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 Unpublished data from trials identified through clinicaltrials.gov, but not yet publicly available, were provided by the vaccine manufacturers.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 |
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
% seroresponders
|
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
% seroresponders
|
Low |
CI=confidence interval, GMT=geometric mean titer, QIV=quadrivalent inactivated influenza vaccine, RCT=randomized controlled trial
- % seroresponders = proportions of participants with a ≥4-fold rise in serotype-specific opsonophagocytic assay (OPA) responses.
- 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.
- 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.
- 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.
- 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.
- 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 |
Table 4 GRADE Summary of Findings Tables
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 |
|
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 |
- Other considerations include publication bias and factors that increase the quality of evidence.
- These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.
- 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.
- 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.
- 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.
- 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.
- 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 |
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
- = 315 |
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
- = 13 |
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
- = 8 |
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
- = 156 |
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
- = 18 |
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
|
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
- Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged ≥65 years who previously received a 13-valent pneumococcal conjugate vaccine (PCV13) | CDC. September 25, 2023. Accessed August 25, 2024. https://www.cdc.gov/vaccines/acip/recs/grade/PCV20-prev-vax-older-adults.html
- Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged 19–64 years with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant who previously received a 13-valent pneumococcal conjugate vaccine (PCV13) | CDC. September 25, 2023. Accessed August 25, 2024. https://www.cdc.gov/vaccines/acip/recs/grade/PCV20-prev-vax-adults-19-64-risk-based.html
- 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
- 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