# Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged h1>PrintMinusRelated PagesOn This Page- Introduction
- Methods
- Summary
- References
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. 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 (PICO) was defined (Table 1).
Table 1: Policy Question and PICO
 
Table 1: Policy Questions and PICOPolicy question:Should PCV20 be routinely recommended for U.S. children <2 years of age as an option for pneumococcal conjugate vaccination according to currently recommended dosing and schedules?PopulationU.S. children <2 years of ageInterventionPCV20 according to dosing and schedules currently recommended for PCV13 or PCV15ComparisonPCV13 or PCV15 according to currently recommended dosing and schedulesOutcomesVaccine-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.

Studies were included if they included primary data on PCV20 use in children aged <2 years. Seventy-one studies were initially identified; after screening, deduplication and exclusion, 3 were 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, VT pneumococcal deaths, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).
Table 2: Outcomes and RankingsTable 2: Outcomes and RankingsOutcomeImportance*Included in evidence profileVaccine-type invasive pneumococcal diseaseCriticalNo**Vaccine-type pneumoniaCriticalNo**Vaccine-type acute otitis mediaCriticalNo**Vaccine-type pneumococcal deathsCriticalNo**Serious adverse events following immunizationCriticalYes
*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 of 20-valent Pneumococcal Conjugate Vaccine Use in ChildrenTable 3a. Summary of Studies Reporting Immunogenicity of 20-valent Pneumococcal Conjugate Vaccine Use in ChildrenAuthor, yearStudy design; population and ageInterventionN intervention1N comparison1Comparator vaccineIgG GMC ratios [range (serotype)]2Absolute difference in % seroresponders (serotype)3InterpretationStudy limitations (Risk of Bias)Senders, 2021(B7471003)Phase II RCT; healthy infants 42-98 days at time of consentPCV20 @ 2, 4, 6, and 12 months of age given concomitantly with DTaP, Hep B and IPV (doses 1-3)168–189166–187PCV13 @ 2, 4, 6, and 12 months of age given concomitantly with DTaP, Hep B and IPV (doses 1-3)*Post-dose 3*0.75 (23F) to 194 (11A)*Post-dose 4*0.62 (23F) to 1468 (22F)*Post-dose 3*-10.3 (3) to 97.8 (22F)*Post-dose 4*Not reported**GMC ratios***Post-dose 3*- PCV20 < PCV13 for 13/13 shared serotypes
- PCV20 > PCV13 for 7/7 additional serotypes

*Post-dose 4*
- PCV20 < PCV13 for 13/13 shared serotypes
- PCV20 > PCV13 for 7/7 additional serotypes

**% seroresponders***Post-dose 3*
- PCV20 > PCV13 for 6/13 shared serotypes
- PCV20 > PCV13 for 7/7 additional serotypes
LowB7471011Phase III RCT, pivotal study; healthy infants 42-98 days at time of consentPCV20 @ 2, 4, 6, and 12 – 15 months of age given concomitantly with DTaP, Hep B, IPV and Hib (doses 1-3) and MMR and varicella (dose 4)753–833744–802PCV13 @ 2, 4, 6, and 12 months of age given concomitantly with DTaP, Hep B, IPV and Hib (doses 1-3) and MMR and varicella (dose 4)*Post-dose 3*0.60 (6B, 12F) to 4.82 (15B)*Post-dose 4*0.64 (23F) to 5.95 (15B)*Post-dose 3*-18.1 (12F) to 12.8 (22F)*Post-dose 4*-12.1 (3) to 2.6 (15B)**GMC ratios***Post-dose 3*- PCV20 < PCV13 for 13/13 shared serotypes
- PCV20 > PCV13 for 6/7 additional serotypes (not for 12F)
- Non-inferiority 4  met for all 13 shared serotypes and 7 additional serotypes

*Post-dose 4*
- PCV20 < PCV13 for 13/13 shared serotypes
- PCV20 > PCV13 for 6/7 additional serotype (not for 12F)
- Non-inferiority 4  met for 13/13 shared serotypes as measured by IgG GMC ratios.
- Non-inferiority 4  met for 7/7 additional serotypes as measured by IgG GMC ratios.

**% seroresponders***Post-dose 3*
- PCV20 < PCV13 for 12/13 shared serotypes
- PCV20 > PCV13 for 5/7 additional serotypes
- Non-inferiority 5  met for 8/13 shared serotypes
- Non-inferiority 5  met for 6/7 additional serotypes

*Post-dose 4*
- PCV20 < PCV13 for 10/13 shared serotypes
- PCV20 > PCV13 for 6/7 additional serotypes (not st12F)
Low1 The range in numbers reflect the differences in number of participants included for assessment by the endpoints that were assessed2 Ratio calculated as [GMC (PCV20)]/[GMC (comparator vaccine)]; blood draws occurred 30 days or 1 month post-dose.3 Seroresponse: proportion of participants 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; blood draws occurred 30 days or 1 month post-dose.4 Non-inferiority measured 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 3.5 Non-inferiority measured as the lower bound of 2-sided 95% confidence interval for percent difference (PCV20-PCV13)>-10% of participants with IgG concentrations above predefined concentrations 1 month after the infant doses; predefined IgG concentration – ≥0.35 μg/mL for all serotypes except ≥ 0.23 μg/mL, ≥ 0.10 μg/mL and ≥ 0.12μg/mL for serotypes 5, 6B and 19A respectively.Table 3b. Summary of Studies Reporting Safety of 20-valent Pneumococcal Conjugate Vaccine Use in ChildrenTable 3b. Summary of Studies Reporting Safety of 20-valent Pneumococcal Conjugate Vaccine Use in ChildrenAuthor, yearStudy Design; population and ageN interventionN comparisonComparator vaccineAbsolute % difference(% SAE PCV20 –% SAE comparator)*N related to vaccineStudy limitations (Risk of Bias)Senders, 2021Phase II RCT; healthy infants 42-98 days at time of consent231227PCV133.00LowB7471011Phase III RCT; healthy infants 42-98 days at time of consent1001987PCV131.40LowB7471013Phase III RCT; healthy infants 42-98 days at time of consent1000503PCV13-1.20Low
*Reported serious adverse events include those that occurred after dose 1 through 6 months after Dose 4
Table 4. Grade Summary of Findings TableTable 4. Grade Summary of Findings TableCertainty assessmentNo of patientsResultsCertaintyImportanceNo of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsPCV20 InterventionPCV13 comparisonRelative(95% CI)Absolute(95% CI)Vaccine effectiveness: vaccine-type pneumococcal disease (assessed with immunogenicity data)**21-2**Randomized studiesNot seriousNot seriousSeriousaNot seriousNot serious921-1022910-989- PCV20 had numerically lower immune responses compared with PCV13 for most of the 13 shared serotypes.
- PCV20 did not meet one of the noninferiority endpoints b  for some serotypes (1, 4, 9V, 23F, and 12F) after dose 3.
- PCV20 noninferior c  to PCV13 for all 13 shared serotypes after dose 4.
- PCV20 noninferior c  to PCV13 for all 7 additional serotypes after dose 4.
ModerateCriticalSerious adverse events following immunization**21-3**Randomized studiesNot seriousNot seriousNot seriousSeriousdNot serious101/2232 (4.5%)64/1717 (3.7%)No vaccine-related serious adverse events reportedModerateCritical- These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
- Noninferiority for difference in percentages of participants meeting predefined IgG threshold value was defined as the lower 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.
- 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.
- No vaccine-related serious adverse events reported.

**References**
- 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.
- B7471011. 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study of a 4-Dose Series in Healthy Infants.
- B7471013. A Phase 3, Randomized, double-blind trial to evaluate the safety of a 20-valent pneumococcal conjugate vaccine in healthy infants.
Table 5. Summary of Evidence for Outcomes of InterestTable 5. Summary of Evidence for Outcomes of InterestOutcomeImportanceIncluded in profileCertaintyVT- invasive pneumococcal diseaseCriticalNo*ModerateVT- pneumoniaCriticalNo*ModerateVaccine-type acute otitis mediaCriticalNo*ModerateVaccine-type pneumococcal deathsCriticalNo*ModerateSerious adverse events following immunizationCriticalYesModerate
*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 years was determined to be a moderate certainty of evidence for VT-invasive pneumococcal disease, VT-pneumonia, VT-acute otitis media and VT- pneumococcal deaths and was downgraded once for indirectness due to lack of correlates of protection for some of the critical outcomes considered. The evidence type for serious adverse events following immunization was also a moderate certainty of evidence; imprecision was downgraded once 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 of 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.
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.

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.

B7471011. 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study of a 4-Dose Series in Healthy Infants. Accessed August 24, 2023 at https://clinicaltrials.gov/study/NCT04382326?term=B7471011%20&rank=1.

B7471013. A Phase 3, Randomized, double-blind trial to evaluate the safety of a 20-valent pneumococcal conjugate vaccine in healthy infants. Accessed August 24, 2023 at https://clinicaltrials.gov/study/NCT04379713?term=B7471013&rank=1.
AppendicesAppendix 1. Search strategyAppendix 1. Search strategyDatabaseStrategy**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”)ANDExp Child/ OR (Child* OR pediatric* OR paediatric*).ti,ab,kf,hw.ANDTrial* 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”)ANDExp Child/ OR (Child* OR pediatric* OR paediatric*).ti,ab,kw,hw.ANDTrial* OR study OR studies OR rct* OR review.ti,pt.NOTexp 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,abAND[mh Child] OR (Child* OR pediatric* OR paediatric*):ti,abLimit 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 EvidenceAppendix 2. Studies Included in the Review of EvidenceAuthor, yearStudy designInterventionCountryAgeTotal populationN InterventionN comparisonOutcomesFunding sourceSenders, 2021Phase II RCT in healthy full-term infantsPCV20 @ 2, 4, 6, and 12 months of ageUS42–98 days of age at consent460232228Immunogenicity and safetyPfizerB7471011Phase III RCT in healthy full-term infantsPCV20 @ 2, 4, 6, and 12 – 15 months of ageUS42–98 days of age at consent19981001997Immunogenicity and safetyPfizerB7471013Phase III RCT in healthy infantsPCV20 @ 2, 4, 6, and 12 – 15 months of ageUS, Puerto Rico, Canada, Chile, Argentina, EU42–98 days of age at consent15111000551SafetyPfizerTop of Page						Last Reviewed:  September 11, 2023Source: 	National Center for Immunization and Respiratory Diseases- Facebook
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