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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged 2 through 18 years with underlying medical conditions						Print
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			IntroductionMethodsSummaryReferences
		
Introduction
On June 22, 2023, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended use of 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.]) as an option to 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) for: routine vaccination of all children aged 2–23 months; catch-up vaccination for healthy children aged 24–59 months who have not received age-appropriate doses; and children aged 24–71 months with certain underlying medical conditions at increased risk for pneumococcal disease* who have not received age-appropriate doses. In addition, recommendations were updated for children aged 2–18 years with any risk conditions. Indications for risk-based pneumococcal vaccine recommendations were expanded to include children with chronic kidney disease (even if not on maintenance dialysis or nephrotic syndrome), chronic liver disease, and moderate persistent or severe persistent asthma (regardless of high-dose oral corticosteroids use). A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP’s deliberations regarding use of this vaccine.
*Underlying medical 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 persistent 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 neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; and sickle cell disease or other hemoglobinopathies).Methods
A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV20 among pediatric age groups for which the vaccine was approved.  Since only immunogenicity and safety data were available for PCV20, the search included PCV13 efficacy or effectiveness studies to help interpret PCV20 immunogenicity study findings. GRADE assessment was performed for PCV20 studies only. As a basis for the GRADE evidence assessment, the policy question consisting of the population, intervention, comparison, and outcomes of interest was defined (Table 1).Table 1: Policy Question and PICO
Table 1: Policy Questions and PICO
**Policy question:**
Should PCV20 without PPSV23 be recommended as an option for pneumococcal vaccination for U.S. children 2-18 years with underlying conditions according to currently recommended dosing and schedules?Population
U.S. children 2-18 years with underlying medical conditionsIntervention
PCV20 (without PPSV23) for all PCV-unvaccinated childrenComparison
PCV13 or PCV15 according to currently recommended dosing and schedulesOutcomes
Vaccine-type invasive pneumococcal disease, vaccine-type pneumonia, vaccine-type acute otitis media, vaccine-type pneumococcal deaths, serious adverse events following immunizationThis systematic review leveraged strategies used in existing systematic reviews, which captured literature published between January 1994–December 2019 targeting PCV7, PCV10 and PCV13 using various dosing schedules in the general pediatric population. Specifically, we utilized:
Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules (Loo 2014); searched literature from January 1994 – September 2010
Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules and Products (Cohen 2017); searched literature from October 2010 – December 2016
Updated literature search to Cohen 2017, which was conducted to review evidence regarding dosing schedule changes; searched literature from January 2017 – December 2019In addition, we conducted a search of literature published during January 2010–October 2022 from the following databases: Medline (OVID), Embase (OVID), Cochrane Library, CINAHL (EbscoHost), Scopus (for WOS). The search terms are included in Appendix 1. The updated search sought to capture:
Pneumococcal vaccine studies specifically targeting children with underlying medical conditions, which were not captured in the previous literature searches,
Additional literature on pneumococcal vaccines published since January 2020 to update the previous systematic reviews evaluating PCV13 use in the general pediatric populations.Search results were supplemented by an updated Pubmed search using “PCV20 or 20-valent pneumococcal conjugate vaccine” and a search of clinicaltrials.gov using “20-valent pneumococcal”, limiting to trials in children aged <19 years. Unpublished data were provided by the vaccine manufacturer.
Due to a paucity of evidence in children with underlying medical conditions, studies were included if they included primary data on PCV20 use in children aged 2-18 years. Seventy-one studies were initially identified; after screening, deduplication and exclusion, 1 was included for GRADE. No PCV20 studies directly assessed vaccine effectiveness against the critical outcomes. Characteristics of this study are included in Appendix II.  Beneficial and harmful outcomes for the GRADE assessment were selected by the ACIP Pneumococcal Vaccines Work Group during calls and via an email survey in which Work Group members were asked to rank the relative importance of each outcome. Vaccine-type (VT) invasive pneumococcal disease, VT non-bacteremic pneumococcal pneumonia, VT acute otitis media, vaccine-type pneumococcal deaths, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).Table 2: Outcomes and Rankings
Table 2: Outcomes and Rankings
Outcome
Importance
Included in evidence profileVaccine-type invasive pneumococcal disease
Critical
No**Vaccine-type pneumonia
Critical
No**Vaccine-type acute otitis media
Critical
No**Vaccine-type pneumococcal deaths
Critical
No**Serious adverse events following immunization
Critical
Yes*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making
**No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomesTable 3a: Summary of Studies Reporting Immunogenicity
Table 3a. Summary of Studies Reporting Immunogenicity
Author, year
Study design;
population and age
Intervention
N intervention1
N comparison1
Comparator vaccine
IgG GMC ratios [range (serotype)]2
% seroresponders [range (serotype)]3
Interpretation
Study limitations
(Risk of Bias)B7471014
Phase III non-randomized clinical trial; healthy children 15m to <18 years
Single dose PCV20 @ 15m to <24m; previous vaccination ≥3 doses of PCV13
188–190
n/a
None
3.02 (7F) to 7.0 (19A)
22.0 (12F) to 957.0 (22F)
40.0 (12F) to 100.0 (8)
IgG GMCs were higher 1-month post-PCV20 dose compared to before vaccination for 13/13 shared serotypes and 7/7 additional serotypes
Some concerns4Single dose PCV20 @ 2y to <5y; previous vaccination ≥3 doses of PCV13
183
n/a
None
12.6 (7F) to 45.1 (6A)
38.0 (12F) to 623.0 (22F)
Not reported
IgG GMCs were higher 1-month post-PCV20 dose compared to before vaccination for 13/13 shared serotypes and 7/7 additional serotypesSingle dose PCV20 @ 5y to <10y
184–186
n/a
None
0.68 (14) to 124.8 (6B)
23.3 (11A) to 196.0 (22F)
Not reported
IgG GMCs were higher 1-month post-PCV20 dose compared to before vaccination for 13/13 shared serotypes and 7/7 additional serotypesSingle dose PCV20 @ 10y to <18y
197–198
n/a
None
4.1 (3) to 97.1 (14)
10.4 (11A) to 88.3 (22F)
Not reported
IgG GMCs were higher 1-month post-PCV20 dose compared to before vaccination for 13/13 shared serotypes and 7/7 additional serotypes
The range in numbers reflect the differences in number of participants included for assessment by the endpoints that were assessed
Ratio calculated as [GMC (before PCV20 dose)]/[GMC (post-PCV20 dose)]; blood draws occurred 30 days or 1 month post-dose.
Seroresponse: proportion of participants meeting IgG threshold value of >=0.35μg/mL; blood draws occurred 30 days or 1 month post-dose. Only reported for the 7 additional serotypes unique to PCV20.
Study was a non-randomized, single arm trial comparing the immune response of a single PCV20 dose before and 1 month after vaccination; no randomization, no comparison group.Table 3b: Summary of Studies Reporting Safety
Table 3b: Summary of Studies Reporting Safety
Author, year
Study Design; population and age
N intervention
N comparison
Comparator vaccine
SAE reported1
N related to vaccine
Study limitations (Risk of Bias)B7471014
Phase III non-RCT; healthy children 15m to <24m previously vaccinated
209
n/a
None
2
0
Some concerns2Phase III non-RCT; healthy children 2y to <5y previously vaccinated
216
n/a
None
0
0Phase III non-RCT; healthy children 5y to <10y
201
n/a
None
1
0Phase III non-RCT; healthy children 10y to <18y
205
n/a
None
3
0
Reported serious adverse events include those that occurred from vaccination through 6 months after vaccination.
Study was a non-randomized, single arm trial comparing the immune response of a single PCV20 dose before and 1 month after vaccination; no randomization, no comparison group.Table 4: Grade Summary of Findings Table
Table 4: Grade Summary of Findings Table
Certainty assessment
No of patients
Results
Certainty
ImportanceNo of studies
Study design
Risk of bias
Inconsistency
Indirectness
Imprecision
Other considerations
**PCV20****Intervention**
Relative
(95% CI)
Absolute
(95% CI)Vaccine effectiveness: vaccine-type pneumococcal disease (assessed with immunogenicity data)**11**
Non-randomized clinical trial
Very seriousa
Not applicable
Very Seriousb,c
Not serious
Not serious
752-757
IgG 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 groups
Very Low
CriticalSerious adverse events following immunization**11**
Randomized studies
Very seriousa
Not applicable
Seriousb
Seriousd
Not serious
5/831 (0.6%)
No vaccine-related SAEs reported
Very Low
Critical
Study design is an open label non-randomized controlled trial with no comparator group. Downgraded for lack of randomization, lack of blinding, and lack of a comparison group.
Study population did not include children with underlying conditions.
This is an immunogenicity study and there are no correlates of protection for some critical outcomes considered.
No vaccine-related serious adverse events reported.**References**
B7471014. Safety and Immunogenicity Study of 20vPnC in Healthy Children 15 Months Through 17 Years of Age.Table 5. Summary of Evidence for Outcomes of Interest
Table 5. Summary of Evidence for Outcomes of Interest
Outcome
Importance
Included in profile
CertaintyVT- invasive pneumococcal disease
Critical
No*
Very lowVT- pneumonia
Critical
No*
Very lowVaccine-type acute otitis media
Critical
No*
Very lowVaccine-type pneumococcal deaths
Critical
No*
Very lowSerious adverse events following immunization
Critical
Yes
Very low
*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomesSummary
The evidence type for use of PCV20 in children aged 2-18 years of age with underlying medical conditions was determined to be a very low certainty of evidence for VT-invasive pneumococcal disease, VT-pneumonia, VT-acute otitis media and VT- pneumococcal deaths. The study design was an open label non-randomized clinical trial with no comparator group and risk of bias was downgraded to very serious due to a lack of randomization, lack of blinding, and lack of a comparison group.
Indirectness was downgraded twice to very serious due to lack of correlates of protection for some of the critical outcomes considered and the study population did not include children with underlying conditions. The evidence type for serious adverse events following immunization was a very low certainty of evidence.  Risk of bias was downgraded to very serious for lack of randomization, lack of blinding, and lack of a comparison group. Indirectness and imprecision were downgraded to serious; indirectness because the study population did not include children with underlying conditions and imprecision for no vaccine-related serious adverse events reported. The ACIP reviewed the results of both the GRADE evidence assessment and the preliminary Work Group interpretation Evidence to Recommendations (EtR) framework in February 2023. An updated EtR table was shared with the ACIP in June 2023. On June 22 2023, the ACIP recommended use of PCV20 as an option to PCV15 for: routine vaccination of all children aged 2–23 months; catch-up vaccination for healthy children aged 24–59 months who have not received age-appropriate doses; and children aged 24–71 months with certain underlying medical conditions at increased risk for pneumococcal disease who have not received age-appropriate doses. In addition, recommendations were updated for children aged 2–18 years with any risk conditions. Indications for risk-based pneumococcal vaccine recommendations were expanded to include children with chronic kidney disease (even if not on maintenance dialysis or nephrotic syndrome), chronic liver disease, and moderate persistent or severe persistent asthma (regardless of high-dose oral corticosteroids use).
References
Loo JD, Conklin L, Deloria Knoll M, Fleming-Dutra K, et al. Methods for a Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules. PIDJ. 2014; 33(1,S2); S182-S187.
Cohen OG. Pneumococcal Conjugate Vaccine (PCV) Product Assessment. Accessed August 2, 2021 at https://www.jhsph.edu/ivac/wp-content/uploads/2018/05/pcv-product-assessment-april-25-2017.pdf.
B7471014. Safety and Immunogenicity Study of 20vPnC in Healthy Children 15 Months Through 17 Years of Age. Accessed August 24, 2023 at https://clinicaltrials.gov/study/NCT04642079?term=B7471014&rank=1.Appendices
Appendix 1. Search strategy
Appendix 1. Search strategy
Database
Strategy**Medline****(OVID)****1946-**
(((pneumococcal OR pneumococci OR streptococcus pneumoni* OR s? pneumoni*) ADJ5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR pnu immune vaccine* OR pnuimmune vaccine* OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”)
AND
Exp Child/ OR (Child* OR pediatric* OR paediatric*).ti,ab,kf,hw.
AND
Trial* OR study OR studies OR rct* OR review.ti,pt.
Limit English; 2010 –**Embase****(OVID)****1988-**
(((pneumococcal OR pneumococci OR streptococcus pneumoni* OR s? pneumoni*) ADJ5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR pnu immune vaccine* OR pnuimmune vaccine* OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”)
AND
Exp Child/ OR (Child* OR pediatric* OR paediatric*).ti,ab,kw,hw.
AND
Trial* OR study OR studies OR rct* OR review.ti,pt.
NOT
exp animal/ NOT exp human/
Limit English; 2010 – ; not pubmed/medline ; not conference abstracts**Cochrane Library**
[mh “pneumococcal vaccines”] OR (((pneumococcal OR pneumococci OR streptococcus pneumoni* OR s? pneumoni*) ADJ5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR pnu immune vaccine* OR pnuimmune vaccine* OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”):ti,ab
AND
[mh Child] OR (Child* OR pediatric* OR paediatric*):ti,ab
Limit English; 2010 –**CINAHL****(EbscoHost)**
(((pneumococcal OR pneumococci OR “streptococcus pneumoni*” OR “s? pneumoni*”) N5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR “pnu immune vaccine*” OR “pnuimmune vaccine*” OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”)
AND
(Child* OR pediatric* OR paediatric*)
Limit English; 2010 – ; exclude Medline records**Scopus**
**TITLE-ABS-KEY**(((pneumococcal OR pneumococci OR “streptococcus pneumoni*” OR “s? pneumoni*”) W/5 (vaccin* OR immunization* OR immunisation*)) OR pneumovax OR “pnu immune vaccine*” OR “pnuimmune vaccine*” OR ppv23 OR “ppv 23” OR “23 valent” OR “23valent”) AND**TITLE-ABS-KEY**(Child* OR pediatric* OR paediatric*) AND NOT INDEX(medline)
Limit English; 2010 – ;Appendix 2. Studies Included in the Review of Evidence
Appendix 2. Studies Included in the Review of Evidence
Last name first author, Publication year
Study design
Intervention
Country
Age
Total population
N Intervention
N comparison
Outcomes
Funding sourceB7471014
Phase III non-randomized clinical trial in healthy children, some previously vaccinated
Single dose PCV20 @ 15m to <24m; previous vaccination ≥3 doses of PCV13
US
15m to <24m
209
209
None
Immunogenicity and safety
PfizerSingle dose PCV20 @ 2y to <5y; previous vaccination ≥3 doses of PCV13
2y to <5y
216
216
NoneSingle dose PCV20 @ 5y to <10y
5y to <10y
201
201
NoneSingle dose PCV20 @ 10y to <18y
10y to <18y
205
205
NoneTop of Page
							
					
							Last Reviewed:  September 11, 2023						Source: 	National Center for Immunization and Respiratory Diseases
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