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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)						Print
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			IntroductionMethodsSummaryReferences
		
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
Table 1: Policy Questions and PICO
Population
U.S. adults aged 19–64 years with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant who previously received PCV13Intervention
One dose of PCV20Comparison
Use of PPSV23 based on currently recommended dosing and scheduleOutcomes
VT-IPD, VT-nonbacteremic pneumococcal pneumonia, VT-pneumococcal mortality, serious adverse events following vaccinationVT=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

Table 2: Outcomes and Rankings
Outcome
Importance
Included in evidence profileVT-IPD**
Critical
YesVT-nonbacteremic pneumococcal pneumonia**
Critical
YesVT-pneumococcal mortality**
Critical
YesSAEs 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 outcomesTable 3a: Summary of Studies Reporting Immunogenicity
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**
Previous PCV13 > previous PPSV23 for all 20 serotypes; significantly higher for 17/20 serotypes**%seroresponders**
Previous PCV13 > previous PPSV23 for 18/20 serotypes (not for 6A or 19A); significantly higher for 8/18 serotypes
LowPCV20 (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**
Previous PCV13+PPSV23 > previous PPSV23 for 19/20 serotypes (not for 7F); significantly higher for 23F**%seroresponders**
Previous PCV13+PPSV23 > previous PPSV23 for 3/20 serotypes (14, 15B, 33F); none significantly higherB7471004
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**
Previous PCV13 > previous PPSV23 for all 20 serotypes; significantly higher for 6/20 serotypes**%seroresponders**
Previous PCV13 > previous PPSV23 for 13/20 serotypes; significant for 15B
LowPCV20 (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**
Previous PCV13+PPSV23 > previous PPSV23 for 15/20 serotypes; significantly higher for 6B, 18C, and 23F**%seroresponders**
Previous PCV13+PPSV23 > previous PPSV23 for 6/20 serotypes; none significantly higher
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
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
LowRCT (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
Table 4: Grade Summary of Findings Table
Certainty assessment
No of patients
Results
Certainty
ImportanceNo 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
CriticalSerious 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
These are all immunogenicity studies and there are no correlates of protection for the critical outcomes considered
No studies among adults aged 19–64 years with underlying medical conditions; study populations are adults aged ≥ 65 years without immunocompromising conditions
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
Table 5. Summary of Evidence for Outcomes of Interest
Outcome
Importance
Included in profile
CertaintyVT-IPD
Critical
Yes
3VT-nonbacteremic pneumococcal pneumonia
Critical
Yes
3VT-pneumococcal mortality
Critical
Yes
3SAEs following immunization
Critical
Yes
3Summary
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 https://www.cdc.gov/vaccines/acip/recs/grade/pneumo-PCV20-age-based.html
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
March 1, 2021 – March 31, 2022
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 2021-2022Appendix 2. Studies Included in the Review of Evidence
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 sourceCannon, 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)
PfizerPCV20, previous PCV13+PPSV23: 125PCV20, previous PCV13: 248
PPSV23, previous PCV13: 127
Safety (serious adverse events following immunization)PCV20, previous PCV13+PPSV23: 125
noneB7471004*
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)
PfizerPrevious 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 + PCV20Top of Page
							
					
							Last Reviewed:  July 20, 2023						Source: 	National Center for Immunization and Respiratory Diseases
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