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

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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 conditions
Intervention PCV20 (without PPSV23) for all PCV-unvaccinated children
Comparison PCV13 or PCV15 according to currently recommended dosing and schedules
Outcomes Vaccine-type invasive pneumococcal disease, vaccine-type pneumonia, vaccine-type acute otitis media, vaccine-type pneumococcal deaths, serious adverse events following immunization

This 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 2019

In 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 profile
Vaccine-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 outcomes

Table 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 concerns4
Single 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 serotypes
Single 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 serotypes
Single 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
  1. The range in numbers reflect the differences in number of participants included for assessment by the endpoints that were assessed
  2. Ratio calculated as [GMC (before PCV20 dose)]/[GMC (post-PCV20 dose)]; blood draws occurred 30 days or 1 month post-dose.
  3. 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.
  4. 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 concerns2
Phase III non-RCT; healthy children 2y to <5y previously vaccinated 216 n/a None 0 0
Phase III non-RCT; healthy children 5y to <10y 201 n/a None 1 0
Phase III non-RCT; healthy children 10y to <18y 205 n/a None 3 0
  1. Reported serious adverse events include those that occurred from vaccination through 6 months after vaccination.
  2. 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 № of patients Results Certainty Importance
№ 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 Critical
Serious 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
  1. 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.
  2. Study population did not include children with underlying conditions.
  3. This is an immunogenicity study and there are no correlates of protection for some critical outcomes considered.
  4. No vaccine-related serious adverse events reported.

References

  1. 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 Certainty
VT- invasive pneumococcal disease Critical No* Very low
VT- pneumonia Critical No* Very low
Vaccine-type acute otitis media Critical No* Very low
Vaccine-type pneumococcal deaths Critical No* Very low
Serious adverse events following immunization Critical Yes Very low

*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes

Summary

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 source
B7471014 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 Pfizer
Single dose PCV20 @ 2y to <5y; previous vaccination ≥3 doses of PCV13 2y to <5y 216 216 None
Single dose PCV20 @ 5y to <10y 5y to <10y 201 201 None
Single dose PCV20 @ 10y to <18y 10y to <18y 205 205 None
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