Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 21-valent Pneumococcal Conjugate Vaccine (PCV21) Use among Adults Aged 50–64 Years Who Currently Do Not Have a Risk-Based Pneumococcal Vaccine Indication

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Introduction

On June 27, 2024 the U.S. Advisory Committee on Immunization Practices (ACIP) recommended 21-valent pneumococcal conjugate vaccine (PCV21) as an option for adults aged ≥19 years who currently have a recommendation to receive a dose of pneumococcal conjugate vaccine (PCV). A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for evidence assessment and decision-making informed ACIP’s deliberations regarding use of this vaccine.

Methods

A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV21 among adults. 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).

We updated a previously published systematic review presented to ACIP in October 2022, which included literature published through March 2022.12 Pubmed, Embase, Cinhal, Web of Science, Epistemonikos, and Cochrane databases were searched to include published literature through September 18, 2023 using search terms listed in Appendix 1. In addition, we conducted an additional Pubmed search on October 17, 2023 using search terms specific to PCV21 and the results were further supplemented by a search of clinicaltrials.gov using "V116", "21-valent pneumococcal conjugate vaccine" or "PCV21" (Appendix 2). Unpublished data from trials identified through clinicaltrials.gov, but not yet publicly available, were provided by the vaccine manufacturers.

Studies were eligible for inclusion into the review if they presented primary data on PCV21 use from phase II or III clinical trials in adults aged ≥19 years. Of the 25 titles identified through the updated Pubmed search and 10 trials identified through clinicaltrials.gov, 6 trials met the inclusion criteria after double-screening of title/abstract and full-text screening. Eligible titles identified through the original search on September 18, 2023 were all captured through the updated Pubmed search in October. Characteristics of these studies are presented in Appendix 3. Outcomes critical and important for decision-making were previously identified by the ACIP Pneumococcal Vaccines Work Group. Work Group members rated and ranked outcomes using a survey, identifying a final list to drive the systematic review (Table 2). Vaccine-type (VT) invasive pneumococcal disease (IPD), VT nonbacteremic pneumococcal pneumonia (NBPP), VT pneumococcal mortality, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).

Tables

Table 1: Policy Question and PICO

Policy question: Should PCV21 be recommended for US adults aged 50–64 years who currently do not have a risk-based pneumococcal vaccine indication?
Population US adults aged 50–64 years who currently do not have a risk-based pneumococcal vaccine indication
Intervention One dose of PCV21
Comparison No vaccination
Outcomes VT-IPD, VT-NBPP, VT-pneumococcal mortality, serious adverse events
VT: vaccine-type, IPD: invasive pneumococcal disease, NBPP: non-bacteremic pneumococcal pneumonia

Table 2: Outcomes and Rankings

Outcome Importance* Included in evidence profile
VT-IPD Critical Yes
VT-NBPP Critical Yes
VT-pneumococcal mortality Critical Yes
Serious adverse events following immunization Critical Yes

*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making

Table 3: Summary of Studies Reporting Outcomes of Interest

Table 3a. Summary of Studies Reporting Immunogenicity

Study Study design; population and age N intervention N comparison Comparator vaccine GMT ratios, range (serotype) Absolute difference in % seroresponders1, range (serotype) Interpretation Study limitations (Risk of Bias)
Platt, Lancet ID 2023 Phase II RCT; US adults ≥50 years 252 254 PPSV23 Shared:
0.94 (33F) to 2.57 (12F)
Unique:
3.00 (15C) to 34.91 (31)
 Shared:
-7.3 (33F) to 740.1 (11A)
Unique:
17.5 (15C) to 67.5 (24F)
 GMT ratios
  • (V116)/(PPSV23)>1 for 9/12 common serotypes; 95% CI did not cross 1 for 5/9
  • (V116)/(PPSV23)>1 for 9/9 unique serotypes; 95% CI did not cross 1 for all serotypes
  • V116 met non-inferiority criteria2 for 12/12 shared and superiority criteria3 9/9 unique serotypes vs. PPSV23

% seroresponders

  • V116 > PPSV23 for 6/12 common serotypes
  • V116 > PPSV23 for 9/9 unique serotypes
 Low
V116-003 Phase III RCT; adults 18-49 years; pneumococcal vaccine – naïve 1145 - 1161 1150 - 1162 PCV20 Shared:
0.76 (19A) to 1.55 (3)
Unique:
2.03 (15C) to 38.70 (24F)
 Unique:
9.2 (15C) to 74.2 (24F)		 GMT ratios
  • (V116)/(PCV20) > 1 for 6/10 shared serotypes; 95% CI did not cross 1 for 4/6
  • (V116)/(PCV20) > 1 for 11/11 unique serotypes; 95% CI did not cross 1 for all serotypes
  • V116 met non-inferiority criteria4 for 10/10 shared and superiority criteria5 for 10/11 unique serotypes (not st15C) vs. PCV20

% seroresponders

  • V116 > PCV20 for 11/11 unique serotypes
  • V116 met superiority criteria6 for 10/11 unique serotypes (not st15C) vs. PCV20
 Low

CI=confidence interval, GMT=geometric mean titer, QIV=quadrivalent inactivated influenza vaccine, RCT=randomized controlled trial

  1. % seroresponders = proportions of participants with a ≥4-fold rise in serotype-specific opsonophagocytic assay (OPA) responses.
  2. Noninferiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio ({V116:PPSV23} to be > 0.33.
  3. Superiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio [V116:PPSV23] to be > 1.0.
  4. Noninferiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be >0.5.
  5. Superiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be >2.0.
  6. Superiority for difference in proportions of participants with a ≥4-fold rise in serotype-specific OPA responses from baseline to 30 days postvaccination was defined as the lower bound of the 2-sided 95% CI of the differences [V116 / PCV20] between the proportions of participants with a ≥4-fold rise from baseline to 30 days postvaccination to be >0.1.

Table 3b. Summary of Studies Reporting Safety

Study Study design; population and age N participants, intervention N participants, comparison Comparator vaccine Absolute % difference
(% SAE PCV21 –
% SAE comparator)		 Number related to vaccine Study limitations (Risk of Bias)
Platt, Lancet ID 2023 Phase II RCT; US adults ≥50 years 254 254 PPSV23 1% 0 Low
V116-003 Phase III RCT; adults ≥50 years; pneumococcal vaccine – naïve 1177 1175 PCV20 -0.4% (-1.6, 0.7) 0 Low
SAE= serious adverse event

Table 4 GRADE Summary of Findings Tables

References in this table:34

Certainty assessment № of patients Effect Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerationsa PCV21 Comparison Relative
(95% CI)		 Absolute
(95% CI)
VT-IPD, VT-NBPP, VT-pneumococcal mortality outcome (Assessed with: Immunogenicity)
23,4 Randomized studies Not serious Not serious Seriousb Not serious Not serious 252 - 1161 254 - 1162
  • V116 met non-inferiority criteriac for 9/9 shared and superiority criteriad for 12/12 unique serotypes vs. PPSV23
  • V116 met non-inferiority criteriae for 10/10 shared and superiority criteriaf 10/11 unique serotypes vs. PCV20
 Moderate Critical
Serious adverse events following immunization
23,4 Randomized studies Not serious Not serious Not serious Seriousg Not serious 23/1431
(1.6%)		 27/1429
(1.9%)		 Absolute % difference for SAEs across studies is -0.3%; no vaccine-related serious adverse events reported Moderate Critical
  1. Other considerations include publication bias and factors that increase the quality of evidence.
  2. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
  3. Noninferiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio ({V116:PPSV23} to be > 0.33.
  4. Superiority for GMT ratio was defined as the lower bound of the 95% CI of the estimated OPA GMT ratio [V116:PPSV23] to be > 1.0.
  5. Noninferiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be >0.5.
  6. Superiority for GMT ratio was defined as the lower bound of the 2 sided 95% CI of the OPA GMT ratio [V116 / PCV20] to be >2.0.
  7. No vaccine-related serious adverse events reported.

Table 5: Summary of Evidence for Outcomes of Interest

Outcome Importance Included in profile Certainty
VT-IPD Critical Yes* Moderate
VT-NBPP Critical Yes* Moderate
VT-pneumococcal mortality Critical Yes* 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 certainty of evidence for use of PCV21 for adults aged 50–64 years who currently do not have a risk-based pneumococcal vaccine indication was determined to be moderate for VT-IPD, VT-NBPP, and VT-pneumococcal mortality. Assessment on indirectness was downgraded to serious since only immunogenicity studies were available and there are no established correlates of protection for PCV21 against some of the critical outcomes. The certainty of evidence for SAEs following immunization was determined to be moderate; assessment on imprecision was downgraded to serious because few vaccine-related serious adverse events were reported in studies with small sample sizes. ACIP reviewed the results of both the GRADE evidence assessment and the Evidence to Recommendations (EtR) framework during February and June 2024 ACIP meetings. On June 27, 2024, ACIP recommended the use of PCV21 as an option for adults aged ≥19 years who currently have a recommendation to receive a dose of PCV.

Appendices

Appendix 1. Search Strategy

Database Strategy Run Date Records
Medline
(OVID)		 1. streptococcus pneumoniae/
2. (pneumococcal or pneumococci or "streptococcus pneumonie" or "streptococcus pneumoniae" or "s pneumoniae").tw,kf.
3. 1 or 2
4. vaccination/ or immunization/ or Vaccines, Conjugate/
5. (vaccine? or vaccination? or immunisation or immunization).tw,kf.
6. 4 or 5
7. Pneumococcal Vaccines/
8. (heptavalent or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or pcv10 or "pcv 10" or "13valent" or "13 valent" or pcv13 or "pcv 13" or ppv23 or "ppv 23" or "23 valent" or "23valent").tw,kf.
9. 7 or 8
10. (3 and 6)
11. 10 or 9
12. comparative effectiveness research/ or treatment outcome/ or Vaccine Potency/
13. (efficacy or effectiveness or effects or "immune response" or impact or "treatment outcome").tw,kf.
14. 12 or 13
15. exp adult/
16. (adult? or elderly or elderlies).tw,kf.
17. 15 or 16
18. 11 and 14 and 17
March 2022 - current
 09/18/2023 203
Embase
(OVID)
1988-		 1. Streptococcus pneumoniae/
2. (pneumococcal or pneumococci or "streptococcus pneumonie" or "streptococcus pneumoniae" or "s pneumoniae").tw,kw.
3. 1 or 2
4. vaccination/ or immunization/ or vaccine/
5. (vaccine? or vaccination? or immunisation or immunization).tw,kw.
6. 4 or 5
7. Pneumococcus vaccine/
8. (heptavalent or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or pcv10 or "pcv 10" or "13valent" or "13 valent" or pcv13 or "pcv 13" or ppv23 or "ppv 23" or "23 valent" or "23valent").tw,kw.
9. 7 or 8
10. 3 and 6
11. 9 OR 10
12. comparative effectiveness/ or treatment outcome/
13. (efficacy or effectiveness or effects or "immune response" or impact or "treatment outcome").tw,kw.
14. 12 or 13
15. exp adult/
16. (adult? or elderly or elderlies).tw,kw.
17. 15 or 16
18. 11 and 14 and 17
March 2022 - current
 09/18/2023 495

-
duplicates

= 315
unique items
Cochrane Library (
(
(pneumococcal or pneumococci or "streptococcus pneumonie" or "streptococcus pneumoniae" or "s pneumoniae"):ti,ab
AND
([mh Vaccines] OR [mh Immunization] OR (vaccine# or vaccination# or immunisation or immunization):ti,ab)
)
OR
[mh "Pneumococcal Vaccine"] OR (heptavalent or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or pcv10 or "pcv 10" or "13valent" or "13 valent" or pcv13 or "pcv 13" or ppv23 or "ppv 23" or "23 valent" or "23valent") OR AB (heptavalent or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or pcv10 or "pcv 10" or "13valent" or "13 valent" or pcv13 or "pcv 13" or ppv23 or "ppv 23" or "23 valent" or "23valent")
)
AND[mh "Treatment Outcomes"] OR (efficacy or effectiveness or effects or "immune response" or impact or "treatment outcome"):ti,abAND[mh ^Adult] OR (adult# or elderly or elderlies):ti,ab
March 2022 - current
 09/18/2023 21

-
duplicates

= 13
unique items
CINAHL
(EbscoHost)		 (
(TI (pneumococcal or pneumococci or "streptococcus pneumonie" or "streptococcus pneumoniae" or "s pneumoniae") OR AB (pneumococcal or pneumococci or "streptococcus pneumonie" or "streptococcus pneumoniae" or "s pneumoniae")) AND ((MH "Vaccines") OR (MH "Immunization") OR TI (vaccine# or vaccination# or immunisation or immunization) OR AB (vaccine# or vaccination# or immunisation or immunization))
OR
(MH "Pneumococcal Vaccine") OR TI (heptavalent or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or pcv10 or "pcv 10" or "13valent" or "13 valent" or pcv13 or "pcv 13" or ppv23 or "ppv 23" or "23 valent" or "23valent") OR AB (heptavalent or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or pcv10 or "pcv 10" or "13valent" or "13 valent" or pcv13 or "pcv 13" or ppv23 or "ppv 23" or "23 valent" or "23valent")
)
AND
(MH "Treatment Outcomes") OR TI (efficacy or effectiveness or effects or "immune response" or impact or "treatment outcome") OR AB (efficacy or effectiveness or effects or "immune response" or impact or "treatment outcome")
AND
((MH "Adult+") OR (MH "Aged+") OR TI (adult# or elderly or elderlies) OR AB (adult# or elderly or elderlies))
March 2022 - current
 09/18/2023 39

-
duplicates

= 8
unique items
Scopus
(for WOS)		 (TITLE-ABS-KEY("heptavalent" or "7 valent" or "7valent" or "pcv 7" or pcv7* or "10 valent" or "10valent" or "pcv10" or "pcv 10" or "13valent" or "13 valent" or "pcv13" or "pcv 13" or "ppv23" or "ppv 23" or "23 valent" or "23valent") OR (TITLE-ABS-KEY("vaccine$" or "vaccination$" or "immunisation" or "immunization") AND TITLE-ABS-KEY("pneumococcal" or "pneumococci" or "streptococcus pneumonie" or "streptococcus pneumoniae" or "s pneumoniae"))) AND TITLE-ABS-KEY("adult$" or "elderly" or "elderlies") AND TITLE-ABS-KEY("efficacy" or "effectiveness" or "effects" or "immune response" or "impact" or "treatment outcome")
March 2022 - September 2023
 09/18/2023 525

-
duplicates

= 156
unique items
Epistemonikos Search 1:
(pneumococcal OR pneumococci OR "streptococcus pneumonie" OR "streptococcus pneumoniae" OR "s pneumoniae") AND (vaccine* OR vaccination* OR immunisation OR immunization) AND (efficacy OR effectiveness OR effects OR "immune response" OR impact OR "treatment outcome") AND (adult* OR elderly OR elderlies)
– limited to 2022-2023Search 2:
(heptavalent OR "7 valent" OR "7valent" OR "pcv 7" OR pcv7* OR "10 valent" OR "10valent" OR pcv10 OR "pcv 10" OR "13valent" OR "13 valent" OR pcv13 OR "pcv 13" OR ppv23 OR "ppv 23" OR "23 valent" OR "23valent") AND (efficacy OR effectiveness OR effects OR "immune response" OR impact OR "treatment outcome") AND (adult* OR elderly OR elderlies)
– limited to 2022-2023 

– limited to 2022-2023

 09/18/2023 111

-
duplicates

= 18
unique items

Appendix 2. Updated Search conducted on October 17, 2023

Database Strategy
clinicaltrials.gov Search terms (searched separately): "V116"; "21-valent pneumococcal conjugate vaccine";"PCV21"
Inclusion: Relevant Phase 2 or 3 randomized controlled trials of PCV21
  • Involved human subjects
  • Reported primary data
  • Included adults (age ≥19 years)
  • Included data relevant to the efficacy or effectiveness or immunogenicity and safety outcomes being measured
Pubmed "V116" or "21-valent pneumococcal conjugate vaccine" or "PCV21"
Included studies using the criteria listed above
Additional resources Unpublished and other relevant data by consulting with vaccine manufacturers and subject matter experts

Appendix 3: Studies Included in the Review of Evidence

Study Study design Country (or more detail, if needed) Age (measure central tendency – mean/SD; median/IQR; range) Total population N Intervention N comparison Outcomes Funding source
Platt, Lancet ID 2023 RCT (Phase II) US Adults ≥50 years 508 254 PPSV23: 254 Immunogenicity and Safety MERCK
V116-003 RCT (Phase III); pivotal study US, Australia, Belgium, Chile, Germany, Korea, New Zealand, Puerto Rico, Sweden, Taiwan, Turkey Healthy adults ≥50 years, pneumococcal vaccine – naïve 2,663 1179 PCV20: 1,177 Immunogenicity and Safety MERCK
Healthy adults 18 - 49 years, pneumococcal vaccine – naïve 200 PCV20: 100

N=number of participants; RCT=randomized controlled trial

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Content Source:
National Center for Immunization and Respiratory Diseases (NCIRD)
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  3. Platt H, Omole T, Cardona J, et al. Safety, tolerability, and immunogenicity of a 21-valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, US-based trial. The Lancet Infectious diseases. Published online September 15, 2022. doi:10.1016/s1473-3099(22)00526-6
  4. Merck Sharp & Dohme LLC. A Phase 3, Randomized, Double-Blind, Active Comparator-Controlled Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine-Naïve Adults. clinicaltrials.gov; 2023. Accessed December 31, 2023. https://clinicaltrials.gov/study/NCT05425732