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)

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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. In addition, ACIP recommended shared clinical decision-making regarding administration of PCV20 for adults aged ≥65 years who completed their vaccine series with both PCV13 and PSPV23. 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 PCV20.

Methods

A systematic literature search was completed to review all available evidence on the efficacy, effectiveness, or 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 ≥65 years who previously received PCV13
Intervention One dose of PCV20
Comparison Use of PPSV23 based on currently recommended dosing and schedule
Outcomes VT-IPD, VT-nonbacteremic pneumococcal pneumonia, VT-pneumococcal mortality, serious adverse events following vaccination

VT=vaccine-type, IPD=invasive pneumococcal disease

We updated a previously published 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 in the review if they presented primary data on PCV20 use in adults who 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). Vaccine-type (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 profile
VT-IPD** Critical Yes
VT-nonbacteremic pneumococcal pneumonia** Critical Yes
VT-pneumococcal mortality** Critical Yes
SAEs 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

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
 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
  • 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 higher
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 vaccine 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
 Low
PCV20 (1 dose) after previous PCV13+PPSV23 328 – 388 80 – 94 PCV20 (1 dose), previous PPSV23 vaccine 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

  1. Ratio calculated as [GMT (PCV20) intervention]/[GMT (PCV20) comparator]; blood draws occurred 1 month post-dose.
  2. 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 Low
RCT (Phase III); U.S. and Swedish adults aged ≥65 years with previous PCV13 + PPSV23 vaccination 125 0 none 1.6% 0

RCT=randomized controlled trial
*Reported serious adverse events 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 № 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 Seriousa 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		 2 Critical
Serious adverse events following immunization
11 Randomized studies Not serious Not serious Not serious Seriousb Not serious 8/371 2/127 — 0.8 to 1.6% 2 Critical
  1. These are all immunogenicity studies and there are no correlates of protection for the critical outcomes considered
  2. Few vaccine-related SAEs reported do not meet the optimal information size

References

  1. 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.
  2. 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 Certainty
VT-IPD Critical Yes 2
VT-nonbacteremic pneumococcal pneumonia Critical Yes 2
VT-pneumococcal mortality Critical Yes 2
SAEs following immunization Critical Yes 2

Summary

The certainty of evidence for use of PCV20 in adults aged ≥65 years without an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant who have previously received a pneumococcal conjugate vaccine was determined to be 2 (moderate certainty of evidence) for VT-invasive pneumococcal disease, VT-pneumonia, and VT-pneumococcal deaths and was downgraded once for indirectness due to lack of correlates of protection for the critical outcomes considered. The certainty of evidence for SAEs following immunization was 2 (moderate certainty of evidence) due to imprecision from few events reported. 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. In addition, ACIP recommended shared clinical decision-making regarding administration of PCV20 for adults aged ≥65 years who completed their vaccine series with both PCV13 and PSPV23.

References

  1. 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
  2. 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.
  3. 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 2021-2022

Appendix 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 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

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