real or perceived
barriers is plausible.
13•Current recommendations might be
less of a barrier now, since cell -
based (egg -free) inactivated vaccine
is approved for ages ≥6 mos.
-However, there is only one such vaccine
licensed for children <18 years, compared
with four egg -based vaccines available for
this age group.
Is Vaccination of Egg -Allergic Persons an Issue of Public
Health Importance?
14
0
6
33
61
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=18)
EtR Domain 2: Benefits and Harms
•Does the available evidence concerning the 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?
–Review focused on Harms (safety) —did not include review of
effectiveness/efficacy data.Review Question
16
Population, Intervention, and Comparators
▪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: Any influenza vaccine.
▪Comparators: Placebo, non egg -based influenza vaccine, non -influenza
control vaccine, no vaccine, no comparator
17
Outcomes
Important
•Allergic reaction symptoms
requiring outpatient or emergency
department medical attention†
•Allergic reaction including
cardiovascular symptoms,
respiratory symptoms, angioedema,
or generalized urticariaCritical
•Death
•Anaphylaxis meeting Brighton
criteria Levels 1 -3*
•Anaphylaxis otherwise
classified*
•Allergic symptoms requiring
hospitalization
* These two outcomes are combined in the tables that follow.
† Includes instances treated with medications, without explicit mention of outpatient or emergency department care .18Within 4 hours of vaccination:
Study Designs, Vaccines, and Comparison Groups
▪47 reports describing 52 studies.
•1 randomized study (compared full -dose with 10%/90% split dose).
•1 VAERS report summary.
•Remainder retrospective/prospective cohort studies and case series.
•2 involved only recombinant vaccine (egg -free).
▪No studies include a relevant comparison group (e.g., an alternative or no vaccine).
▪14 abstracts only (no related paper found).
▪All studies were reviewed descriptively.
▪28 reports (31 studies) included in GRADE:
•Egg-based vaccines only (seasonal and monovalent).
•Full-dose or split -dose administration.
•For the randomized study, full -and split -dose groups combined; treated as a cohort study.
•Data with unknown/unclear vaccine type, unspecified administration protocol, graded (≥3 steps)
dosing, and/or unknown denominator excluded.
•Since there are no comparators, data are summarized as frequencies. 19
Summary of Events by Vaccine Type: Egg Allergy of All severities
Outcome Seasonal IIVs* Monovalent IIVs* LAIV Importance Certainty
Death 0/1591 (0%) 0/5235 (0%) 0/1129 (0%) Critical Very low
Anaphylaxis 0/1591 (0%) 0/5235 (0%) 0/1129 (0%) Critical Very low
Reaction requiring hospitalization 0/1591 (0%) 0/5235 (0%) 0/1129 (0%) Critical Very low
Reaction requiring outpatient/ED
attention (includes those given
symptomatic medications)3/1591 (0.2%) 77/5235 (1.5%) 0/1129 (0%) Important Very low
Allergic reaction including
cardiovascular symptoms, respiratory
symptoms, angioedema, or
generalized urticaria5/1591 (0.3%) † 33/5235 (0.6%) 10/1129 (0.8%) Important Very low
20*Includes several papers for which vaccine type not explicitly stated, but presumed based upon season, study
location, and/or use of graded/split dosing.  Seasonal IIV data include one paper describing a virosomal vaccine.
†One study reported 6 instances of reactions including “wheezing, eczema exacerbation, or hives on chest”, but
not specifying number with each symptom.  If assumed that all six included wheezing, frequency would be
11/1591=0.7%
Summary of Events by Vaccine Type: Persons with Anaphylaxis to Egg
Outcome Seasonal IIVs* Monovalent IIVs* LAIV Importance Certainty
Death 0/322 (0%) 0/68 (0%) 0/412 (0%) Critical Very low
Anaphylaxis 0/322 (0%) 0/68 (0%) 0/412 (0%) Critical Very low
Reaction requiring hospitalization 0/322 (0%) 0/68 (0%) 0/412 (0%) Critical Very low
Reaction requiring outpatient/ED attention 0/295 (0%) 0/68 (0%) 0/412 (0%) Important Very low
Allergic reaction including cardiovascular
symptoms, respiratory symptoms,
angioedema, or generalized urticaria0/291 (0%) 0/68 (0%) 0/27 (0%) Important Very low
21*Includes several papers for which vaccine type not explicitly stated, but presumed to be IIV based upon season,
study location, and/or use of graded/split dosing.
Summary of Evidence for Outcomes of Interest
Outcome Importance Included in
profileCertainty
Death Critical Yes Very low
Anaphylaxis Critical Yes Very low
Allergic reaction symptoms requiring hospitalization Critical Yes Very low
Allergic reaction symptoms requiring outpatient or
emergency department medical attentionImportant Yes Very low
Allergic reaction including cardiovascular symptoms,
respiratory symptoms, angioedema, or generalized urticariaImportant Yes Very low
22
Report of Brighton Level 1 Anaphylaxis
▪One report of Brighton Level 1 anaphylaxis in person with “possible” egg allergy
within 30 minutes of receiving monovalent vaccine.
•In paper summarizing VAERS reports following monovalent pandemic influenza vaccine during
2009 -10 season.1
•Unclear from paper whether documented to be egg -allergic.
▪Doses administered that season unknown
•Reaction not included in counts in GRADE evidence profiles (as denominator undefined).
▪Paper states approximately 127 million doses distributed that season.
▪Other reactions:
•2 of respiratory hypersensitivity
•1 sensation of throat closure
1. Halsey NA, et al. Vaccine. 2013 Dec 9;31(51):6107 -12. doi: 10.1016/j.vaccine.2013.09.066. Epub 2013 Oct 8. PMID: 24120547 .
Descriptions Of Reactions Following Egg -free Vaccines
24•Woo et al  2015, 2017: summaries of VAERS reports following
recombinant influenza vaccine (RIV):
•Reports of serious allergic reactions following RIV, some of which occurred
among persons with egg allergy.
•RIV is egg, gelatin, antibiotic, and preservative -free.
•Authors note that the occurrence of such reactions might reflect an
underlying predisposition to atopy.
•Reports also highlight unpredictability of severe allergic reactions, and
importance of being prepared in all vaccination settings, for all
recipients, and with all vaccines.
Limitations and WG Considerations
▪Observational data with no comparator groups meeting criteria.
▪Some data only available from abstracts.
▪Many (particularly older) studies employed skin testing with egg proteins and/or
vaccine prior to decision to vaccinate.
▪Considerable variability in level of detail in which outcomes are described.
▪Observation time post -vaccination varied; time elapsed post -vaccination not often
reported for delayed reactions.
•Observation for immediate reactions under 4 hours for most studies; generally 30 min to 2 hours.
▪Ovalbumin content was not reported/unknown in most instances.
•In most instances where noted, was <1µg/dose; in some cases substantially less.
•Difficult to know how this compares with current vaccines, since expressed as an upper limit.
▪Data specifically for persons with anaphylaxis to egg were limited.
•Not all studies specified that persons with severe egg allergy were included.
•Where included, not all studies reported reactions specifically for this subgroup. 25
Egg Allergy and Anaphylaxis Reports after IIVs in
VAERS, 2017 -2022
•178 anaphylaxis reports after any IIV
•18 had an egg allergy (based on VAERS report)
•Clinical review revealed 7 reports of anaphylaxis and egg allergy (all in 2017 -18):
•4 in children (ages 2, 4, 9, 11 yrs);  3 in adults (ages 21, 52, 61 yrs)
•4 Brighton level 1; 1 Brighton level 3; 2 did not meet Brighton
•Influenza vaccines:
›Fluarix quadrivalent: 2
›Fluzone quadrivalent: 2
›Fluvirin trivalent: 1
›Flucelvax quadrivalent: 1
›Flublok quadrivalent: 1
•Difficult to assess if reaction was due to egg protein due to limited laboratory data.
26 Vaccine Adverse Event Reporting System (VAERS) (hhs.gov)
How Substantial are the Undesirable Anticipated Effects?
27
39
44
6
0
11
0Minimal
Small
Moderate
Large
Varies
Don't Know% ofrespondents (N=18)
EtR Domain 3: Values
•No direct evidence found.
•Change in recommendations might be reassuring to some who have
wanted to be vaccinated but were hesitant/perceived it is unsafe;
•Or might be source of concern.
–WG member expressed that change might be viewed unfavorably if it is
perceived as trade -off between safety vs. increasing coverage/reducing missed
opportunities for vaccination.Does the Target Population Feel that the Desirable Effects
are Large Relative To Undesirable Effects?
29
Does the Target Population Feel that the Desirable Effects
are Large Relative To Undesirable Effects?
30
0
6
22
17
6
50No
Probably no
Probably yes
Yes
Varies
Don't Know% of respondents (N=18)
•No direct evidence found.
–Presumably, greater value attached to the more serious outcomes (death,
anaphylaxis, hospitalization).Is There Important Uncertainty About, or Variability In, How
Much People Value the Main Outcomes?
31
Is there important uncertainty about, or variability in, how
much people value the main outcomes?
32
0
28
67
6
0Important uncertainty or variability
Probably important uncertainty or
variability
Probably not important uncertainty or
variability
No important uncertainty or variability
No known undesirable outcomes% of respondents (N=18)
EtR Domain 4: Acceptability
•No direct evidence found.
•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.
•As of 2022 -23, package inserts for egg -based vaccines continue to carry a
contraindication of severe hypersensitivity reaction to any vaccine components.
–However, ACIP has previously recommended influenza vaccination with any appropriate vaccine
(egg -based or not), regardless of severity of reaction to egg.Is the Intervention Acceptable to Key Stakeholders?
34
Acceptability: WG Considerations
•Alignment of recommendations
among public health organizations
and professional societies facilitates
consistent messaging to providers
and patients.
35•Concern that some settings might
not be prepared to manage severe
reactions (e.g., retail).
•Acceptability will be severely
impacted if anaphylaxis occurs in a
setting unprepared to manage it.
-Importance of stressing that every
setting must be able to manage
anaphylaxis, or should not administer
any vaccines to any recipient.
•Concer n for potential liability issues.
Is the Intervention Acceptable to Key Stakeholders?
36
0
0
56
44
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=18)
EtR Domain 5: Resource Use
•No economic analysis was conducted.
–The target population is small.
–Lack of data for some factors.
›No reliable estimate of the proportion of those with egg allergy who have had
severe reaction to egg.
›Proportions of individuals with egg allergy by age uncertain.
›Proportions of persons receiving egg -based vs. egg -free vaccines uncertain.
•Primary emphasis of assessment was safety rather than cost.Is the Intervention a Reasonable and Efficient Allocation of
Resources?
38
•CMS payment allowances and VFC costs higher for egg -free vaccines that are approved for children
(rounded to nearest dollar):Relative Costs of Egg -Based vs. Egg -Free Influenza Vaccines
39Vaccine (based on 0.5mL dose) CMS Rate 2022 -231 VFC List 2023 -242
Egg-based
Average for egg -based vaccines for ≥6 mos:    Multidose $20.00 $20.00
Average for egg -based vaccines for ≥6 mos:    Preservative -free $22.00 (IIV4s)
$27.00 (LAIV4)$21.00 (IIV4s)
$24.00 (LAIV4)
Fluzone High -Dose Quadrivalent: Preservative -free (≥65 yrs only) $70.00 -
Fluad Quadrivalent:                        Preservative -free (≥65 yrs only) $72.00 -
Egg-free
Flucelvax Quadrivalent:   Multidose (≥6 mos) $31.00 $29.00
Preservative -free (≥6 mos) $32.00 $30.00
Flublok Quadrivalent        Preservative -free (≥18 yrs only) $70.00 -
1.https://www.cms.gov/Medicare/Medicare -Fee-for-Service -Part-B-Drugs/McrPartBDrugAvgSalesPrice/VaccinesPricing
2.CDC Vaccine Price List (Private sector cost per dose)
Resource Use: WG Considerations
•Removing existing restrictions
could result more efficient
allocation of resources, if data
suggest no or minimal increase in
adverse events.
40•Change in recommendations and
lower cost of egg -based vaccines
might lead to their increased use,
which might be associated with
increased costs if these is an
increase in reactions requiring
medical attention.
Is the Intervention a Reasonable and Efficient Allocation of
Resources?
41
0
0
24
76
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=17)*
* Answer from one respondent who selected “Probably yes” and “Yes” excluded
EtR Domain 6: Equity
•No direct evidence found.
•Some racial/ethnic groups at increased risk for severe influenza illness, highlighting
importance of vaccination:
–Influenza associated hospitalization and ICU admission rates higher among Black, Hispanic, and
American Indian/Alaska Native children <4 yrs of age compared with White children.1
–Black children were disproportionately represented among children with egg allergy in one
series (23.4%, relative to comprising 13.2% of the U.S. pediatric population).2
–If current recommendations are a barrier to vaccination, the intervention could improve equity
with regard to risk of severe influenza illness.What Would Be the Impact on Health Equity?
431.O’Halloran et al J AMA Netw Open. 2021 Aug 2;4(8):e2121880
2.Samady W et al. J Allergy Clin Immunol Pract. 2020 Oct;8(9):3066 -3073.e6. doi: 10.1016/j.jaip.2020.04.058 .
•Issues related to trust in the healthcare system, from the patient’s
perspective :
–A change in recommendations might mean vaccination occurs more widely in
more settings than previously, and perhaps increased use of egg -based vaccines
rather than egg -free vaccines in some settings.
–The fact that egg -based vaccines are less expensive might reinforce belief that
providers/ healthcare systems do not care to use the necessary resources to
provide a potentially safer vaccine.Equity: WG Considerations
44
What Would Be the Impact on Health Equity?
45
0
17
11
50
0
6
17Reduced
Probably reduced
Probably no impact
Probably increased
Increased
Varies
Don't know% of respondents (N=18)
EtR Domain 7: Feasibility
Is the Intervention Feasible to Implement?
•Considerations favoring feasibility:
-The proposed change i s a simplification
of the previous recommendation.
-It does not specify particular vaccines.
-It does not change recommendations
for emergency equipment and
resources.
›The General Best Practices indicate that
epinephrine and equipment to manage
an airway should be available in all
vaccination settings.1
47•Consideration against feasibility:
-Vaccination settings not already
prepared to manage severe allergic
reactions would 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.1
1. Kroger AT et al. https://www.cdc.gov/vaccines/hcp/acip -recs/general -recs/index.html.
Is the Intervention Feasible to Implement?
48
0
0
11
89
0
0No
Probably no
Probably yes
Yes
Varies
Don't know% of respondents (N=18)
Balance of Consequences and Sufficiency
of Information
Balance of Consequences
50
0
0
0
39
61
0Undesirable consequences clearly outweigh desirable consequences
in most settings
Undesirable consequences probably outweigh desirable consequences
in most settings
The balance between desirable and undesirable consequences is
closely balanced or uncertain
Desirable consequences probably outweigh undesirable consequences
in most settings
Desirable consequences clearly outweigh undesirable consequences
in most settings
There is insufficient evidence to determine the balance of consequences0 10 20 30 40 50 60 70 80 90 100% of respondents (N=18)
Is There Sufficient Information to Move Forward With a
Recommendation?
51•Of 18 respondents,
–18 responded “Yes”
–0 responded “No”
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY:  1 -888-232-6348    www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.

Search
•First search 03 -14-2019; updated search 10 -26-2022.
•Medline, Embase, PsycInfo, CINAHL, NTIS, Scopus, Cochrane Library,
ClinicalTrials.gov; no date or language restriction.
Included reports
•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 papers found were included.
Excluded reports
•Animal studies, duplicate reports, reviews*, clinical trial registry summaries.*Literature Search, Inclusion/Exclusion Criteria
* Used to help identify other potentially relevant reports 53
PRISMA Diagram
381 reports excluded
•255 review/other non -primary source
•67 wrong study design
•20 wrong patient population
•16 abstract (paper found) or registry summary
•6 wrong intervention
•3 wrong outcomes
•14 insufficient information477 reports retrieved
47 reports abstracted428 full -text reports assessed454 reports screened23 duplicates removed
26 studies irrelevant
19 reports excluded from GRADE
•12 unclear dosing protocol
• 4 unclear vaccine
• 2 egg -free vaccine
• 1 graded dosing only28reports included in GRADE
54
1. Question and PICO
Policy
question:Whether available evidence concerning safety of influenza vaccines in persons with a history of
egg allergy favors 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 treated with medications, without explicit mention of outpatient or emergency department care. 55
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 urticariaImportant Yes
56*These outcomes are combined in the evidence profile tables.
†Includes instances treated with medications, without explicit mention of outpatient or emergency department care.
3a. Summary of Studies and Outcomes —Seasonal IIV (1)
*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62.  Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Anvari 2011 Not specified 86 None None Unclear
Chung 2010 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) yrs171 None None Moderate
Comeau 2016 † Not specified 88 None None Serious
Des Roches 2012 -1 <2 yrs: 27
2-4 yrs: 83
5-11 yrs: 82
>12 yrs: 37230 None None Low
DesRoches 2012 -2 <2 yrs: 29
2-4 yrs: 53
5-11 yrs: 51
>12 yrs: 4137 None None Low
Erlewyn -Lajeunesse 2010 † Not specified 16 doses None Cardiovascular, respiratory, angioedema,
or generalized urticaria: 1 Moderate
57
3a. Summary of Studies and Outcomes —Seasonal IIV (2)
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern
Esposito 2008 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 Median 11 -12 mos 31 Comparison of full -vs.
split -dose (combined in
this review)None Low
Greenhawt 2012 -2 Median 12 mos at
diagnosis112 None None Low
Hotte 2008 † Not provided 115 None None Unclear
Howe 2011 Not specified 69 Non -allergic group None Unclear
James 1998 Median 3 (1 -46) yrs 83 Non -allergic group Outpatient or emergency department
medical attention: 2
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 3Low
Leo 2010 † Not provided 31 None None Unclear
Park 2008 † Mean 36.1 +/ -19.1
(11 to 105 mos)45 None None Unclear
Paschall 2011 † Mean 3.8 yrs 65 doses None None Unclear
Shimizu 2016 Median 15
(IQR 13 -20) mos17 None None Low
Thanik 2010 Not specified 214 doses None None Unclear
58*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62.  Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.
3b. Summary of Studies and Outcomes —Monovalent IIV (1)
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Didenko 2010 median 4 (2 -11) yrs 6 None None Moderate
Forsdahl 2012 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 -1 173 <2 yrs
280 2 -4 yrs
277 5 -11 yrs
100 ≥12 yrs830 Non -allergic group Outpatient or emergency department
medical attention: 4
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 6Low
Gagnon 2010 -2 Not specified 3460 None Outpatient or emergency department
medical attention: 68
Cardiovascular, respiratory, angioedema,
or generalized urticaria: 26Unclear
Greenhawt 2010 Mean 5.5 (range
0.4-20.4) yrs105 Non -allergic group None Low
59*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62.  Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
3b. Summary of Studies and Outcomes —Monovalent IIV (2)
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Leo 2010 † Not specified 50 None None Unclear
Paschall 2011 † Mean 3.8 yrs 66 None None Unclear
Pien 2010 Mean 3.7 +/ -3.0 yrs 59 None None Moderate
Pitt 2011 Mean 5.6 (1 -27) yrs 59 None None Moderate
Schuler 2011 Mean 4.5 yrs
(10 mos -16 yrs)62 None Outpatient or emergency department
medical attention: 4Moderate
Siret -Alatrista 2010 † Unclear 53 None None Unclear
Spiegel 2010 † Range 1 -56 yrs 150 None None Unclear
Upton 2012 3-5 yrs:12
6-9 yrs:24
10-13 yrs:28
14+ yrs:1075 None None Moderate
60*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62.  Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.
3c. Summary of Studies and Outcomes —LAIV
Author
Publication yearAge/other
characteristicsN Comparator Events by outcome Methodological
quality concern*
Des Roches 2015 2-16 yrs 68 Non -allergic group None Low
Turner 2015a Median 4.9 yrs
(2-17 yrs)282 None Cardiovascular symptoms, respiratory
symptoms, angioedema, or generalized
urticaria: 6Low
Turner 2015b Median 5.3 yrs
(2-18 yrs)779 None Cardiovascular symptoms, respiratory
symptoms, angioedema, or generalized
urticaria: 4Low
61*Adapted from Murad MH et al, BMJ Evid Based Med 2018;23(2):60 -62.  Domains assessed included Selection, Ascertainment,
Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
†Abstract only.
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone0/1591 (0%)
instancesVery Low CRITICAL1. Death
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone0/1591 (0%)
instancesVery Low CRITICAL
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone0/1591 (0%)
instancesVery Low CRITICAL2. Anaphylaxis
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies without comparator interventions, with the exception of one randomized study which compared adminis tration of full dose vs split dose.  Full dose and split dose
administration are treated as equivalent in this review, and so this study is treated as a cohort study. Six of 17 are of unc lear methodological quality. Six of 17 are abstracts.
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.3. Allergic reaction symptoms requiring hospitalization4a: Seasonal IIV administered full -or split -dose, egg allergy of all severities (1)
62
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
17Observa -
tionalSeriousaNot serious SeriousbSeriouscNone3/1591 (0.2%)
instancesVery Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
17Observa -
tionalSeriousaNot Serious SeriousbSeriouscNone5/15 91 (0.3%)†
instancesVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*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 [51].  Domains assesse d
included Selection, Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Re porting.
† One study reported 6 instances of reactions included “wheezing, eczema exacerbation, or hives on chest”, but not specifying number with each symptom.  These are
excluded here.  If assumed that all six included wheezing, frequency would be 10/1591=0.6%
a. All are cohort studies without comparator interventions, with the exception of one randomized study which compared adminis tration of full dose vs split dose.  Full
dose and split dose administration are treated as equivalent in this review, and so this study is treated as a cohort study. Sixof 17 are of unclear methodological
quality. Six of 17 are abstracts.
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.4a: Seasonal IIV administered full -or split -dose, egg allergy of all severities (2)
63
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
10a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/322 (0%)
instancesVery Low CRITICAL1. Death
10a Observa -
tionalSeriousbNot serious Not seriousbSeriouscNone0/322 (0%)
instancesVery Low CRITICAL
10a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/322 (0%)
instancesVery Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
a. Includes only studies which explicitly mentioned inclusion of egg -anaphylactic patients for whom data are specifically report ed.
b. All are cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) protocols. Two of 10 studies are abstracts, and 3 of 10 have
uncertain methodological quality.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
d. Studies removed from denominator which included persons with a history of anaphylaxis to egg and reported event(s), but wh ichdid not indicate whether these occurred in a person with a
history of anaphylaxis to egg. 4b: Seasonal IIV administered full -or split -dose, persons with anaphylaxis to egg (1)
64
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
9a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/295 (0%)
instancesdVery Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting
a. Includes only studies which explicitly mentioned inclusion of egg -anaphylactic patients for whom data are specifically report ed.
b. All are cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) protocols. Two of 10 studies are abstracts, and 3 of 10 have
uncertain methodological quality.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
d. Studies removed from denominator which included persons with a history of anaphylaxis to egg and reported event(s), but wh ichdid not indicate whether these occurred in a person with a
history of anaphylaxis to egg.  8a Observa -
tionalSeriousbNot serious Not serious SeriouscNone0/291 (0%)
instancesdVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria 4b: Seasonal IIV administered full -or split -dose, persons with anaphylaxis to egg (2)
65
4c: Monovalent IIV administered full -or split -dose, egg allergy of all severities (1)
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone0/5235 (0%)
instancesVery Low CRITICAL1. Death
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone0/5235 (0%)
instances dVery Low CRITICAL
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone0/5235 (0%)
instancesVery Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All were cohort studies without comparator intervention groups, including administration via either full dose or split -dose ( 2-step) protocols. Concerns regarding methodological quality were
"Low" for only two studies, moderate for 6, and unclear for 4.  History of egg allergy was by self report only for the larges t study (n=3640).
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions without confidence intervals; however some degree of imprecision must b e assumed.
d. One instance of Brighton Level 1 anaphylaxis was reported in a VAERS surveillance data summary from the 2009 -10 influenza sea son. This instance is not represented in the table as no
denominator is available for this paper. However, it was reported that 127,075,320 doses of monovalent influenza vaccine were distributed in the United States for the season. 66
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
13Observa -
tionalVery
seriousa Not serious SeriousbSeriouscNone77/5235 (1.5%)
instancesVery Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
13Observa -
tionalSeriousaNot serious SeriousbSeriouscNone33/5235 (0.6%)
instancesVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All were cohort studies without comparator intervention groups, including administration via either full dose or split -dose ( 2-step) protocols. Concerns regarding methodological quality were
"Low" for only two studies, moderate for 6, and unclear for 4.
b. Only 143 of total participants reported to have a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions without confidence intervals; however some degree of imprecision must b e assumed.
d. One instance of Brighton Level 1 anaphylaxis was reported in a VAERS surveillance data summary from the 2009 -10 influenza sea son. This instance is not represented in the table as no
denominator is available for this paper. However, it was reported that 127,075,320 doses of monovalent influenza vaccine were distributed in the United States for the season. 4c: Monovalent IIV administered full -or split -dose, egg allergy of all severities (2)
67
4d: Monovalent IIV administered full -or split -dose, persons with anaphylaxis to egg (1)
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone0/68 (0%)
InstancesVery Low CRITICAL1. Death
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low CRITICAL
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. Cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) p rotocols.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.68
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
3Observa -
tionalVery
Seriousa Not Serious Not Serious SeriousbNone 0/68 instances Very Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. Cohort studies without comparator intervention groups, including administration via either full dose or split -dose (2 -step) p rotocols.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.4d: Monovalent IIV administered full -or split -dose, persons with anaphylaxis to egg (2)
69
4e. Seasonal LAIV, egg allergy of all severities (1)
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low CRITICAL1. Death
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low CRITICAL
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies without a comparison intervention.
b. Most studies did not report data specifically for persons with a history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.70
Certainty Assessment
ImpactCertaint
yImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone 0/1129 instances Very Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
3Observa -
tionalSeriousaNot serious SeriousbSeriouscNone10/1129 (0.8%)
instancesVery Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies without a comparison intervention.
b. Majority of persons in each study did not have history of anaphylaxis to egg.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.4e. Seasonal LAIV, egg allergy of all severities (2)
71
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low CRITICAL1. Death
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low CRITICAL
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low CRITICAL2. Anaphylaxis
3. Allergic reaction symptoms requiring hospitalization
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies with no comparison groups.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed. Very low denominator count. 4f. Seasonal LAIV, persons with anaphylaxis to egg (1)
72
Certainty Assessment
Impact Certainty ImportanceNo. of
studiesStudy
DesignMethod -
ological
Quality*Inconsistency Indirectness ImprecisionOther
considerations
3Observa -
tionalSeriousaNot serious Not serious SeriousbNone 0/412 instances Very Low IMPORTANT4. Allergic reaction symptoms requiring outpatient or emergency department medical attention
1Observa -
tionalSeriousaNot serious Not seriousVery
seriousc None 0/27 instances Very Low IMPORTANT5. Allergic reaction including cardiovascular symptoms, respiratory symptoms, angioedema, or generalized urticaria
*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 [51].  Domains assesse d included Selection,
Ascertainment, Causality (excluding items pertaining to alternative causes and dose -response effect), and Reporting.
a. All are cohort studies with no comparison groups.
b. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed.
c. Cannot assess imprecision as these are proportions with no confidence intervals. However, some degree of imprecision shoul d be assumed. Very low denominator count.
d. Studies removed from denominator which included persons with a history of anaphylaxis to egg and reported event(s), but which did not indicate whether these occurred in a person with a
history of anaphylaxis to egg. 4f. Seasonal LAIV, persons with anaphylaxis to egg (2)
73
Appendix 1.  Event Summary: Death
Author
Publication yearAge N egg allergic N anaphylaxis to egg Events
No studies reported this outcome.
74
Appendix 2. Event Summary: Anaphylaxis
Author
Publication yearAge N egg allergic N anaphylaxis to egg Events
No studies reported this outcome.
75
Appendix 3. Event Summary: Hospitalization
Author
Publication yearAge N egg allergic N anaphylaxis to egg Events
No studies reported this outcome.
76
Appendix 4. Event Summary: Outpatient/Emergency Care (1)
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
eggEvents
Esposito 2008 Mean 6.03 +/ -3.33 Seasonal
virosomal44 11 •1 bronchospasm in mildly
allergic child, treated with
bronchodilator and
steroid.
James 1998 Mean 6.25
(10mos -16.5 years)Seasonal IIV 83 27 •1 delayed (>1 hour post -
vaccination) emesis, mild
cough, wheeze treated
with nebulizer.*
•1 delayed (>1 hour post -
vaccination) erythema at
injection site treated.*
*Uncertain whether occurred in individual with anaphylaxis to egg.
77
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Forsdahl 2012 Mean 6.25 yrs
(10 mos -16.5 yrs)Monovalent IIV 80 19 •1 wheal on lip, diffuse
rash, and loose stools a
few minutes after 90%
step; treated with
antihistamine.
Gagnon 2010 -1 173 <2 yrs
280 2 -4 yrs
277 5 -11 yrs
100 ≥12 yrsMonovalent IIV 830 - •1 wheeze treated with
bronchodilator.
•1 hives treated with
antihistamines
•1 ocular pruritis treated
with antihistamines
•1 angioedema treated
with antihistamines.Appendix 4. Event Summary: Outpatient/Emergency Care (2)
78
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Gagnon 2010 -2 Not provided Monovalent IIV 3460 - •1 mouth/throat tingling 10 -15 min
post -vaccination; received two
doses epinephrine and observed in
emergency department; recovered.
•1 continuous crying with wheezing
30 min post -vaccination.  Received
epinephrine and bronchodilator (6
treatments), observed 4 hours,
recovered.
•66 skin and respiratory symptoms,
treated with antihistamines
•42 with skin involvement
•17 with throat
tingling/tightening
•7 with cough (4 also treated
with bronchodilator)Appendix 4. Event Summary: Outpatient/Emergency Care (3)
79
Author
Publication yearAge Vaccine N egg
allergicN anaphylaxis to
egg/severe allergyEvents
Schuler 2011 Mean 4.5 yrs
(10 mos -16 yrs)Monovalent IIV 62 - •1 vasovagal response requiring
symptomatic management.
•1 hyporesponsive episode;
referred to emergency
department.
•2 hives treated with
antihistamines.Appendix 4. Event Summary: Outpatient/Emergency Care (4)
80
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis
to egg/severe
allergyEvents
Erlewyn -
Lajeunesse 2010 Children Seasonal IIV 16 doses 4 •1 instance subjective wheeze*
Esposito 2008 Mean 6.03 +/ -3.33 Seasonal IIV 44 11 •1 instance bronchospasm in mildly
allergic child, treated with
bronchodilator and steroid.
James 1998 Mean 6.25
(10mos -16.5 years)Seasonal IIV 83 27 •1 with mild throat itching, cough,
and wheeze.*
•1 delayed (>1 hour post -vaccination)
emesis, mild cough, wheeze treated
with nebulizer.*
•1 mild URI symptoms.*
*Uncertain whether occurred in individual with anaphylaxis to egg.Appendix 5.  Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (1)
81
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Forsdahl 2012 Mean 6.25 yrs
(10 mos -16.5 yrs)Monovalent IIV 80 19 •1 sneezing without
bronchospasm.
Gagnon 2010 -1 173 <2 yrs
280 2 -4 yrs
277 5 -11 yrs
100 ≥12 yrsMonovalent IIV 830 - •1 sensation of throat
closure
•1 hoarse voice
•1 angioedema
•1 bilateral wheeze
•2 generalized urticariaAppendix 5.  Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (2)
82
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Gagnon 2010 -2 Not provided Monovalent IIV 3460 - •1 mouth/throat tingling 10 -15
min post -vaccination;
received two doses
epinephrine and observed in
emergency department;
recovered.
•1 continuous crying with
wheezing 30 min post -
vaccination.  Received
epinephrine and
bronchodilator (6 treatments),
observed 4 hours, recovered.
•17 with throat
tingling/tightening
•7 with cough (4 also treated
with bronchodilator)Appendix 5.  Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (3)
83
Author
Publication yearAge Vaccine N egg allergic N anaphylaxis to
egg/severe allergyEvents
Turner 2015a Median 4.9 yrs
(2-17 yrs)LAIV3 282 115 •6 rhinitis within 30 min post -
vaccination.
Turner 2015b Median 5.3 yrs
(2-18 yrs)LAIV4 779 157 •4 rhinitis within 2 hours post -
vaccination.Appendix 5.  Event Summary: Cardiovascular, Respiratory, Angioedema, or
Generalized Urticaria (4)
84
Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty
Death Critical Yes Very low
Anaphylaxis Critical Yes Very low
Allergic reaction symptoms requiring hospitalization Critical Yes Very low
Allergic reaction symptoms requiring outpatient or
emergency department medical attentionImportant Yes Very low
Allergic reaction including cardiovascular symptoms,
respiratory symptoms, angioedema, or generalized
urticariaImportant Yes Very low
85
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18. Halsey, N.A., et al., Immediate hypersensitivity reactions following monovalent 2009 pandemic influenza A (H1N1) vaccines : Reports to VAERS. Vaccine, 2013. 31(51): p.
6107 -6112.
19. Hotte SL. A 6 -year Experience with Influenza Vaccination in Egg Allergic Patients. J Allerg Clin Immunol 2008;121:s239.
20. Howe, L.E., et al., Safe administration of seasonal influenza vaccine to children with egg allergy of all severities. Ann alsof Allergy, Asthma, & Immunology, 2011. 106(5): p.
446-7.
21. James, J.M., et al., Safe administration of influenza vaccine to patients with egg allergy. Journal of Pediatrics, 1998. 133(5): p. 624 -8.
22. Kawahara, H., et al., [Immediate adverse reactions after administration of the influenza vaccine to patients with positiv e CAP-RAST to egg white]. Arerugi -Japanese
Journal of Allergology, 2002. 51(7): p. 559 -64.
23. Kawahara, H., et al., [Safe administration of influenza vaccine in asthmatic children]. Arerugi -Japanese Journal of Allergology, 1998. 47(7): p. 679 -86.
24. Khan, F.S., et al., Influenza vaccine administration in egg allergic children. Journal of Allergy and Clinical Immunology , 2012. 1): p. AB70.
25. Kletz , M.R., et al., Administration of egg -derived vaccines in patients with history of egg sensitivity. Annals of Allergy, 1990. 64( 6): p. 527 -9.
26. Leo, S.H., J. Dean, and E.S. Chan, Safety of H1N1 and seasonal influenza vaccines in egg allergic patients in British Col umb ia. Allergy, Asthma and Clinical Immunology.
Conference: Canadian Society of Allergy and Clinical Immunology Annual Scientific Meeting, 2010. 6(SUPPL. 2).
27. Murad, M.H., et al., Methodological quality and synthesis of case series and case reports. BMJ Evid Based Med, 2018. 23(2 ): p. 60 -63.
28. Murphy, K.R. and R.C. Strunk, Safe administration of influenza vaccine in asthmatic children hypersensitive to egg protei ns.Journal of Pediatrics, 1985. 106(6): p. 931 -3.
29. Nickolls , C., et al., The safety of H1N1/seasonal influenza vaccination in egg allergic children -A prospective study. Internal Medicin e Journal, 2010. 4): p. 16.
30. Owens, G. and A. MacGinnitie , Higher -ovalbumin -content influenza vaccines are well tolerated in children with egg allergy. Journal of Allergy & Clinical Imm unology, 2011.
127(1): p. 264 -5.
31. Park, A., et al. Administration of influenza vaccine to patients with egg allergy. J Allergy Clin Immunol , 2008 (Februar y).p. S240.
32. Paschall, V.L., et al., Do egg -specific IgElevels predict reactions to seasonal influenza or H1N1 vaccination? Journal of Allergy and Clinical Immunology, 2011. 1): p. AB182.
33. Pien , G.C., et al., Coordination of multidisciplinary resources for vaccination of egg -allergic individuals during an H1N1 (novel) i nfluenza pandemic. Allergy & Asthma
Proceedings, 2010. 31(6): p. 507 -10.
34. Pitt, T., et al., Assessment of epicutaneous testing of a monovalent Influenza A (H1N1) 2009 vaccine in egg allergic patients. Allergy, Asthma, & Clinical Immunology :
Official Journal of the Canadian Society of Allergy & Clinical Immunology, 2011. 7(1): p. 3.
35. Schuler, J.E., et al., Administration of the adjuvanted pH1N1 vaccine in egg -allergic children at high risk for influenza A/ H1N1 disease. Can J Public Health, 2011. 102(3): p.
196-9.
36. Seyerle , J., R. Scherzer, and E.A. Erwin, Testing and administration of seasonal and pandemic influenza vaccines in egg allergic pat ients. Annals of Allergy, Asthma and
Immunology, 2010. 105 (5): p. A109.
37. Shimizu, M., et al., [Safety of Influenza Vaccination in Children with Severe Allergy to Hen's Eggs: A Prospective Case S eries Study]. Arerugi -Japanese Journal of
Allergology, 2016. 65(2): p. 128 -33.
38. Siret -Alatrista , A., et al., The 2009 -2010 H1N1 vaccination campaign for patients with egg allergy in a region of France. Allergy, 2011. 66(2): p. 298 -9.
39. Spiegel, W. and R. Anolik , Administration of H1N1 vaccine in an eggallergic population. Annals of Allergy, Asthma and Immunology, 2010. 105 (5): p. A4.
40. Thanik , E.S., A.L. Cox, and H.A. Sampson, Administration of a low egg -containing influenza vaccine [ fluarix ] in an egg -alphallergic pediatric population. Journal of Allergy
and Clinical Immunology, 2010. 1): p. AB25.
41. Tounian , P ., et al., [Vaccinations of children allergic to eggs with vaccine prepared with egg]. Archives Francaises de Pediatrie , 1993. 50(3): p. 191 -5.
42. Tozandehjani , S., et al., Safety of Inactivated Influenza Vaccine in Patients with Egg Allergy in Kurdistan Province, Iran. Iranian Journ al of Public Health, 2019. 48(4): p. 758 -
763.
43. Turner, P .J., et al., Safety of live attenuated influenza vaccine in atopic children with egg allergy. Journal of Allergy & Clinical Immunology, 2015. 136(2): p. 376 -81.
44. Turner, P .J., et al., Safety of live attenuated influenza vaccine in young people with egg allergy: multicentre prospective cohort study. BMJ, 2015. 351: p. h6291.
45. Upton, J.E., et al., No systemic reactions to influenza vaccination in egg -sensitized tertiary -care pediatric patients. Alle rgy, Asthma, & Clinical Immunology : Official Journal
of the Canadian Society of Allergy & Clinical Immunology, 2012. 8: p. 2.
46. Webb, L., et al., Single -dose influenza vaccination of patients with egg allergy in a multicenter study. Journal of Allergy & Clinical Immunology, 2011. 128(1): p. 218 -9.
47. Woo, E.J., Allergic reactions after egg -free recombinant influenza vaccine: reports to the US Vaccine Adverse Event Reportin g System. Clinical Infectious Diseases, 2015.
60(5): p. 777 -80.
48. Woo, E.J., et al., Postmarketing safety surveillance of trivalent recombinant influenza vaccine: Reports to the Vaccine Adverse Event Reporting System. Vaccin e,2017.
35(42): p. 5618 -5621.
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY:  1 -888-232-6348    www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.

Summary: National Center for Immunization & Respiratory Diseases Influenza Vaccination of Persons with Egg Allergy: Evidence to Recommendations Discussion and Work Group Considerations Lenee H. Blanton Lisa A. Grohskopf Influenza Division, CDC/NCIRD Advisory Committee on Immunization Practices June 21, 2023 •Donna Hummell •Karen Broder •Pedro Moro •Geta Aynalem •Shashi Sharma •Elaine Miller •Andrew Leidner •Rebecca Morgan •Doug Campos -OutcaltAcknowledgements 2 Background •Affects approximately 1 -3%…


03 influenza grohskopf 508

National Center for Immunization & Respiratory Diseases
Influenza Vaccine Safety Update and
Proposed Recommendations for the 2023 -24 Influenza Season
Lisa A. Grohskopf
Influenza Division, CDC/NCIRD
Advisory Committee on Immunization Practices
June 21, 2023
Influenza Division
•Lenee Blanton
•Jill Ferdinands
•Lindsay Trujillo
•Lynette Brammer
•Alicia Budd
•Jessie Chung
•Brendan Flannery
•Sinead Morris
•Samantha Olson
•Sascha Ellington
•Carrie Reed
•Mark Tenforde
•Tim UyekiImmunization Safety Office
•Geta Aynalem
•Karen Broder
•Pedro Moro
•Elaine Miller
•Shashi Sharma
•David Shay
•Tom Shimabukuro
Immunization Services Division
•Andrew Kroger
CDC Library
•Joanna TalianoCISA
•Donna HummellAcknowledgements
Influenza Vaccine Safety Update
Vaccine Safety Update: 2022 -2023 Influenza Season
▪~173 million doses of influenza vaccine distributed in United States*
▪Vaccine Adverse Event Reporting System (VAERS) (co-managed by CDC and FDA)
•No new safety concerns identified for influenza vaccines
▪Vaccine Safety Datalink (VSD) (collaboration between CDC and 9 integrated healthcare
organizations)
•~5.5 million doses of influenza vaccine administered in VSD
•No new safety concerns identified in influenza vaccine monitoring**
•Statistical signal for ischemic stroke after Pfizer -BioNTech bivalent mRNA COVID -19 vaccine in persons
aged ≥65 years detected in VSD analysis for COVID -19 vaccine safety monitoring, previously presented
to ACIP***
•Post -signal analysis in VSD found an elevated rate ratio for ischemic stroke after simultaneous vaccination with
Pfizer -BioNTech bivalent mRNA COVID -19 vaccine and high -dose or adjuvanted influenza vaccine, which has
attenuated over time
•Separate analyses did not detect an elevated rate ratio for ischemic stroke after influenza vaccine administered
without bivalent mRNA COVID -19 vaccine
4* Weekly Flu Vaccination Dashboard | FluVaxView | Seasonal Influenza (Flu) | CDC
** Outcomes monitored in VSD: acute disseminated encephalomyelitis, anaphylaxis, Bell’s Palsy, encephalitis, Guillain -Barré syndrome, seizures, transverse myel itis
*** Shimabukuro T, ACIP presentation on April 19, 2023 mRNA COVID -19 bivalent booster vaccine safety update (cdc.gov)
Overview of Proposed Recommendations for
2023 -24
•Vaccination of all persons aged ≥6 months who do not have contraindications
continues to be recommended.
•Recommendations regarding timing of vaccination are unchanged from 2022 -23.
•Changes include:
–Updated U.S. influenza vaccine composition for 2023 -24.
–Proposed changes to the recommendations for vaccination for persons with egg
allergy.Overview of Proposed Recommendations
Timing of Vaccination
•Unchanged from last season.
•For most persons who need only 1 dose of influenza vaccine for the season,
vaccination should ideally be offered during September or October.
•Vaccination should continue after October and throughout the influenza season as
long as influenza viruses are circulating and unexpired vaccine is available.
•Vaccination during July and August are not recommended for most groups.
•Considerations for July and August vaccination are noted for adults, children, and
pregnant persons.Timing of Influenza Vaccination
•For most adults (particularly adults aged ≥65 years) and for pregnant persons in the
first or second trimester, vaccination during July and August should be avoided
unless there is concern that vaccination later in the season might not be possible.Timing of Influenza Vaccination —
Adults and Pregnant Persons in First/Second Trimester
•Children who require 2 doses:
–Should receive their first dose as soon as possible (including during July and
August, if vaccine is available) to allow the second dose (which must be
administered ≥4 weeks later) to be received, ideally, by the end of October.
•Children who require only 1 dose:
–Vaccination during July and August can be considered for children of any age
who need only 1 dose of influenza vaccine for the season . Timing of Influenza Vaccination —
Children
•Vaccination during July and August can be considered because vaccination might
reduce risk for influenza illness in their infants during the first months after birth,
when they are too young to receive influenza vaccine.Timing of Influenza Vaccination —
Pregnant Persons in Third Trimester
Influenza Vaccine Composition for 2023 -24
•All vaccines available in the U.S. are quadrivalent.
•The 2023 -24 composition includes updated influenza A(H1N1)pdm09 components.
•All U.S. -licensed influenza vaccines will include hemagglutinin derived from:
–An influenza A/Victoria/4897/2022 (H1N1)pdm09-like virus (egg-based vaccines)
An influenza A /Wisconsin /67/2022 (H1N1)pdm09 -like virus (cell and recombinant vaccines)
–An influenza A/Darwin/9/2021 (H3N2) -like virus (egg -based vaccines)
An influenza A /Darwin/6/2021 (H3N2) -like virus (cell and recombinant vaccines)
–An influenza B/Austria/1359417/2021 -like virus (B/Victoria lineage)
–An influenza B/Phuket/3073/2013 -like virus (B/Yamagata lineage)U.S. Influenza Vaccine Composition for 2023 -24
Vaccines and Related Biological Products Advisory Committee March 7, 2023 Meeting Announcement -03/07/2023 | FDA
Proposed Recommendations for Vaccination of
Persons with Egg Allergy
•All persons aged ≥6 months with egg allergy should receive influenza vaccine unless a
contraindication exists. Any influenza vaccine that is otherwise appropriate for the recipient’s age and
health status can be used (egg based or non -egg based).
•Egg allergy in and of itself necessitates no additional safety measures for influenza vaccination
beyond those recommended for any recipient of any vaccine, regardless of severity of previous
reaction to egg.
•Severe and life -threatening reactions to vaccines can rarely occur with any vaccine and in any vaccine
recipient, regardless of allergy history. Providers are reminded that all vaccines should be
administered in settings in which personnel and equipment needed for rapid recognition and
treatment of acute hypersensitivity reactions are available.  All vaccination providers should be
familiar with their office emergency plan and be certified in cardiopulmonary resuscitation.Proposed Recommendations for Vaccination of
Persons with Egg Allergy
For more information, contact CDC
1-800-CDC-INFO (232 -4636)
TTY:  1 -888-232-6348    www.cdc.gov
The findings and conclusions in this report are those of the authors and do not necessarily represent the
official position of the Centers for Disease Control and Prevention.

Summary: National Center for Immunization & Respiratory Diseases Influenza Vaccine Safety Update and  Proposed Recommendations for the 2023 -24 Influenza Season Lisa A. Grohskopf Influenza Division, CDC/NCIRD Advisory Committee on Immunization Practices June 21, 2023 Influenza Division •Lenee Blanton •Jill Ferdinands •Lindsay Trujillo •Lynette Brammer •Alicia Budd •Jessie Chung •Brendan Flannery •Sinead Morris •Samantha Olson •Sascha Ellington •Carrie Reed •Mark Tenforde •Tim UyekiImmunization Safety…


01 Pneumococcal Poehling 508

Pneumococcal Vaccines
Katherine A. Poehling, MD, MPH
Pneumococcal Vaccines Work Group Chair
Advisory Committee on Immunization Practices
June 22, 2023
Pneumococcal Vaccines Work Group
ACIP Members
•Katherine Poehling (Chair)
•Sarah Long
Ex Officio Members
•Jeffrey Kelman  (CMS)
•Lucia Lee            (FDA)
•Tina Mongeau   (FDA)
•Uzo Chukwuma (IHS)
•Mamodikoe Makhene (NIH)
CDC Lead
•Miwako Kobayashi (NCIRD)Liaison Representatives and Consultants
•Lynn Fisher                (AAFP)
•Mark Sawyer             (AAP/COID)
•Jason Goldman         (ACP)
•David Nace                (AGS/AMDA)
•Cora Hoover              (AIM)
•Aleksandra Wierzbowski   (NACI)
•James McAuley         (IDSA)
•William Schaffner     (NFID)
•Virginia Caine            (NMA)
•Monica Farley           (VAMC/Emory)
•Keith Klugman          (BMGF)
•Arthur Reingold        (UC Berkley)
•Lorry Rubin                (CCMC)
•Richard Zimmerman (U. of Pittsburgh)
Pneumococcal Vaccines Work Group
CDC Contributors
•Adam Cohen           (Respiratory Diseases Branch)
•Ryan Gierke             (Respiratory Diseases Branch)
•Jennifer Farrar        (Respiratory Diseases Branch)
•Diepreye Ayabina   (Division of Bacterial Diseases)
•Pedro Moro             (Immunization Safety Office)
•Andrew Leidner      (Immunization Services Division)
•Liz Velazquez            (Immunization Services Division)
•Marc Fischer            (Arctic Investigations Program)
•Noele Nelson      (Division of Bacterial Diseases)
GRADE/ EtR consultants
•Doug Campos -Outcalt
•Rebecca Morgan
Serotypes contained in pneumococcal vaccines
Pneumococcal conjugate vaccine s (PCVs): PCV13, PCV15, PCV20
Pneumococcal  polysaccharide vaccine (PPSV): PPSV23
•PCV15 non -PCV13 : serotypes 22F and 33F
•PCV20 non -PCV15 : serotypes 8, 10A, 11A, 12F, and 15B
•PPSV23 non -PCV20 : serotypes 2, 9N, 17F, and 201 3 4 5 6A 6B 7 F 9V 14 18
C19
A19
F23
F22
F33
F8 10
A11
A12
F15
B2 9N 17
F20
PCV13
PCV15
PCV20
PPSV23
4
Extended indication for PCV20 use among children approved on
April 27, 2023
2021 2022 2023
Pediatric  PCV20  use approved
April 2023
Pediatric  PCV15  use approved
June 2022PCV15  and PCV20  approved
for use  in adults in 2021

Both PCV15 and PCV20 were approved based on safety and
immunogenicity data compared with PCV13
•No direct PCV15 vs PCV20 comparison
•Unknown clinical implications:
•Numerically lower antibody responses vs PCV13
•Numerically higher antibody response against serotype 3 in PCV15 vs PCV13
February 2022, 2023 ACIP meeting presentations
All children under age 2 years have the same
pneumococcal vaccine recommendations
•3 primary series and a booster=“3+1” schedule
2 months
PCV4 months
PCV12–15 months
PCV6 months
PCV
Primary Series Booster
Currently, either PCV13  or PCV15  can be used
Children with certain underlying conditions are recommended
to receive PPSV23 in addition to the recommended PCV doses
Use of 15 -Valent Pneumococcal Conjugate Vaccine Among U.S. Children: Updated Recommendations of the Advisory Committee on Immuni zation
Practices — United States, 2022 | MMWR (cdc.gov)PPSV23
PPSV23 PPSV23
≥8 weeks ≥5 years
PPSV23CMC, CSF leak,
cochlear
implant Recommended
PCV doses
≥8 weeks
Immuno-
compromisedRecommended
PCV doses
CMC aged 6 –18
years
Note:  Excludes catch -up vaccination schedules.
CMC=chronic medical conditions, including chronic heart disease, chronic lung disease, diabetes mellitus
CSF=cerebrospinal fluid Recommended
PCV dosesHealthy
children
Current Risk -Based Pneumococcal Vaccine Recommendations
Children Adults
Alcoholism
Chronic heart disease
Chronic lung disease
Chronic liver disease
Cigarette smoking
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Chronic renal failure or nephrotic syndrome
Congenital or acquired asplenia, or splenic
dysfunction
Congenital or acquired immunodeficiency
Diseases and conditions treated with
immunosuppressive drugs or radiation therapy
HIV infection
Sickle cell disease or other hemoglobinopathies
Solid organ transplant•Children: Including asthma if treated with high -dose oral
corticosteroid therapy.
•Adults: Includes chronic obstructive pulmonary disease,
emphysema, and asthma.
→ Should we expand the indication for asthma in children?
Current Risk -Based Pneumococcal Vaccine Recommendations
Children Adults
Alcoholism
Chronic heart disease
Chronic lung disease
Chronic liver disease
Cigarette smoking
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Chronic renal failure or nephrotic syndrome
Congenital or acquired asplenia, or splenic
dysfunction
Congenital or acquired immunodeficiency
Diseases and conditions treated with
immunosuppressive drugs or radiation therapy
HIV infection
Sickle cell disease or other hemoglobinopathies
Solid organ transplantShould we add “chronic liver disease” as part of pediatric
risk-based recommendation?
Current Risk -Based Pneumococcal Vaccine Recommendations
Children Adults
Alcoholism
Chronic heart disease
Chronic lung disease
Chronic liver disease
Cigarette smoking
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Chronic renal failure or nephrotic
syndrome
Congenital or acquired asplenia, or splenic
dysfunction
Congenital or acquired immunodeficiency
Diseases and conditions treated with
immunosuppressive drugs or radiation therapy
HIV infection
Sickle cell disease or other hemoglobinopathies
Solid organ transplantShould we expand the indication to those with stage 2 –5
chronic kidney disease?
Policy questions considered by the Work Group
•Should PCV20  be recommended as an option for pneumococcal
conjugate vaccination according to currently recommended dosing
and schedules, for U.S. children aged <2 years ?
•Should PCV20 without PPSV23 be recommended as an option for
pneumococcal vaccination for U.S. children aged 2 –18 years with
underlying medical conditions that increase the risk of
pneumococcal disease?
Today’s Pneumococcal Vaccines session outline
Introduction Dr. Katherine Poehling
(ACIP, WG Chair)
Economic analysis and public health impact of PCV20
use in childrenDr. Charles Stoecker
(Tulane University)
Comparison of cost -effectiveness analyses on PCV20
use in childrenDr. Ayabina Diepreye
(CDC/NCIRD)
Summary of WG interpretation of EtR and policy
optionsDr. Miwako Kobayashi
(CDC/NCIRD)
VFC resolution Dr. Jeanne Santoli
(CDC/NCIRD)

Summary: Pneumococcal Vaccines Katherine A. Poehling, MD, MPH Pneumococcal Vaccines Work Group Chair Advisory Committee on Immunization Practices June 22, 2023 Pneumococcal Vaccines Work Group ACIP Members •Katherine Poehling (Chair) •Sarah Long  Ex Officio Members •Jeffrey Kelman  (CMS) •Lucia Lee            (FDA) •Tina Mongeau   (FDA) •Uzo Chukwuma (IHS) •Mamodikoe Makhene (NIH) CDC Lead •Miwako Kobayashi (NCIRD)Liaison Representatives and Consultants •Lynn Fisher                (AAFP) •Mark…


02 Pneumococcal Stoecker 508

1E conomic A ssessment of R outine PC V 20 for C hildren
C harles Stoecker
Tulane University
School of Public Health and Tropical Medicine
ACIP
June 22,  2023

2Conflicts of Interest
Dr. Stoecker has no conflicts of interest to declare.
3Acronyms
 PC V :  pneumococcal conjugate vaccine
 PCV 13:  13 valent PCV
 PCV 15:  15 valent PCV
 PCV 20:  20 valent PCV
 PPSV 23:  23 valent pneumococcal polysaccharide vaccine
 V E :  vaccine effectiveness
 V T: vaccine type
 ST: s e r o t yp e
 AOM: acute otitis media
 NBP : n o n -bacteremic  pneumonia
 IPD: invasive p neumococcal disease
 IPT: inp atient
 OPT :  outpatient
 QAL Y : quality adjusted life year
 I C :  immunocompromised
 CMC: chronic medical conditions, b ut not IC
 C PI :  C onsumer price index
 NIS: National Immunization Survey
 ABCs: Active Bacterial Core Surveillance System
4Policy Question 1
Should PCV20 be recommended as an option for
pneumococcal conjugate vaccination according to currently
recommended dosing and schedules, for U.S. children aged
<2 years?
Evaluate the disease and cost impacts of using PCV20 in
place of existing conjugate vaccines in six interventions:
Intervention Comparator Population
P CV2 0 P CV1 3 Healthy
PCV 20+PPSV PCV 13+PPSV CMC
PCV 20+PPSV +PPSV PCV 13+PPSV +PPSV IC
P CV2 0 P CV1 5 Healthy
PCV 20+PPSV PCV 15+PPSV CMC
PCV 20+PPSV +PPSV PCV 15+PPSV +PPSV IC
C onjugate doses are given in a 3+1 schedule (3 doses at age 0,  1 dose at age 1),
PPSV  doses are given at age 2 for CMC &  I C and at age 7 for I C
5Policy Question 2
Should PCV20 without PPSV23 be recommended as an
option for pneumococcal vaccination for U.S. children aged
2–18 years with underlying medical conditions that
increase the risk of pneumococcal disease?
Evaluate the disease and cost impacts of using PCV20 in
place of existing schedules that include conjugate and
polysaccharide in six interventions:
Intervention Comparator Population
P CV2 0 PCV 13+PPSV CMC
P CV2 0 PCV 13+PPSV +PPSV IC
P CV2 0 PCV 15+PPSV CMC
P CV2 0 PCV 15+PPSV +PPSV IC
PCV 20+PPSV P CV2 0 CMC
PCV 20+PPSV +PPSV P CV2 0 IC
C onjugate doses are given in a 3+1 schedule (3 doses at age 0,  1 dose at age 1),
PPSV  doses are given at age 2 for CMC &  I C and at age 7 for I C
6Methods
Cohort model
United States birth cohort 3,939,295
•91.1% healthy a
•8.8% CMC a
•0.1% IC a
•Background mortality rates from National Center for Health Statistics
Vital Statistics
Societal p ersp ective
•Medical & nonmedical (work loss) costs
A ll future outcomes (health &  cost) discounted at 3%
Costs inflated to 2022$ by CPI or CPI Medical Care
Disease incidence followed for 15 years after final PCV20 shot
•Direct & indirect protection followed over this cohort
•QA L Y  losses from death and permanent disease states aggregated over the lifetime
a Pelton 2014.  T ables 1 &  2.
7Outcomes
IPD cases (meningitis & other)
Meningitis sequelae (deafness & other disability)
Non-invasive pneumonia (inpatient & outpatient)
Otitis media & tympanostomy tube placement
Deaths
QALYs & life years
Costs
Cost/QALY
8Complete Series PCV Vaccine Effectiveness
VE Reference
VT IPD (e xce p t  ST3, ST19F) 86 (76,  92) Moore 2016
ST3 IPD 26 (0, 68) Andrews 2014
ST19F IPD 75 (37, 90) Andrews 2014
VT NBP (except ST3, ST19F) 51.6 (45.6, 55.2) b
ST3 NBP 15.6 (0, 40.8) b
ST19F NBP 45 (22.2, 54) b
VT AOM (except ST3, ST19F) 54 (41, 64) Eskola  2001
ST3 AOM 16.3 (12.4, 19.3) c
ST19F AOM 47.1 (35.8, 55.8) d
Note:  T he displayed V E  values apply only after receipt of 4th dose.   V E  during the 1st year (age 0 -1) is 75.7% of these numbers.
(A dapted from Whitney et al.   2006)
b A pplied ratio of V E  for NB P to V E  for I PD for adults from C A PI T A  study to pediatric V E s vs I PD above
c Ap p lied ratio of p ediatric ST3 IPD to other VT IPD ab ove to Esko la  estimate for V T  A OM
d Ap p lied ratio of p ediatric ST19F IPD to other VT IPD ab ove to Esko la  estimate for V T  A OM
9PPSV Vaccine Effectiveness
VE Source
VT IP D 59.7 (47.4,  69.1)Falkenhorst  2017 &
Thorrington  2018
VT NBP 20 (0, 40) ACIP WG Discussion
VT AOM 0 ACIP WG Discussion
10Indirect Effects
Effects on other children
A pply to unvaccinated children and children whose vaccination protection is not
100% (i.e., all children)
A pply to PC V 20 unique types only
R emove 7.8% of disease each year
Effects on adults
For childhood cohort model, modeled effects on all U.S. adults (258 million)
U sed inputs from our model previously used to analyze PC V 20 effects on adults
Modeled 1 year of impacts on adults for this childhood cohort
•2nd year of impacts on adults would be influenced by 2nd childhood cohort,  etc.
U sed output from previously used C DC  Win BUGS  model that shows each childhood
cohort responsible for 4.12% decline in previous year’ s disease on average
•W e modified this 4.17% to account for an anticipated 15 years of use to arrive at an average of 3.12%
disease reduction per childhood cohort
I ndirect effects from adults (QA L Y s and cost savings) were then apportioned to
each risk status of children according to their contribution to total QA L Y s saved.
•If vaccinating healthy children was resp onsib le for 50% of total QAL Ys saved among
children,  then 50% of cost and QA L Y  savings from adults were allocated to the healthy
group.
11Other Vaccine Assumptions
Coverage
3-dose PC V  series (completed by 13 months,  applied to 1st year)
•94.2% (93.6, 94.8)  Hill MMWR 2023
4-dose PC V  series
•81.9% (80.9,  82.2) Hill MMWR  2023
1st d o se  PPSV (CMC & IC)
•78.1%
2nd d ose PPSV (IC)
•64.0%
Waning
P C V: Ye a r s  0 -5 get full VE
•Waning linearly to 0% over next 10 years
PPSV : Wane linearly to 50% in first 5 years
•W ane linearly to 30% in next 5
•W ane to 0% in last 5 years
Adverse events
A ll vaccines were assumed to have no adverse events
12AOM Incidence
Ag e 0 1 2 3 4
All cause AOM visits,
   healthy (p er 1k) a507
(358,701 )507
(358,701 )319
(229,435)319
(229,435)319
(229,435)
All cause AOM visits,
   CMC/ IC (p e r 1k) b1533
(1083,2117)1533
(1083,2117)686
(491,936)686
(491,936)686
(491,936)
% of A OM  with tympanostomy
tube insertion c12% (6- 15) 12% (6- 15) 8% (4 -15)8% (4 -15)8% (4 -15)
% pneumococcal A OM  d 14.0% 14.0% 16.0% 16.0% 16.0%
Note:   No A OM  incidence assumed for ages 5+.a overall numb ers from National Amb ulatory Medical Survey/National Hosp ital Amb ulatory Medical Care Survey+Market  Scan data
2016+2018,b Market Scan Data 2016 -2018
c Pichichero  et al.   2013
d K aur et al.   2022
13NBP Incidence
Age 0 1 2 3 4 5 6 7 8 9+
OPT  NB P ,  healthy (per
100k) a640
(594,686)1291
(1192,1386)1512
(1368,1658)785
(715,859)639
(583,693)678
(618,733)575
(524,622)711
(626,800)357
(323,391)319
(294,345)
OPT NBP, CMC/ IC (p e r 100k)
b9249
(56388,
65090)18656
(113162,
131601)14881
(74090,
89811)7728
(38714,
46492)6294
(31556,
37506)5060
(21862,
25905)4296
(18546,
21986)5308
(22121,
28290)2664
(11413,
13815)2384
(10384,
12189)
% pneumococcal c 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10) 6% (1 -10)
I PT  NB P ,  healthy (per 100k)
d588
(546,630)417
(385,448)390
(353,427)202
(184,221)165
(150,179)121
(111,131) 103 (94,112)127
(112,143) 64 (58,70) 57 (52,61)
IPT NBP, CMC (p e r 100k)
e
1642
(1524,1759)1164
(1075,1250)1087
(984,1193)564
(514,617)461
(420,499)544
(496,588)462
(422,500)568
(500,639)286
(258,313)255
(235,275)
IPT  NB P ,  IC (per 100k)
e
3283
(3048,3518)2328
(2150,2501)2174
(1968,2386)1128
(1027,1234)922
(840,998)1328
(1212,1436)1129
(1029,1220)1386
(1220,1560)697
(631,764)623
(573,672)
% IPT NPB fatality d
1.3% (1.02 -
1.59)0.53%
(0.37- 0.70)0.40%
(0.23- 0.58)0.42%
(0.21- 0.64)0.61%
(0.32- 0.91)0.39%
(0.15- 0.63)0.32%
(0.06- 0.59)0.78%
(0.35- 1.20)0.51%
(0.13- 0.89)1.72%
(1.42- 2.01)
% pneumococcal c 12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)12% (2- 20)
a overall mean from Tong et al. 2018, 5th & 9 5th p ercentiles calculated using the ratio of 5th & 9 5th to mean in I PT  NB P for each age; adjusted by (1 -% CMC+IC p o p  * CMC+IC
ratio)/% healthy pop;  C MC +I C  ratio from MarketScan  2016 -2018
b based on Tong et al. 2018, but scaled by age -sp ecific ratios of CMC+IC to healthy calculated from MarketScan  2016 -2018
c A dapted from Jain et al. 2015 with expert input.d Overall numbers from 2018 -2019 NIS Data, scaled by (1 -(% IC p o p  * IC ratio  + % CMC p o p  * CMC ratio )) /  % h e alth y p o p , ratio s f o r IC an d  CMC fro m  Pe lto n  e t al. 2014
e Overall numbers from 2018 -2019 NI S Data, scaled by rate ratios for health: CMC:I C from Pelton et al. 2014
14IPD Incidence
Ag e 0 1 2 3 4 5 6 7 8 9+
IPD In cid e n ce ,
healthy (per 100k)
a14 (11, 16) 10 (7, 12) 5 (3, 6) 5 (3, 6) 3 (2, 4) 5 (3, 6) 3 (1, 4) 2 (1, 3) 1 (0, 2) 1 (1, 1)
IPD In cid e n ce , CMC (p e r 100k)
a24 (20,29) 18 (13,22) 8 (5,11) 9 (5,11) 6 (4,7) 15 (10,20) 9 (3,13) 7 (3,10) 5 (0,7) 3 (3,3)
IPD In cid e n ce , IC (per 100k)
a152
(123,179)112
(78,134)51
(34,67)54
(34,67)34
(22,45)182
(120,241)112
(40,160)81
(40,120)56
(0,80)40
(40,40)
% meningitis a15.87
(14.45,17.43)15.87
(14.45,17.43)15.87
(14.45,17.43)15.87
(14.45,17.43)15.87
(14.45,17.43)20.05
(18,22.33)20.05
(18,22.33)20.05
(18,22.33)20.05
(18,22.33)20.05
(18,22.33)
% meningitis resulting in fatality
a10.48
(7.85,13.99)10.48
(7.85,13.99)10.48
(7.85,13.99)10.48
(7.85,13.99)10.48
(7.85,13.99)0.00% 0.00% 0.00% 0.00% 0.00%
% o t h e r IPD resulting in fatality
a3.61
(2.92,4.47)3.61
(2.92,4.47)3.61
(2.92,4.47)3.61
(2.92,4.47)3.61
(2.92,4.47)3.83
(2.93,5.02)3.83
(2.93,5.02)3.83
(2.93,5.02)3.83
(2.93,5.02)3.83
(2.93,5.02)
a AB C’ s data 2018- 2019.
b Olarte  et al.  2015;  E dmond et al.  2010Ag e 0-4 5+
Disability % b 7 (4,  11) 11 (8, 18)
Deafness % b 9 (7,  13) 14 (11, 22)Meningitis Sequelae
15IPD/NBP Serotype Distributions
Ag e 0 1 2 to 5 6+
% PCV 13 (+6C -3-19F) 3.68% 1.23% 9.76% 10.64%
% ST3 11.90% 3.68% 10.93% 14.22%
% ST19F 7.35% 7.37% 5.65% 9.17%
% PCV 15 only (ST 22F ,  33F) 17.41% 21.01% 14.97% 14.14%
% PCV20 only 12.86% 19.78% 11.45% 13.52%
% PPSV23 only 1.84% 1.23% 0.73% 5.83%
% PCV 13 (+6C -3-19F) 3.06%
% ST3 3.06%
% ST19F 3.06%
% PCV 15 only (ST 22F ,  33F) 8.16%
% PCV20 only (ST 8, 10A, 11A,
12F, 15B)23.47%AOM Serotype Distributions
IPD serotype distributions from AB Cs data 2018 -2019.   Applied to NB P by assumption.
AOM serotyp e distrib utions from Kaur et al. 2022 modified by exp ert inp ut.
16Vaccine Prices
PCV 13 Private $226.43 CDC Price Listb
PCV13 Pub lic $158.18 CDC Price List
PCV 15 Private $216.086 CDC Price Listb
PCV15 Pub lic $162.27 CDC Price List
PCV20 Private $253.96 a
PCV20 Public $187.27 a
PPSV23 Private $117.08 CDC Price Listb
PPSV23 Public $65.80 CDC Price List
V accine Admin $30.13 Tsai Prev  Med Reports 2019
Travel/Caregiver Time $35.96 Maciosek  Am J Prev  Med 2006
a Ratio of PCV20:PCV15 cost in adults sep arately for p ub lic and p rivate from CDC Price list and ap p lied to PCV15 costs in childr e n .
E stimation procedure discussed with manufacturer.
b Private list price inflated 7.1% to account for differences between C DC  private list price and average reimbursement (L eidn er e t  a l.
2021)
17Disease Cost ($)
Medical cost aNon-medical
cost b, c
Disability $258,084 ($206,467,  $309,701) $1,413,847
Deafness $48,354 ($38,683,  $58,025) $583,399
AOM $83 ($67,  $100) $253
Tym p  tube $3,610 ($2,888,  $4,332) $253
IPD $19,196 ($15,357,  $23,035) $624
IPD-mening $25,691 ($20,553,  $30,829) $3,273
IPT NBP $10,965 ($8,772,  $13,158) $624
OPT NBP $351 ($281,  $421) $467
a Medical costs are from MarketScan  2004- 2006 data inflated to 2022$ using Medical component of CPI.   R anges +/ - 20%.
b Disability &  deafness:  MMWR  53(03);57- 59 and Errata. E.g.: assistive devices, home modifications, sp ecial education costs,
p roductivity losses, etc.
c Other conditions:  R ay et al.  2006 PIDJ
18QALY Decrements
AOM 0.0016 (0,  0.0155)
Tym p  tube 0.0016 (0,  0.0155)
OPT NBP 0.0004 (0.0001,  0.0329)
IPT disease (not mening ) 0.0105 (0.0001,  0.0155)
IPD mening  no sequelae 0.0165 (0.0001,  0.0166)
Deafness 0.2137 (0.07,  0.72)
Disability 0.2456 (0.16,  0.49)
QA L Y  decrement are low,  median,  and high estimates from the survey by T ang et al.  2021.  T he upper bound of A OM  is capped at t he
upper bound of inpatient disease.  T ympanostomy tube placement which follows Delgleize  et al. 2016 in setting equal to AOM.
QA L Y  decrements are scaled by background QA L Y  values which range from 0.94 for age 0 to 0.92 for age 15 (E rickson et al.  Stat istical
Notes 1995)
19Indirect Effects from Adult Program
Ba s e
(indirect rate =
3.17%)10% less effective
(indirect rate =
2.853%)Same effect as on
kids
(indirect rate = 7.8%)
Health Outcomes
IPD ca se s -182 -164 -447
I PT  pneumonia cases -3,210 -2,889 -7,899
OPT  pneumonia Cases -7,335 -6,601 -18,048
Deaths due to I PD -24 -21 -59
Deaths due to pneumonia -127 -115 -314
Q A LYs 1,262 1,136 3,105
Life-years 1,849 1,664 4,549
Costs (million $)
T otal cost -$80 -$72 -$197
Medical costs -$80 -$72 -$197
V accine costs $0 $0 $0
20Policy Questions
1.PCV20 in place of existing conjugate vaccines among
all risk groups.
2.PCV20 in place of existing schedules that include
conjugate and polysaccharide among CMC & IC
populations
21Direct Swap PCV20 for PCV13
PCV 20 vs PCV 13PCV 20+PPSV  vs
PCV 13+PPSVPCV 20+PPSV +PPSV  vs
PCV 13+PPSV +PPSV
Healthy CMC IC
IPD meningitis cases -55 -8 -1
IPD n o n -meningitis cases -276 -40 -3
Deafness -4 -1 0
Disab ility -6 -1 0
I PT  pneumonia cases -1,106 -277 -7
OPT  pneumonia cases -1,798 -1,552 -18
AOM ca s e s -145,371 -36,645 -444
Ty m p  tubes -14,647 -3,815 -46
Deaths due to I PD -14 -2 0
Deaths due to pneumonia -8 -2 0
Childhood QAL Ys 917 190 7
Adult QAL Ys (indirect) 1,039 215 8
Life-years 685 128 7
Costs (million $)
T otal cost $153 -$17 -$0.92
Medical costs -$108 -$27 -$0.56
Non-medical costs -$52 -$13 -$0.27
Adult costs (indirect) -$66 -$14 -$0.53
V accine costs $379 $37 $0.44
Cost ratios ($)
C o s t / Q A LY 78,115 Cost-saving Cost-saving
Cost/life -year 223,192 Cost-saving Cost-savingPolicy Question 1
22Direct Swap PCV20 for PCV15
PCV 20 vs PCV 15
HealthyPCV 20+PPSV  vs
PCV 15+PPSV
CMCPCV 20+PPSV +PPSV  vs
PCV 15+PPSV +PPSV
IC
IPD menigitis  cases -25 -4 0
IPD n o n -meningitis cases -125 -18 -2
Deafness -2 0 0
Disab ility -3 0 0
I PT  pneumonia cases -500 -126 -3
OPT  pneumonia cases -824 -716 -8
AOM ca s e s -107,856 -27,188 -329
Ty m p  tubes -10,867 -2,830 -34
Deaths due to I PD -7 -1 0
Deaths due to pneumonia -4 -1 0
Childhood QAL Ys 488 104 4
Adult QAL Ys (indirect) 1,033 221 8
Life-years 308 58 3
Costs (million $)
T otal cost $234 -$1 -$0.48
Medical costs -$68 -$17 -$0.32
Non-medical costs -$35 -$9 -$0.16
Adult costs (indirect) -$65 -$14 -$0.48
V accine costs $402 $39 $0.47
Cost ratios ($)
C o s t / Q A LY 153,715 Cost-saving Cost-saving
Cost/life -year 757,901 Cost-saving Cost-savingPolicy Question 1
23Direct Swap PCV20 for PCV15
Sensitivity Analysis: PCV20 VE 10% Lower
PCV 20 vs PCV 15 PCV 20+PPSV  vs
PCV 15+PPSV  PCV 20+PPSV +PPSV  vs
PCV 15+PPSV +PPSV
Healthy CMC IC
IPD meningitis cases -16 -2 0
IPD n o n -meningitis cases -82 -10 -1
Deafness -1 0 0
Disab ility -2 0 0
IPT pneumonia cases -392 -95 -2
OPT pneumonia cases -651 -542 -6
AOM cases -85,628 -21,597 -262
Ty m p  tubes -8,633 -2,250 -27
Deaths due to I PD -4 -1 0
Deaths due to pneumonia -3 -1 0
Childhood QAL Ys 360 76 2
Adult QAL Ys (indirect) 933 197 6
Life-years 216 39 2
Costs (million $)
T otal cost $263 $6 -$0.22
Medical costs -$53 -$13 -$0.22
Non-medical costs -$27 -$7 -$0.11
Adult costs (indirect) -$59 -$12 -$0.36
V accine costs $402 $39 $0.47
Cost ratios ($)
C o s t / Q A LY 203,365 23,832 Cost-saving
Cost/life -year 1,216,977 168,181 Cost-savingPolicy Question 1
24Direct Swap PCV20 for PCV15
Sensitivity Analysis: Adult Indirect Effects 7.8%
PCV 20 vs PCV 15 PCV 20+PPSV  vs
PCV 15+PPSV  PCV 20+PPSV +PPSV  vs
PCV 15+PPSV +PPSV
Healthy CMC IC
IPD meningitis cases -25 -4 0
IPD n o n -meningitis cases -125 -18 -2
Deafness -2 0 0
Disab ility -3 0 0
IPT pneumonia cases -500 -126 -3
OPT pneumonia cases -824 -716 -8
AOM cases -107,856 -27,188 -329
Ty m p  tubes -10,867 -2,830 -34
Deaths due to I PD -7 -1 0
Deaths due to pneumonia -4 -1 0
Childhood QAL Ys 488 104 4
Adult QAL Ys (indirect) 2,542 545 19
Life-years 308 58 3
Costs (million $)
T otal cost $138 -$21 -$1.18
Medical costs -$68 -$17 -$0.32
Non-medical costs -$35 -$9 -$0.16
Adult costs (indirect) -$161 -$35 -$1.17
V accine costs $402 $39 $0.47
Cost ratios ($)
C o s t / Q A LY 45,551 Cost-saving Cost-saving
Cost/life -year 447,389 Cost-saving Cost-savingPolicy Question 1
25Direct Swap PCV20 for PCV15, Healthy
Multivariate Sensitivity, 90% Confidence Interval
PCV 20 vs PCV 15 5th 95th
Healthy Healthy Healthy
IPD meningitis cases -25 -28 -21
IPD n o n -meningitis cases -125 -135 -104
Deafness -2 -3 -1
Disab ility -3 -4 -2
IPT pneumonia cases -500 -829 -82
OPT pneumonia cases -824 -1,363 -136
AOM cases -107,856 -130,202 -87,612
Ty m p  tubes -10,867 -14,286 -7,866
Deaths due to I PD -7 -8 -5
Deaths due to pneumonia -4 -6 -1
Childhood QAL Ys 488 362 1,263
Adult QAL Ys (indirect) 1,033 402 2,541
Life-years 308 206 388
Costs (million $)
T otal cost $234 $135 $279
Medical costs -$68 -$85 -$49
Non-medical costs -$35 -$42 -$30
Adult costs (indirect) -$65 -$162 -$24
V accine costs $402 $401 $404
Cost ratios ($)
C o s t / Q A LY 153,715 51,105 210,518
Cost/life -year 757,901 409,958 1,144,176Policy Question 1
26Direct Swap PCV20 for PCV15, Healthy
One-way Sensitivity
Influential Inputs on Cost/QALY
All inp uts were included in multivariate sensitivity analysis.  The top  5 according to size of change in cost p er QAL Y are ch arted
here.   E nds of bars represent the cost/QA L Y  when the particular input is set to the min/max (or 5th & 9 5th) of the input
distrib ution. $-  $50,000  $100,000  $150,000  $200,000  $250,000  $300,000  $350,000  $400,000VE PCV vs AoM !ST3 !ST19IPT NBP due to pneumococcusAoM QALY DecrementIndirect Adult CostsIndirect Adult QALYsPolicy Question 1
27PCV20 without PPSV23, PCV13 Context
PCV 20 vs PCV 13+PPSV PCV 20 vs PCV 13+PPSV +PPSV
CMC IC
IPD meningitis cases -7 -1
IPD n o n -meningitis cases -35 -3
Deafness -1 0
Disab ility -1 0
I PT  pneumonia cases -267 -6
OPT  pneumonia cases -1,497 -17
AOM ca s e s -36,645 -444
Ty m p  tubes -3,815 -46
Deaths due to I PD -2 0
Deaths due to pneumonia -2 0
Childhood QAL Ys 180 6
Adult QAL Ys (indirect) 204 7
Life-years 118 6
Costs (million $)
T otal cost -$55 -$1.57
Medical costs -$27 -$0.51
Non-medical costs -$12 -$0.24
Adult costs (indirect) -$13 -$0.45
V accine costs -$3 -$0.38
Cost ratios ($)
C o s t / Q A LY Cost-saving Cost-saving
Cost/life -year Cost-saving Cost-savingPolicy Question 2
28PCV20 without PPSV23, PCV15 Context
PCV 20 vs
PCV 15+PPS
CMC
VPCV 20 vs
PCV 15+PPSV +PPSV
ICPCV 20 vs PCV 15+PPSV ,
Half PPSV  Coverage
CMCPCV 20 vs
PCV 15+PPSV +PPSV ,
Half PPSV  Coverage
IC
IPD meningitis cases -3 0 -4 0
IPD n o n -meningitis cases -13 -1 -21 -2
Deafness 0 0 0 0
Disab ility 0 0 0 0
IPT pneumonia cases -116 -2 -138 -3
OPT  pneumonia Cases -661 -7 -786 -9
AOM cases -27,188 -329 -27,188 -329
Ty m p  tubes -2,830 -34 -2,830 -34
Deaths due to I PD -1 0 -1 0
Deaths due to pneumonia -1 0 -1 0
Childhood QAL Ys 95 3 111 4
Adult QAL Ys (indirect) 108 3 125 5
Life-years 48 2 64 4
Costs (million $)
T otal cost -$33 -$0.91 $4 -$0.66
Medical costs -$17 -$0.26 -$18 -$0.34
Non-medical costs -$8 -$0.12 -$9 -$0.18
Adult costs (indirect) -$7 -$0.18 -$8 -$0.29
V accine costs -$1 -$0.35 $39 $0.15
Cost ratios ($)
C o s t / Q A LY Cost-saving Cost-saving 18,722 Cost-saving
Cost/life -year Cost-saving Cost-saving 68,612 Cost-savingPolicy Question 2
29Adding PPSV23 to a PCV20 Primary Series
PCV 20+PPSV  vs PCV 20PCV 20+PPSV +PPSV  vs
P CV2 0
CMC IC
IPD meningitis cases -1 0
IPD n o n -meningitis cases -5 -1
Deafness 0 0
Disab ility 0 0
I PT  pneumonia cases -10 -1
OPT  pneumonia cases -55 -1
AOM ca s e s 0 0
Ty m p  tubes 0 0
Deaths due to I PD 0 0
Deaths due to pneumonia 0 0
Q A LYs 9 1
Life-years 10 1
Costs (million $)
T otal cost 39 $0.73
Medical costs -1 -$0.06
Non-medical costs 0 -$0.04
V accine costs 40 $0.82
Cost ratios ($)
S a v i n g s / Q A LY 4,086,881 690,388
Savings/life -year 3,923,758 658,925Policy Question 2
30Limitations
Uncertainty around indirect effects on adults
Uncertainty around QALY decrements
AOM
PCV20 VE based on immunogenicity trials
Sa m e  VE fo r  a ll P CV valencies
ST3 VE limited data
31Conclusion
Policy Question 1
Replacing PCV13 with PCV20 costs:
$57k/QAL Y  (aggregate)
•$78k/QAL Y  (healthy)
•Co st -savin g  (CMC)
•Co st -Saving (IC)
Replacing PCV15 with PCV20 costs:
$125k/QAL Y  (aggregate)
•$154k/QAL Y  (healthy)
•Co st -savin g  (CMC)
•Co st -sa vin g  (IC)
32Replacing PCV13+PPSV23 (or PCV15+PPSV23) with PCV20
by itself in CMC/IC is cost saving
Adding PPSV23 to PCV20 for CMC/IC costs:
$3.9 million/QAL Y  (aggregate)
•$4.1 million/QAL Y (CMC)
•$0.7 million/QAL Y (IC)Conclusion
Policy Question 2
33Thank you!
Please send comments to:
cfstoecker@tulane.edu
Contributors:
Miwako Kobayashi
Dipreye  Ayabina
Namrata Prasad
Andrew Leidner
H
SREB – Ec o n  Te a mNational Center for Immunization & Resp iratory Diseases

Summary: 1E conomic A ssessment of R outine PC V 20 for C hildren C harles Stoecker Tulane University School of Public Health and Tropical Medicine ACIP June 22,  2023  2Conflicts of Interest Dr. Stoecker has no conflicts of interest to declare. 3Acronyms  PC V :  pneumococcal conjugate vaccine  PCV 13:  13 valent PCV  PCV 15:  15 valent PCV  PCV 20:  20 valent PCV  PPSV 23:  23 valent pneumococcal polysaccharide vaccine  V E :  vaccine effectiveness  V T: vaccine type  ST: s e r o t yp e …