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Evidence to Recommendations Framework and Policy Options:
Use of 20 -valent Pneumococcal Conjugate Vaccine in U.S. Children
Miwako Kobayashi, MD, MPH
Pneumococcal Vaccines Work Group
Advisory Committee on Immunization Practices
June 22, 2023National Center for Immunization & Respiratory Diseases
PICO
QuestionShould PCV20 be recommended as an option for pneumococcal vaccination
for U.S. children?
Population All U.S. children aged <2 yearsU.S. children aged 2 –18 years with
underlying medical conditions
InterventionPCV20 according to currently
recommended dosing and
schedulesPCV20 (without PPSV23)
Comparison PCV13 or PCV15 according to currently recommended dosing and schedules
OutcomesVT-IPD, VT -pneumonia, VT -AOM, VT -pneumococcal deaths, serious adverse
events following vaccination
VT: vaccine -type, IPD: invasive pneumococcal disease, AOM: acute otitis media2
PICO
QuestionShould PCV20 be recommended as an option for pneumococcal vaccination
for U.S. children?
Population All U.S. children aged <2 yearsU.S. children aged 2 –18 years with
underlying medical conditions
InterventionPCV20 according to currently
recommended dosing and
schedulesPCV20 (without PPSV23)
Comparison PCV13 or PCV15 according to currently recommended dosing and schedules
OutcomesVT-IPD, VT -pneumonia, VT -AOM, VT -pneumococcal deaths, serious adverse
events following vaccination
VT: vaccine -type, IPD: invasive pneumococcal disease, AOM: acute otitis media3
PICO
QuestionShould PCV20 be recommended as an option for pneumococcal vaccination
for U.S. children?
Population All U.S. children aged <2 yearsU.S. children aged 2 –18 years with
underlying medical conditions
InterventionPCV20 according to currently
recommended dosing and
schedulesPCV20 (without PPSV23)
Comparison PCV13 or PCV15 according to currently recommended dosing and schedules
OutcomesVT-IPD, VT -pneumonia, VT -AOM, VT -pneumococcal deaths, serious adverse
events following vaccination
VT: vaccine -type, IPD: invasive pneumococcal disease, AOM: acute otitis media4
Risk group/Condition
Children without immunocompromising conditions
Chronic heart disease†
Chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in
immunocompromising conditions)
Chronic liver disease
Chronic lung disease (including moderate persistent or severe persistent asthma)
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Children with immunocompromising conditions
On maintenance dialysis 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
†Recommendations are of particular importance for children with cyanotic congenital heart disease and cardiac failure.
¶Includes B -(humoral) or T -lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3, and C4 deficiency; and phago cytic disorders (excluding chronic granulomatous disease).
** Including malignant neoplasms, leukemias, lymphomas, and Hodgkin disease.5
Risk group/Condition
Children without immunocompromising conditions
Chronic heart disease†
Chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in
immunocompromising conditions)
Chronic liver disease
Chronic lung disease (including moderate persistent or severe persistent asthma)
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Children with immunocompromising conditions
On maintenance dialysis 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
†Recommendations are of particular importance for children with cyanotic congenital heart disease and cardiac failure.
¶Includes B -(humoral) or T -lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3, and C4 deficiency; and phago cytic disorders (excluding chronic granulomatous disease).
** Including malignant neoplasms, leukemias, lymphomas, and Hodgkin disease.6
Risk group/Condition
Children without immunocompromising conditions
Chronic heart disease†
Chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in
immunocompromising conditions)
Chronic liver disease
Chronic lung disease (including moderate persistent or severe persistent asthma)
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Children with immunocompromising conditions
On maintenance dialysis 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
†Recommendations are of particular importance for children with cyanotic congenital heart disease and cardiac failure.
¶Includes B -(humoral) or T -lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3, and C4 deficiency; and phago cytic disorders (excluding chronic granulomatous disease).
** Including malignant neoplasms, leukemias, lymphomas, and Hodgkin disease.7
Rationale for updating indications for risk -based
recommendations
▪Improve harmonization between pediatric and adult recommendations
▪Data supporting increased risk of pneumococcal disease in this population
•Increased pneumococcal pneumonia1or IPD1,2risk in children with
asthma without long -term oral corticosteroid use
•Increased risk of IPD in children with chronic kidney disease
(regardless of stage)2,3
•Increased pneumococcal pneumonia2or IPD2,4risk in children with
chronic liver disease
IPD=invasive pneumococcal disease
1. Talbot et al. NEJM 2005 . Long -term oral corticosteroid use of ≥120 days defined as high risk
2. Pelton et al. CID 2014. Long -term oral corticosteroid use of ≥30 days defined as severe asthma
3. Hjuler et al. Pediatrics 2008.
4. Van Hoek et al. Journal of Infection 2012
ValuesEvidence to Recommendations ( EtR) framework
EtRDomain Question
Public Health Problem •Is the problem of public health importance?
Benefits and Harms •How substantial are the desirable anticipated effects?
•How substantial are the undesirable anticipated effects?
•Do the desirable effects outweigh the undesirable effects?
•What is the overall certainty of this evidence for the critical outcomes?
•Does the target population feel the desirable effects are large relative
to the undesirable effects?
•
Equity •Is there important variability in how patients value the outcomes?
Acceptability •Is the intervention acceptable to key stakeholders?
Feasibility •Is the intervention feasible to implement?
Resource Use •Is the intervention a reasonable and efficient allocation of resources?
What would be the impact of the intervention on health equity?9
Evidence to Recommendations ( EtR) framework
EtRDomain Question
Public Health Problem •Is the problem of public health importance?
Benefits and Harms •How substantial are the desirable anticipated effects?
•How substantial are the undesirable anticipated effects?
•Do the desirable effects outweigh the undesirable effects?
•What is the overall certainty of this evidence for the critical outcomes?
Values •Does the target population feel the desirable effects are large relative
to the undesirable effects?
•Is there important variability in how patients value the outcomes?
Acceptability •Is the intervention acceptable to key stakeholders?
Feasibility •Is the intervention feasible to implement?
Resource Use •Is the intervention a reasonable and efficient allocation of resources?
Equity •What would be the impact of the intervention on health equity?10
EtRDomain: Public Health Problem
Pneumococcal disease epidemiology in children
•Use of PCVs (PCV7, PCV13) significantly decreased the incidence of
pneumococcal disease in U.S. children.
•Outpatient ARIs caused by pneumococcus, such as AOM, sinusitis, and
pneumonia, are common causes of outpatient visits and antibiotic prescribing.
•Estimated incidence of outpatient visits and antibiotic prescriptions
attributable to PCV20, non -PCV13 serotypes: 4–5 times PCV15, non -PCV13
•In 2018 –2019, the proportion of IPD caused by vaccine serotypes was:
•PCV20, non -PCV13: ~30% of IPD
•PCV15, non -PCV13: ~15% of IPD
•PPSV23, non -PCV20: 1 –5% of IPD
•Risk of pneumococcal disease remains high in children with underlying
conditions that increase the risk of pneumococcal disease.
AOM=acute otitis media; ARI= acute respiratory illness; IPD=invasive pneumococcal disease
Gierke. February 2023 ACIP meeting presentation
King. February 2023 ACIP meeting presentation12
Monthly IPD rates (per 100,000) among children aged
<5 years old, 2018 –2022
0.000.200.400.600.801.001.201.40
Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec2018 2019 2020 2021 2022 *
IPD=invasive pneumococcal disease
CDC ABCs unpublished data. *2022 estimates are preliminar y13
Public Health Problem
Is pneumococcal disease of public health importance in U.S.
children?
□
□
□
□
□
□No
Probably no
Probably yes
Yes
Varies
Don’t know
14
EtRDomain: Benefits and Harms
Summary of evidence: Benefits, children <2 years
•Informed by 2 randomized controlled trials (Phase II and III)1,2
•Healthy children randomized to either PCV13 or PCV20
•PCVs given using 3+1 schedule
•Summary of findings
•PCV20 had numerically lower IgG geometric mean concentrations vs. PCV13
for the 13 shared serotypes
•Post dose 3 :
•PCV20 did not meet noninferiority criteria* vs. PCV13 for serotypes 1, 3, 4, 9V, 23F, and
12F*** for one of the outcomes
•Post dose 4 :
•PCV20 noninferior **to PCV13 for all 13 shared serotypes
•PCV20 noninferior to PCV13*** for all 7 additional serotypes
*Measured as lower bound of 2 -sided 95% CI for percent difference proportion of participants (PCV20 -PCV13) meeting IgG threshold value of >=0.35μg/mL for all serotypes except ≥
0.23 μg/mL, ≥ 0.10 μg/mL and ≥ 0.12μg/mL for serotypes 5, 6B and 19A respectively
**Measured as lower bound of 2 -sided 95% CI for IgG geometric mean concentration ratio (PCV20/PCV13) >0.5
***Compared with the serotype with lowest immune response among PCV13 serotypes except for serotype 3
1. Senders et al. PIDJ 2021
2. Pfizer unpublished data from B747101116
Summary of evidence: Safety, children <2 years
•Serious adverse events (SAEs) across 3 studies (dose 1 through 6 months after
dose 4)1-3:
•PCV20: 4.5% (101 of 2,232) vs PCV13: 3.7% (64 of 1,717)
•None were considered to be vaccine -related
1. Senders et al. PIDJ 2021
2. Pfizer B7471011, https://www.fda.gov/media/149987/download
3. Pfizer B7471013, https://www.fda.gov/media/149987/download17
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?
Type Outcome ImportanceIncluded in
evidence profileCertainty of
evidence
BenefitsVT-IPD Critical Yes Moderate
VT-pneumonia Critical Yes Moderate
VT-AOM Critical Yes Moderate
VT-pneumococcal
deathsCritical Yes Moderate
HarmsSAEs following
vaccinationCritical Yes Moderate
AOM=acute otitis media, IPD=invasive pneumococcal disease, SAE=serious adverse events, VT=vaccine -type18
Summary of evidence:
Benefits, children 2 –18 years with underlying conditions
•No studies conducted among children with underlying medical conditions
•Informed by 1 non -randomized trial (Phase III), no comparator
•Healthy children aged 15 months to 17 years received a dose of PCV20
•Children aged <5 years received ≥3 doses of PCV13
•Summary of findings
•PCV20 was immunogenic * for all 20 vaccine serotypes 1 month after
vaccination vs. pre-vaccination.
*Measured as IgG GMCs and GMFR and OPA GMFRs
Pfizer unpublished data from B747101419
Summary of evidence:
Safety, children 2 –18 years with underlying conditions
•Serious adverse events (SAEs) :
•PCV20: 0.6% (5/831)
•None were considered to be vaccine -related
Pfizer unpublished data from B747101420
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?
Type Outcome ImportanceIncluded in evidence
profile Certainty of evidence
BenefitsVT-IPD Critical Yes Very Low
VT-pneumonia Critical Yes Very Low
VT-AOM Critical Yes Very Low
VT-pneumococcal
deathsCritical Yes Very Low
HarmsSAEs following
vaccinationCritical Yes Very Low
AOM=acute otitis media, IPD=invasive pneumococcal disease, SAE=serious adverse events, VT=vaccine -type21
□
□
□
□
□
□Minimal
Small
Moderate
Large
Varies
Don’t knowBenefits and Harms
How substantial are the desirable anticipated effects?
▪Routine PCV20 use for children aged <2 years
▪PCV20 without PPSV23 for children aged 2 –18 years with underlying conditions
•PCV20 provides the broadest serotype coverage among available
PCVs.
•Unknown how substantial the protection conferred from PCV20 will
be based on available data.
•No PCV20 data among children with underlying medical conditions .
22
Benefits and Harms
How substantial are the undesirable anticipated effects?
▪Routine PCV20 use for children aged <2 years
▪PCV20 without PPSV23 for children aged 2 –18 years with underlying conditions
□
□Minimal
Small
□Moderate
□Large
□Varies
□Don’t know
23
Benefits and Harms
Do the desirable effects outweigh the undesirable effects?
▪Routine PCV20 use for children aged <2 years
▪PCV20 without PPSV23 for children aged 2 –18 years with underlying conditions
□
□
□Favors intervention*
Favors current recommendation
Favors both
□Favors neither
□Varies
□Don’t know*Intervention: PCV20 use
Comparison:
•Children <2 years: PCV13 or PCV15 use
•Children 2 –18 years with underlying
conditions: PPSV23 use after currently
recommended PCV (PCV13 or PCV15)
doses
24
EtRDomain: Equity
Summary of evidence
•Disparities in pneumococcal vaccine coverage by race/ethnicity, insurance coverage,
and poverty level exist1
•Nationally representative PPSV23 vaccine coverage data among children with
indications are limited2–5
•Range ~20 –60%, many reports from single institution
•Disparities in IPD rates by race and the percentage of census tract poverty remain6,7
•Most of the remaining disparities were due to serotypes not included in PCV20
1. ChildVaxView Interactive Child Vaccination Coverage | CDC
2. Reeves et al. Pediatric Blood & Cancer, 2018
3. Tran et al. Frontiers in Pediatrics, 2021
4. Mirza et al. The Ochsner Journal, 2022
5. Harris et al. Pediatrics, 2022
6. Farrar February 2022 ACIP meeting presentation
7. Kobayashi February 2023 ACIP meeting presentation26
Equity
What would be the impact of recommending PCV20 for U.S.
children on health equity?
□
□
□Reduced
Probably reduced
Probably no impact
□Probably increased
□Increased
□Varies
□Don’t know
27
Equity
What would be the impact of recommending PCV20 for U.S.
children aged <2 years on health equity?
Probably reduced:
•New interventions are likely to be accessible to wealthy communities, first
→VFC program mitigates inequities in access to recommended vaccines
Probably no impact:
•Remaining disparities in vaccine -type disease seem to be minimal
Probably increased:
•Post -PCV13 data showed that PCV13 reduced disparities in vaccine -type disease
VFC=Vaccines for Children28
Equity
What would be the impact of recommending PCV20 without
PPSV23 for U.S. children aged 2 –18 years with underlying
medical conditions on health equity?
Probably no impact:
•Risk-based recommendation is less likely to be equitable compared with routine
vaccine recommendations.
Probably increased:
•PCV20 use without PPSV23 could simplify the pneumococcal vaccine
recommendations and improve vaccine coverage.
29
EtRDomain: Values and Preferences
Values and Preferences
Criterion 1: Does the target population feel that the desirable
effects from vaccination are large relative toundesirable effects?
▪Routine PCV20 use for children aged <2 years
•Probably Yes
▪PCV20 without PPSV23 for children aged 2 –18 years with
underlying conditions
•Probably Yes/Yes
31
Values and Preferences
Criterion 2: Is there important uncertainty about, or variability
in, how much people value the main outcomes?
•Routine PCV20 use for children aged <2 years
•Probably important/not important uncertainty or
variability
•PCV20 without PPSV23 for children aged 2 –18 years with
underlying conditions
•Probably not important uncertainty or variability
32
Values and Preferences
Uncertainties:
▪No data assessing the public’s perception of PCV20
▪No data assessing efficacy/effectiveness of PCV20 against disease
▪Benefits from PCV20 use alone without PPSV23 for children with
underlying conditions are uncertain
Probably not important uncertainty or variability:
▪>90% vaccine coverage for ≥3 PCV doses in children by age 24 months1
▪Increased cases of invasive pneumococcal disease (late 2022): caregivers of
the child will likely value the use of PCV20
1.Hill et al. MMWR 2023.33
EtRDomain: Acceptability
Three healthcare provider surveys
▪Web -based surveys among providers who administer pneumococcal
vaccines to children
•1 by Pfizer (manufacturer of PCV13 and PCV20)1
•2 by Merck (manufacturer of PCV15 and PPSV23)2,3
1. Myers K, Pierce N, Poulos C, Arguedas A, Chilson E, Hauber B, et al. US Health Care Providers' Preferences for Pediatric Pneumococcal Conjugate Vaccines. Preliminary Findings. 2023.
2. OPEN Health. Provider Knowledge, Attitude, and Preferences Towards Pediatric Pneumococcal Vaccines. 2023.
3. Merck & Co. Inc. HCP Preferences Concerning Pediatric Pneumococcal Vaccines Report. 2023. 35
Key findings ( Pfizer survey )
Vaccine profiles of PCV15 and PCV20 shown, emphasizing IPD serotype coverage.
Children aged <2 years with incomplete series:
▪76% of providers responded that they would transition patients who started their PCV
series with either PCV13 or PCV15 to PCV20
•To provide protection against as many serotypes as possible ( 94% ).
Children with underlying conditions:
▪43% of providers responded that PCV20 alone without PPSV23 should be
recommended.
•Prefer/store only 1 vaccine instead of multiple vaccines ( 61% ).
•Prefer conjugated vaccines over unconjugated polysaccharide vaccines ( 48% ).
1. Myers K, Pierce N, Poulos C, Arguedas A, Chilson E, Hauber B, et al. US Health Care Providers' Preferences for Pediatric Pneumococcal Conjugate Vaccines. Preliminary Findings. 2023.
36
Key findings ( Merck surveys )
▪Importance of pneumococcal vaccination
•>90% of providers believed that it is important to administer
pneumococcal vaccines to children aged <2 years.1
▪Important vaccine attributes
•≥90% of providers believed that it is important to have product -specific
data for immunocompromised or premature children.1
•Of the five vaccine attributes assessed for hypothetical vaccines, immune
response for the serotypes covered in PCV13 was given the highest
importance.2
1. Merck & Co. Inc. HCP Preferences Concerning Pediatric Pneumococcal Vaccines Report. 2023..
2. OPEN Health. Provider Knowledge, Attitude, and Preferences Towards Pediatric Pneumococcal Vaccines. 2023.37
Acceptability
Is recommending PCV20 acceptable to key stakeholders?
▪Routine PCV20 use for children aged <2 years
•Yes
▪PCV20 without PPSV23 for children aged 2 –18 years with
underlying conditions
•Probably Yes/Yes
•Simplifies storage, less prone to vaccine administration errors
•Some providers may not feel comfortable recommending PCV20 alone without
PPSV23
38
EtRDomain: Resource Use
Summary of evidence
•Routine PCV20 use vs. PCV13 or PCV15 in children aged <2 years
•Base case ranged from cost -saving to $125,000 per QALY gained
•Differences across models related to indirect effects on adult disease
•PCV20 alone without PPSV23 use in children aged 2 –18 years with underlying
conditions
•PCV20 alone instead of PCV13/PCV15+PPSV23* was found to be cost -saving
in most model scenarios
•Addition of PPSV23 to PCV20 had high cost per QALY gained
•Greater than $1.9 million per QALY gained among CMC
•Between $200,000 to $690,000 per QALY gained among IC
CMC=chronic medical conditions, including chronic heart, lung, and liver disease, diabetes
IC=immunocompromising conditions, including chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, HIV,
Hodgkin disease, leukemia, lymphoma, solid organ transplants, cochlear implants, CSF leaks, congenital or acquired asplenia, sic kle cell disease, or other hemoglobinopathies
QALY= quality -adjusted life -years
*CMC received 1 dose of PPSV23, IC received 2 doses of PPSV2340
□
□No
Probably no
□Probably yes
□Yes
□Varies
□Don’t knowResource Use
Is the option a reasonable and efficient allocation of resources?
▪Routine PCV20 use for children aged <2 years
▪PCV20 without PPSV23 for children aged 2 –18 years with underlying conditions
Yes:
•Protects against more pneumococcal serotypes.
Minority opinion :
•Expensive vaccine.
•Uncertainties in the effectiveness remain.
•Onlyimmunogenicity data.
•No PCV20 data from children with underlying conditions.
•Challenging to interpret cost -effectiveness analyses findings that
use different methods and assumptions (routine PCV20 use).
•Sensitive to launch price.
41
EtRDomain: Feasibility
□
□No
Probably no
□Probably yes
□Yes
□Varies
□Don’t knowFeasibility
Is recommending PCV20 feasible to implement?
▪Routine PCV20 use for children aged <2 years
▪PCV20 without PPSV23 for children aged 2 –18 years with underlying conditions
Routine PCV20 use for children aged <2 years:
•PCVs have been recommended for >20 years.
PCV20 without PPSV23 for children with underlying conditions:
•Simpler, streamlined recommendation.
•More feasible in general and are more likely to be followed in
clinical practice.
43
EtRDomains PCV20, <2 years (routine) PCV20, 2 –18 years old
Public Health Problem Yes
Benefits and Harms
a. Benefits Moderate
b. Harms Minimal
c. Benefit>Harm? Favors intervention/Favors both (split)
d. Overall certainty: effectiveness 2 (moderate) 4 (very low)
e. Overall certainty: safety 2 (moderate) 4 (very low)
Values
a. Desirable>Undesirable? Probably yes Probably yes/yes (split)
b. Uncertainty? Probably important uncertainty or
variability/Probably no important uncertainty or
variability (split)Probably no important uncertainty or variability
Acceptability Yes Probably yes/yes (split)
Resource Use Yes
Equity Probably increased (different opinions)
Feasibility YesSummary of Work Group Interpretation of the EtRDomains ( Updated )
44
Summary: Work Group Interpretations
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 ?
Comparison: PCV13 or PCV15
Balance of
consequencesUndesirable
consequences
clearly
outweigh
desirable
consequences
in most
settingsUndesirable
consequences
probably
outweigh
desirable
consequences
in most
settingsThe balance
between
desirable and
undesirable
consequences
is closely
balanced or
uncertainDesirable
consequences
probably
outweigh
undesirable
consequences
in most
settingsDesirable
consequences
clearly
outweigh
undesirable
consequences
in most
settingsThere is
insufficient
evidence to
determine the
balance of
consequences
Summary: Work Group Interpretations
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 ?
In support of recommending PCV20:
•Additional serotypes covered by PCV20 areexpected to prevent additional disease.
In support of recommending both PCV20 and PCV15*:
•We only have immunogenicity study data for both PCV20 and PCV15, clinical
implications are unknown.
•Range in cost -effectiveness analysis findings.
•Good to have options for PCVs, in case of challenges with/delays in access to PCV20.
*PCV13 expected to be removed from market after a transition period
Summary: Work Group Interpretations
Should PCV20 without PPSV23 be recommended as an option for children
aged 2–18 years with underlying medical conditions that increase the risk
of pneumococcal disease?
Comparison: PCV13 or PCV15 + PPSV23 according to current dosing
/schedule
Balance of
consequencesUndesirable
consequences
clearly
outweigh
desirable
consequences
in most
settingsUndesirable
consequences
probably
outweigh
desirable
consequences
in most
settingsThe balance
between
desirable and
undesirable
consequences
is closely
balanced or
uncertainDesirable
consequences
probably
outweigh
undesirable
consequences
in most
settingsDesirable
consequences
clearly
outweigh
undesirable
consequences
in most
settingsThere is
insufficient
evidence to
determine the
balance of
consequences
Summary: Work Group Interpretations
Should PCV20 without PPSV23 be recommended as an option for children
aged 2 to 18 years with underlying medical conditions that increase the
risk of pneumococcal disease?
In support of recommending PCV20 without PPSV23:
•Simplicity of PCV20 use without PPSV23, ease of vaccine storage.
•Immunologic advantages of PCVs over PPSV23.
•PCV20 provides the broadest serotype coverage among available PCVs.
In support of recommending BOTH PCV20 without PPSV23 AND PCV15* + PPSV23:
•No data on PCV20 use in children with underlying medical conditions.
•Harmonization with the updated adult pneumococcal vaccine recommendations
(October 2022 ACIP meeting).
*PCV13 expected to be removed from market after a transition period
Proposed Policy Options for a Vote
1. Routine PCV use for all children aged <24 months
Use of either PCV15 or PCV20 is recommended for all children aged 2 –23
months according to currently recommended PCV dosing and schedules.
50
Age at visit/
Health statusNo. of previous PCV13/PCV15/PCV20
doses received Recommended PCV15 /PCV20 regimen†
All children (healthy and those with risk conditions)
2–6 mos13 additional doses: 2 doses, 8 wks apart; last dose at age
12–15 mos
22 additional doses: 1 dose 8 wks after most recent dose;
last dose ≥8 wks later at age 12 –15 mos
3 1 additional dose at age 12 –15 mos
7–11 mos
1 or 2 (at age <7 mos) 2 additional doses: 1 dose 8 wksafter most recent dose;
last dose ≥8 wkslater at age 12 –15 mos
3 (at age <7 mos) 1 additional dose at age 12 –15 mos
1 (at age ≥7 mos)2 additional doses: 1 dose 8 wksafter most recent dose;
last dose ≥8 wkslater at age 12 –15 mos
2 (at age ≥7 mos) 1 additional dose at age 12 –15 mos
12–23 mos1 (at age <12 mos)2 additional doses: 1 dose ≥8 wksafter most recent dose;
last dose ≥8 wkslater
2 or 3 (at age <12 mos) 1 additional dose, ≥8 wks after most recent dose
1 (at age ≥12 mos) 1 additional dose, ≥8 wksafter most recent dose†
†Minimum interval between doses is 8 weeks except for children vaccinated at age <1 year, for whom minimum interval between do ses is 4 weeks.
51
2. Catch -up PCV doses for children aged 24 –71 months
with an incomplete PCV vaccination status
For healthy children aged 24 –59 months or through age 71 months
for children with any underlying condition that increases the risk of
pneumococcal disease (hereafter, risk condition)* with an incomplete
PCV vaccination status , use of either PCV15 or PCV20 according to
currently recommended PCV dosing and schedules isrecommended.
*Risk conditions include: cerebrospinal fluid leak; chronic heart disease ; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in
immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persiste nt asthma ); cochlear implant; diabetes mellitus;
immunocompromising conditions ( on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired
immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant ne oplasms, leukemias, lymphomas, Hodgkin disease, and
solid organ transplant; HIV infection; and sickle cell disease and other hemoglobinopathies).52
Risk group/Condition
Children without immunocompromising conditions
Chronic heart disease†
Chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in
immunocompromising conditions)
Chronic liver disease
Chronic lung disease (including moderate persistent or severe persistent asthma)
Diabetes mellitus
Cerebrospinal fluid leak
Cochlear implant
Children with immunocompromising conditions
On maintenance dialysis 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
†Recommendations are of particular importance for children with cyanotic congenital heart disease and cardiac failure.
¶Includes B -(humoral) or T -lymphocyte deficiency; complement deficiencies, particularly C1, C2, C3, and C4 deficiency; and phago cytic disorders (excluding chronic granulomatous disease).
** Including malignant neoplasms, leukemias, lymphomas, and Hodgkin disease.53
Age at visit/
Health statusNo. of previous PCV13/PCV15/PCV20
doses received Recommended PCV15/ PCV20 regimen†
Healthy Children
24–59 mos No previous doses or any incomplete
schedule by 24 mos1 additional dose, ≥8 wks after most recent dose
5–18 yrs No previous doses or any incomplete
schedule by 24 mosNo additional dose
Children with risk conditions
24–71 mos No previous doses or any incomplete
schedule and <3 doses by age 24 mos2 doses: 1 dose ≥8 wks after most recent dose; last
dose ≥8 wks later
3 (all at age <12 mos) 1 additional dose, ≥8 wks after most recent dose
†Minimum interval between doses is 8 weeks except for children vaccinated at age <1 year, for whom minimum interval between do ses is 4 weeks.
54
3. Children aged 2 –18 years with any risk condition who have
completed their recommended PCV doses before age 6 years
For children aged 2 –18 years with any risk condition who have
received all recommended doses before age 6 years
•Using ≥1 dose of PCV20: No additional doses of any pneumococcal
vaccine are indicated. This recommendation may be updated as
additional data become available.
•Using PCV13 or PCV15 (no PCV20): A dose of PCV20 or PPSV23 using
previously recommended doses and schedule is recommended.
55
Children aged 2 –18 years with CMC, CSF leak, or cochlear implant
who have received all recommended PCV doses before age 6 years,
current recommendations
CMC=chronic medical conditions, including chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, whic h are included in
immunocompromising conditions), chronic heart disease, chronic liver disease, chronic lung disease (including moderate persis tent or severe persistent asthma),
diabetes mellitus; CSF=cerebrospinal fluidPPSV23Complete with
either PCV13/15≥8 weeks
56
Children aged 2 –18 years with CMC, CSF leak, or cochlear implant
who have received all recommended PCV doses before age 6 years,
proposed recommendations
CMC=chronic medical conditions, including chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, whic h are included in
immunocompromising conditions), chronic heart disease, chronic liver disease, chronic lung disease (including moderate persis tent or severe persistent asthma),
diabetes mellitus; CSF=cerebrospinal fluidPPSV23≥8 weeks Complete with
either PCV13/1 5PCV20Complete with
any PCV20 doseScenario 1PCV vaccination status
No additional doses
indicated
Option 1Scenario 2
≥8 weeksOption 2
57
Children with an immunocompromising condition aged 2 –18 years
who have completed PCV doses before age 6 years, current
recommendations
IC= immunocompromising conditionPPSV23 PPSV23
≥5 yearsComplete with
either PCV13/15 ≥8 weeks
58
Children with an immunocompromising condition aged 2 –18 years
who have completed PCV doses before age 6 years, proposed
recommendations
IC= immunocompromising conditionPPSV23≥8 weeks
PCV20Complete with
any PCV20 dose
PPSV23≥5 yearsScenario 1
PPSV23
≥8 weeksComplete with
either PCV13/15 ≥5 yearsPCV20
≥8 weeksOption 3Option 1
Option 2No additional doses
indicatedScenario 2PCV vaccination status
No additional doses
indicated
59
4. Children aged 6 –18 years with any risk condition
who have not received any dose of PCV
For children aged 6 –18 years with any risk condition who have not
received any dose of PCV13, PCV15, or PCV20, a single dose of PCV15
or PCV20 is recommended at least 8 weeks after the most recent dose
of pneumococcal vaccine. When PCV15 is used, it should be followed
by a dose of PPSV23 at least 8 weeks later if not previously given.
60
Current risk-based pneumococcal vaccine recommendations for PCV
unvaccinated children aged 6 –18 years with risk conditions
PCV13/15 recommendedPPSV23
RecommendedSingle PPSV23 revaccination
5 yrsafter first dose
Chronic heart disease Y
Chronic lung disease Y
Diabetes mellitus Y
Cerebrospinal fluid leak Y Y
Cochlear implant Y Y
Chronic renal failure or
nephrotic syndromeY Y Y
Congenital or acquired
asplenia, or splenic
dysfunctionY Y Y
Congenital or acquired
immunodeficiencyY Y Y
Diseases and conditions
treated with
immunosuppressive drugs or
radiation therapyY Y Y
HIV infection Y Y Y
Sickle cell disease or other
hemoglobinopathiesY Y Y
Solid organ transplant Y Y Y
Proposed risk-based pneumococcal vaccine recommendations for
PCV unvaccinated children aged 6 –18 years with risk conditions
PCV15/ 20recommended PPSV23 Recommended
Chronic heart disease Y Only if PCV15 used
Chronic kidney disease Y Only if PCV15 used
Chronic liver disease Y Only if PCV15 used
Chronic lung disease * Y Only if PCV15 used
Diabetes mellitus Y Only if PCV15 used
Cerebrospinal fluid leak Y Only if PCV15 used
Cochlear implant Y Only if PCV15 used
Maintenance dialysis or nephrotic syndrome Y Only if PCV15 used
Congenital or acquired asplenia, or splenic
dysfunctionY Only if PCV15 used
Congenital or acquired immunodeficiency Y Only if PCV15 used
Diseases and conditions treated with
immunosuppressive drugs or radiation
therapyY Only if PCV15 used
HIV infection Y Only if PCV15 used
Sickle cell disease or other
hemoglobinopathiesY Only if PCV15 used
Solid organ transplant Y Only if PCV15 used
*including moderate persistent or severe persistent asthma
Clinical Guidance
PCV13 use for children aged <6 years
•If only PCV13 is available when the child is scheduled to receive a PCV,
PCV13 may be given as previously recommended.
•If a child started the PCV series with PCV13, the child may complete the
series with PCV15 or PCV20 without giving additional doses. The PCV
series does not need to be restarted.
64
Children aged 6 –18 years with a risk condition who
have received PCV13 only
For children who have previously received PCV13only, either adose of
PCV20atleast 8weeks later orPPSV 23based onprevious dosing and
schedules isrecommended .
65
Children who have received hematopoietic stem cell
transplant (HSCT)
Children who received HSCT are recommended to receive three doses of PCV20 , 4 weeks
apart starting 3 –6 months after HSCT. A fourth PCV20 dose is recommended at least 6
months after the third PCV20 dose, or at least 12 months after HSCT, whichever is later.
HSCT recipients who have started their pneumococcal vaccine series with PCV13 or PCV15
may complete their 4 -dose pneumococcal vaccine series with PCV20 without giving extra
doses.
If PCV20 is not available, three doses of PCV15, followed by a dose of PPSV23 at least
12 months after HSCT may be given. For patients with chronic graft -versus -host disease
who are receiving PCV15, a fourth dose of PCV15 can be given in place of PPSV23 since
these children are less likely to respond to PPSV23.
A patient’s clinical team is best positioned to determine the appropriate timing of
vaccination .
Language aligned with clinical guidance for adults (October 2022 ACIP meeting)66
Acknowledgements
•ACIP and the Pneumococcal Vaccines Work Group
•CDC contributors and consultants: Ryan Gierke, Jennifer Farrar, Kristin Andrejko,
Lindsay Zielinski, Emma Accorsi, Adam Cohen, Alison Albert, Angela Jiles, Noele
Nelson, Diepreye Ayabina, Andrew Leidner, Pedro Moro, Elizabeth Velazquez,
Marc Fischer, Katie Hamilton, Noelle Sobotka, Rebecca Morgan, Doug Campos -
Outcalt
67
Summary of voting language:
No change in PCV doses or schedule
1. Use of either PCV15 or PCV20 is recommended for all children aged 2 –23
months according to currently recommended PCV dosing and schedules.
2. For healthy children aged 24 –59 months or through age 71 months for children
with any underlying condition that increases the risk of pneumococcal disease
(hereafter, risk condition)* with an incomplete PCV vaccination status , use of
either PCV15 or PCV20 according to currently recommended PCV dosing and
schedules isrecommended.
*Risk conditions include: cerebrospinal fluid leak; chronic heart disease ; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in
immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persiste nt asthma ); cochlear implant; diabetes mellitus;
immunocompromising conditions ( on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired
immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant ne oplasms, leukemias, lymphomas, Hodgkin disease, and
solid organ transplant; HIV infection; and sickle cell disease and other hemoglobinopathies).68
Summary of voting language:
Modifications to schedule
3. For children aged 2 –18 years with any risk condition who have received all
recommended doses before age 6 years
•Using ≥1 dose of PCV20: No additional doses of any pneumococcal vaccine are
indicated. This recommendation may be updated as additional data become available.
•Using PCV13 or PCV15 (no PCV20): A dose of PCV20 or PPSV23 using previously
recommended doses and schedule is recommended.
4. For children aged 6 –18 years with any risk condition who have not received any dose
of PCV13, PCV15, or PCV20, a single dose of PCV15 or PCV20 is recommended at least 8
weeks after the most recent dose of pneumococcal vaccination. When PCV15 is used, it
should be followed by a dose of PPSV23 at least 8 weeks later if not previously given.
69
Supplementary Slides
GRADE Summary of Evidence
Search strategy: PCV20 use in children
Database StrategyNo.
identifiedIncluded in
GRADE
Clinicaltrials.gov Inclusion: Relevant Phase 2, or 3 randomized controlled trials of PCV20
•Involved human subjects
•Reported primary data
•Included infants and children (age ≤18 years)
•Included data relevant to the efficacy or effectiveness or immunogenicity and safety
outcomes being measured
•Included data for the dosage and timing being recommended:
o3+1 series for infants starting the vaccine series as currently recommended
oCatch -up vaccine schedule for older infants and children who did not start the 3+1 series
in time
oUse of PCV20 to complete the PCV13 series
oUse of PCV20 in series with PPSV23 in older children with underlying conditions in series
with PPSV2312 3*
Pubmed
Medline“PCV20” or “20 -valent pneumococcal conjugate vaccine”
Included studies using the criteria listed above62 1
Additional
resourcesUnpublished and other relevant data by consulting with the vaccine manufacturer
2 3*
*Same trials. Unpublished data from these trials were obtained from pharmaceutical companies. 71
Included Studies: Routine PCV20 Use in Children Aged <2 years
Author, yearStudy
designIntervention Country Age Total
populationN
InterventionN
comparisonOutcomesFunding
source
Senders,
2021Phase II RCT
in healthy
full-term
infantsPCV20 @ 2, 4, 6,
and 12 months of
ageUS42–98
days of
age at
consent460 232 228Immuno -
genicity and
safetyPfizer
B7471011Phase III RCT
in healthy
full-term
infantsPCV20 @ 2, 4, 6,
and 12 –15
months of ageUS,
Puerto
Rico42–98
days of
age at
consent1998 1001 997Immuno -
genicity and
safetyPfizer
B7471013Phase III RCT
in healthy
infantsPCV20 @ 2, 4, 6,
and 12 –15
months of ageUS,
Puerto
Rico,
Canada,
Chile,
Argentin
a, EU42–98
days of
age at
consent1511 1000 551 Safety Pfizer
RCT=Randomized Controlled Trial72
GRADE Summary of Findings: Routine PCV20 use in Children Aged <2 Years
Certainty assessment № of patients Results
Certainty Importance № of
studiesStudy
designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsIntervention comparisonRelative
(95% CI)Absolute
(95% CI)
Vaccine effectiveness
21-2 RCTNot
seriousNot serious SeriousaNot serious Not serious 921-1022 910-989•PCV20 had numerically lower
immune responses compared
with PCV13 for most of the 13
shared serotypes.
•PCV20 did not meet one of the
noninferiority endpointsbfor
some serotypes (1, 3, 4, 9V, 23F,
and 12F) after dose 3.
•PCV20 noninferiorcto PCV13 for
all 13 shared serotypes after
dose 4.
•PCV20 noninferiorcto PCV13 for
all 7 additional serotypes after
dose 4.Moderate Critical
RCT=randomized clinical trial
a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
b. Noninferiority for difference in percentages of participants meeting predefined IgG threshold value was defined as the low er bound of 2 -sided 95% confidence interval for percent difference (PCV20 -PCV13)> -10%. Additional 7 serotypes contained in
PCV20 but not in PCV13 were compared with a PCV13 serotype with the lowest percentage excluding serotype 3.
c. Noninferiority for GMC ratio was defined as the lower bound of 2 -sided 95% confidence interval of IgG GMC ratio (PCV20/PCV13) >0.5. Additional 7 serotypes contained in PCV20 but not in PCV13 were compared with a PCV13 serotype with the lowest
percentage excluding serotype 3.
References
1. Senders S, Klein NP, Lamberth E, Thompson A, Drozd J, Trammel J, Peng Y, Giardina PC, Jansen KU, Gruber WC, Scott DA, Watson W. Safety and Immunogenicity of a 20 -valent Pneumococcal Conjugate Vaccine in Health y Infants in the United States. Pediatr Infect Dis J. 2021 Oct
1;40(10):944 -951. doi: 10.1097/INF.0000000000003277.
2.B7471011. A Phase 3, Randomized, double -blind trial to evaluate the safety and immunogenicity of a 20 -valent pneumococcal conj ugate vaccine in healthy infants73
GRADE Summary of Findings: Routine PCV20 use in Children Aged <2 Years
Certainty assessment № of patients Results
Certainty Importance № of
studiesStudy
designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsIntervention ComparisonRelative
(95% CI)Absolute
(95% CI)
Serious Adverse Events (SAEs) following vaccination
21-3 RCT Not
seriousNot serious Not serious Seriousa Not serious 101/2232
(4.5%)64/1717
(3.7%)No vaccine -related
serious adverse events
reportedModerate Critical
RCT=randomized clinical trial
a. No vaccine -related serious adverse events reported
References
1.Senders S, Klein NP, Lamberth E, Thompson A, Drozd J, Trammel J, Peng Y, Giardina PC, Jansen KU, Gruber WC, Scott DA, Watson W. Safety and Immunogenicity of a 20 -valent Pneumococcal Conjugate
Vaccine in Healthy Infants in the United States. Pediatr Infect Dis J. 2021 Oct 1;40(10):944 -951. doi: 10.1097/INF.0000000000003277.
2.B7471011. A Phase 3, Randomized, double -blind trial to evaluate the safety and immunogenicity of a 20 -valent pneumococcal conj ugate vaccine in healthy infants
3.B7471013. A Phase 3, Randomized, double -blind trial to evaluate the safety of a 20 -valent pneumococcal conjugate vaccine in he althy infants. Data limited to U.S. and Puerto Rico sites.
74
Included Study: PCV20 Use in Children Aged 2 –18 Years with Underlying
Medical Conditions
Author, year Study design Intervention Country Age Total
populationN
InterventionN
comparisonOutcomesFunding
source
B7471014Phase III
Clinical Trial
in healthy
children,
some
previously
vaccinatedSingle dose PCV20
@ 15m to <24m;
previous
vaccination ≥3
doses of PCV13
US15m
to
<24m209 209 N/A
Immuno -
genicity
and
safetyPfizerSingle dose PCV20
@ 2y to <5y;
previous
vaccination ≥3
doses of PCV132y to
<5y216 216 N/A
Single dose PCV20
@ 5y to <10y5y to
<10y201 201 N/A
Single dose PCV20
@ 10 to <18y10y
to
<18y205 205 N/A75
GRADE Summary of Findings: PCV20 Use in Children Aged 2 –18 Years
with Underlying Medical Conditions
Certainty assessment № of patients Results
Certainty Importance № of
studiesStudy
designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsIntervention comparisonRelative
(95% CI)Absolute
(95% CI)
Vaccine effectiveness
11 Non -RCTVery
Serious
aNot
applicableVery
Seriousb,cNot
seriousNot serious 752-757 NoneIgG GMCs were higher 1 -
month post -PCV20 dose
compared to before
vaccination for 13/13 shared
serotypes and 7/7 additional
serotypes, for all age groupsVery Low Critical
RCT=randomized clinical trial
a. Study design is an open label non -randomized controlled trial with no comparator group. Downgraded for lack of randomization, la ck of blinding, and lack of a comparison group.
b. Study population did not include children with underlying conditions
c. This is an immunogenicity study and there are no correlates of protection for some critical outcomes considered
References
B7471014. Safety and Immunogenicity Study of 20vPnC in Healthy Children 15 Months Through 17 Years of Age76
GRADE Summary of Findings: PCV20 use in Children Aged 2 –18
Years With Underlying Medical Conditions
Certainty assessment № of patients Results
Certainty Importance № of
studiesStudy designRisk of
biasInconsistency Indirectness ImprecisionOther
considerationsPCV20 InterventionRelative
(95% CI)Absolute
(95% CI)
Serious Adverse Events (SAEs) following vaccination
11 Non -RCTSerious
aNot
applicableSeriousb Seriousc Not serious5/831
(0.6%) No vaccine -related
SAEs reported Very Low Critical
RCT=randomized clinical trial
a. Study design is an open label non -randomized controlled trial with no comparator group
b. Study population did not include children with underlying conditions
c. No vaccine -related serious adverse events reported; relative risk crossing 1
Reference
B7471014. Safety and Immunogenicity Study of 20vPnC in Healthy Children 15 Months Through 17 Years of Age
77