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 October 19, 2022, the U.S. Advisory Committee on Immunization Practices (ACIP) recommended the use of either a dose of 20-valent pneumococcal conjugate vaccine (PCV20) or 23-valent pneumococcal polysaccharide vaccine (PPSV23) as previously recommended for adults who have received 13-valent pneumococcal conjugate vaccine (PCV13) with an incomplete vaccination status. 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 PCV20 among adults who have previously received pneumococcal vaccine 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
VT=vaccine-type, IPD=invasive pneumococcal disease
We updated a previously published a systematic review conducted by the World Health Organization’s Strategic Advisory Group of Experts on Immunizations (WHO SAGE) presented to ACIP in October 2021, which included literature up to February 2021 (1). To identify literature published from March 1, 2021, through March 31, 2022, we searched Pubmed, Embase, Cinahl, Web of Science, Epistemonikos, and Cochrane databases. The search terms are included in appendix I. Search results were supplemented by a search of clinicaltrials.gov using the term “PCV20.” Unpublished data from trials identified through clinicaltrials.gov, but not yet publicly available, were provided by the vaccine manufacturers.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 PCV20 use in adults who have previously received a pneumococcal conjugate vaccine. Of the 2,499 titles screened for WHO SAGE and 1,764 titles screened for the updated review in 2021, 1 unpublished and 1 published PCV20 study were included in the analysis (2, 3). Characteristics of these studies are presented in appendix II. Outcomes critical and important for decision-making were identified by the ACIP Pneumococcal Vaccines Work Group during calls. Work Group members rated and ranked outcomes using a survey, identifying a final list to drive the systematic review (Table 2). VT invasive pneumococcal disease, VT non-bacteremic pneumococcal pneumonia, VT pneumococcal mortality, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).
Table 2: Outcomes and Rankings
*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
| Author, year | Study design; population and age | Intervention | N intervention | N comparison | Comparator vaccine | OPA GMT ratios [range (serotype)]1 | Absolute difference in % seroresponders (serotype)2 | Interpretation | Study limitations (Risk of Bias) |
|---|---|---|---|---|---|---|---|---|---|
| Cannon 2021 | RCT (Phase III); U.S. and Swedish adults aged ≥65 years with prior pneumococcal vaccination | PCV20 (1 dose) after previous PCV13 | 201 - 243 | 216 - 246 | PCV20 (1 dose), previous PPSV23 | 1.30 (11A) to 2.97 (23F) | -5.10 (6A) to 34.90 (33F) | OPA GMT ratios
%seroresponders
|
Low |
| PCV20 (1 dose) after previous PCV13+PPSV23 | 102 -121 | 216 - 246 | PCV20 (1 dose), previous PPSV23 | 0.91 (7F) to 1.93 (23F) | -19.40 (11A) to 1.00 (15B) | OPA GMT ratios
%seroresponders
|
|||
| B7471004 | RCT (Phase III); U.S. adults aged ≥65 years with prior pneumococcal vaccination; received influenza vaccination 1 month prior to PCV20 | PCV20 (1 dose) after previous PCV13 | 123 - 146 | 80 - 94 | PCV20 (1 dose), previous PPSV23 | 1.15 (5) to 2.60 (23F) | -10.4 (4) to 22.7 (15B) | OPA GMT ratios
%seroresponders
|
Low |
| PCV20 (1 dose) after previous PCV13+PPSV23 | 328 - 388 | 80 - 94 | PCV20 (1 dose), previous PPSV23 | 0.83 (11A) to 2.26 (23F) | -12.90 (4) to 7.40 (23F) | OPA GMT ratios
%seroresponders
|
Low |
OPA GMT=opsonophagocytic activity geometric mean titer, RCT=randomized clinical trial
- Ratio calculated as [GMT (PCV20) intervention]/[GMT (PCV20) comparator]; blood draws occurred 1-month post-dose.
- Seroresponse: percentage of participants with ≥4-fold rise in pneumococcal OPA titers from before to after 1 month vaccination.
Table 3b: Summary of Studies Reporting Safety
| 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) |
|---|---|---|---|---|---|---|---|
| Cannon 2021 | RCT (Phase III); U.S. and Swedish adults aged ≥65 years with previous PCV13 vaccination | 246 | 127 | PPSV23, previous PCV13 | 0.8% | 0 | Low |
| RCT (Phase III); U.S. and Swedish adults aged ≥65 years with previous PCV13 + PPSV23 vaccination | 125 | 0 | none | 1.6% | 0 |
*Reported SAEs include those that occurred after dose 1 through completion of study participation.
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 following previous PCV13 | Previous PPSV23 receipt | Relative (95% CI) |
Absolute (95% CI) |
||
| VT-IPD, VT-nonbacteremic pneumococcal pneumonia, VT-pneumococcal mortality Outcome (Assessed with: Immunogenicity) | ||||||||||||
| 21-2 | Randomized studies | Not serious | Not serious | Very seriousa,b | Not serious | Not serious | 754 - 898 | 296 - 340 | OPA GMT ratios • Previous PCV13 > previous PPSV23 for all 20 serotypes • Previous PCV13+PPSV23 > previous PPSV23 for 15 to 19 (of 20) serotypes %seroresponders • Previous PCV13 > previous PPSV23 for 13 to 18 (of 20) serotypes • Previous PCV13+PPSV23 > previous PPSV23 for 3 to 6 (of 20) serotypes |
3 | Critical | |
| Serious adverse events following immunization | ||||||||||||
| 11 | Randomized studies | Not serious | Not serious | Seriousb | Seriousc | Not serious | 8/371 | 2/127 | -- | 0.8 to 1.6% | 3 | Critical |
a. These are all immunogenicity studies and there are no correlates of protection for the critical outcomes considered
b. No studies among adults aged 19–64 years with underlying medical conditions; study populations are adults aged ≥ 65 years without immunocompromising conditions
c. Few vaccine-related SAEs reported do not meet the optimal information size
References
- Cannon K, Elder C, Young M, Scott DA, Scully IL, Baugher G, et al. A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination. Vaccine. 2021 Dec 17;39(51):7494-502.
- Pfizer Inc. B7471004 – Post hoc analysis by vaccination history. 2022.
Table 5. Summary of Evidence for Outcomes of Interest
| Outcome | Importance | Included in profile | Certainty |
|---|---|---|---|
| VT-IPD | Critical | Yes | 3 |
| VT-nonbacteremic pneumococcal pneumonia | Critical | Yes | 3 |
| VT-pneumococcal mortality | Critical | Yes | 3 |
| SAEs following immunization | Critical | Yes | 3 |
Summary
The certainty of evidence for use of PCV20 in adults aged 19–64 years with an immunocompromising condition*, cerebrospinal fluid leak, or cochlear implant who have previously received pneumococcal vaccine was determined to be 3 (low certainty of evidence) for VT-invasive pneumococcal disease, VT-pneumonia, and VT- pneumococcal deaths and was downgraded twice for indirectness to very serious: once for indirectness due to lack of correlates of protection for the critical outcomes considered and another for lack of studies among adults 19–64 years of age with underlying medical conditions; all study populations were healthy adults ≥ 65 years of age. The certainty of evidence for SAEs following immunization was 3 (low certainty of evidence) due to imprecision from few events reported and indirectness was downgraded once to serious for lack of studies among adults 19–64 years of age with underlying medical conditions. ACIP reviewed the results of both the GRADE evidence assessment and the Evidence to Recommendations (EtR) framework in October 2022. On October 19, 2022, ACIP recommended the use of either a dose of PCV20 or PPSV23 as previously recommended for adults who have received PCV13 with an incomplete vaccination status.
*chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, HIV, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplant, congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies.
References
- GRADE: 20-valent pneumococcal conjugate vaccine (PCV20) for adults aged ≥65 years. Available at GRADE: 20-valent pneumococcal conjugate vaccine (PCV20) for adults aged ≥65 years | Advisory Committee on Immunization Practices (ACIP) | CDC
- Cannon K, Elder C, Young M, Scott DA, Scully IL, Baugher G, et al. A trial to evaluate the safety and immunogenicity of a 20-valent pneumococcal conjugate vaccine in populations of adults ≥65 years of age with different prior pneumococcal vaccination. Vaccine. 2021 Dec 17;39(51):7494-502.
- Pfizer Inc. B7471004 – Post hoc analysis by vaccination history. 2022.
Appendices
Appendix 1. Search strategy
| Database | Strategy |
|---|---|
| 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. adult/ or aged/ or "aged, 80 and over"/ or frail elderly/ 16. (adult? or elderly or elderlies).tw,kf. 17. 15 or 16 18. 11 and 14 and 17 19. (202103* OR 202104* OR 202105* OR 202106* OR 202107* OR 202108* OR 202109* OR 202110* OR 202111* OR 202112* OR 202201* OR 202202* OR 202203*).ed,ep,yr,dp,dt. 20. 17 and 18 |
| 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. aged/ or adult/ or aged hospital patient/ or frail elderly/ or institutionalized elderly/ or very elderly/ 16. (adult? or elderly or elderlies).tw,kw. 17. 15 or 16 18. 11 and 14 and 17 19. (202103* OR 202104* OR 202105* OR 202106* OR 202107* OR 202108* OR 202109* OR 202110* OR 202111* OR 202112* OR 202201* OR 202202* OR 202203*).dc 20. limit 19 to (conference abstracts or embase) |
| 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 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 (efficacy or effectiveness or effects or "immune response" or impact or "treatment outcome"):ti,abAND[mh Adult] OR [mh Aged+] OR (adult# or elderly or elderlies):ti,abLimit March 2021 – March 2022 |
| 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))Limiters - Published Date: 202103-202203; Exclude MEDLINE records |
| 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")
Limit March 2021 - |
| 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 2021-2022Search 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 2021-2022 |
March 1, 2021 – March 31, 2022
Appendix 2. Studies Included in the Review of Evidence
| Last name first author, Publication year | 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 |
|---|---|---|---|---|---|---|---|---|
| Cannon, 2021 | RCT (Phase III) | US (33 sites) and Sweden (8 sites) | Adults aged ≥65 years with previous pneumococcal vaccination | Total: 875 Cohort 1 (previous PPSV23, >= 1 year): 375 Cohort 2 (previous PCV13, ≥6 months): 375 Cohort 3 (previous PCV13 and PPSV23, ≥ 1 year): 175 |
PCV20, previous PCV13: 248 | PCV20, previous PPSV23: 253 | Immunogenicity (OPA GMT ratios, absolute difference in % seroresponders) | Pfizer |
| PCV20, previous PCV13+PPSV23: 125 | ||||||||
| PCV20, previous PCV13: 248 | PPSV23, previous PCV13: 127 | Safety (serious adverse events following immunization) | ||||||
| PCV20, previous PCV13+PPSV23: 125 | none | |||||||
| B7471004* | RCT (Phase III) | US | Adults aged ≥65 years with previous pneumococcal vaccination; received influenza vaccination 1 month prior to PCV20 | Total: 668 | Previous PCV13: 157 | Previous PPSV23: 108 | Immunogenicity (OPA GMT ratios, absolute difference in % seroresponders) | Pfizer |
| Previous PCV13 and PPSV23: 403 |
*Analysis included for GRADE is post-hoc analysis of cohort who received influenza vaccination one month prior to one dose PCV20, stratified by previous pneumococcal vaccination status. Primary analysis of RCT compares separate administration of influenza vaccine and PCV20 with co-administration of influenza vaccine + PCV20