Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged <2 years

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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. 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 PICO
Policy 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?
Population U.S. children <2 years of age
Intervention PCV20 according to dosing and schedules currently recommended for PCV13 or PCV15
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.

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 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 of 20-valent Pneumococcal Conjugate Vaccine Use in Children

Table 3a. Summary of Studies Reporting Immunogenicity of 20-valent Pneumococcal Conjugate Vaccine Use in Children
Author, year Study design; population and age Intervention N intervention1 N comparison1 Comparator vaccine IgG GMC ratios [range (serotype)]2 Absolute difference in % seroresponders (serotype)3 Interpretation Study limitations (Risk of Bias)
Senders, 2021
(B7471003)		 Phase II RCT; healthy infants 42-98 days at time of consent PCV20 @ 2, 4, 6, and 12 months of age given concomitantly with DTaP, Hep B and IPV (doses 1-3) 168–189 166–187 PCV13 @ 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
 Low
B7471011 Phase III RCT, pivotal study; healthy infants 42-98 days at time of consent PCV20 @ 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) 753–833 744–802 PCV13 @ 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-inferiority4 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-inferiority4 met for 13/13 shared serotypes as measured by IgG GMC ratios.
  • Non-inferiority4 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-inferiority5 met for 8/13 shared serotypes
  • Non-inferiority5 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)
 Low
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 (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 Children

Table 3b. Summary of Studies Reporting Safety of 20-valent Pneumococcal Conjugate Vaccine Use in Children
Author, year Study Design; population and age N intervention N comparison Comparator vaccine Absolute % difference
(% SAE PCV20 –
% SAE comparator)*		 N related to vaccine Study limitations (Risk of Bias)
Senders, 2021 Phase II RCT; healthy infants 42-98 days at time of consent 231 227 PCV13 3.0 0 Low
B7471011 Phase III RCT; healthy infants 42-98 days at time of consent 1001 987 PCV13 1.4 0 Low
B7471013 Phase III RCT; healthy infants 42-98 days at time of consent 1000 503 PCV13 -1.2 0 Low

*Reported serious adverse events include those that occurred after dose 1 through 6 months after Dose 4

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 PCV13 comparison Relative
(95% CI)		 Absolute
(95% CI)
Vaccine effectiveness: vaccine-type pneumococcal disease (assessed with immunogenicity data)
21-2 Randomized studies Not serious Not serious Seriousa Not 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 endpointsb for some serotypes (1, 4, 9V, 23F, and 12F) after dose 3.
  • PCV20 noninferiorc to PCV13 for all 13 shared serotypes after dose 4.
  • PCV20 noninferiorc to PCV13 for all 7 additional serotypes after dose 4.
 Moderate Critical
Serious adverse events following immunization
21-3 Randomized studies Not serious Not serious Not serious Seriousd Not serious 101/2232 (4.5%) 64/1717 (3.7%) No vaccine-related serious adverse events reported Moderate Critical
  1. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
  2. 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.
  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.
  4. 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. 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study of a 4-Dose Series in Healthy Infants.
  3. 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 Interest

Table 5. Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty
VT- invasive pneumococcal disease Critical No* Moderate
VT- pneumonia Critical No* Moderate
Vaccine-type acute otitis media Critical No* Moderate
Vaccine-type pneumococcal deaths Critical No* Moderate
Serious adverse events following immunization Critical Yes Moderate

*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.

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,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 Evidence

Appendix 2. Studies Included in the Review of Evidence
Author, year Study design Intervention Country Age Total population N Intervention N comparison Outcomes Funding source
Senders, 2021 Phase II RCT in healthy full-term infants PCV20 @ 2, 4, 6, and 12 months of age US 42–98 days of age at consent 460 232 228 Immunogenicity and safety Pfizer
B7471011 Phase III RCT in healthy full-term infants PCV20 @ 2, 4, 6, and 12 – 15 months of age US 42–98 days of age at consent 1998 1001 997 Immunogenicity and safety Pfizer
B7471013 Phase III RCT in healthy infants PCV20 @ 2, 4, 6, and 12 – 15 months of age US, Puerto Rico, Canada, Chile, Argentina, EU 42–98 days of age at consent 1511 1000 551 Safety Pfizer
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