GRADE: 20-valent pneumococcal conjugate vaccine (PCV20) for adults aged ≥65 years

Grading of Recommendations, Assessment, Development, and Evaluation

Introduction

On October 21, 2021, the ACIP recommended use of 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.]) alone or 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme Corp.]) in series with 23-valent pneumococcal polysaccharide vaccine (PPSV23) [Pneumovax23, Merck Sharp & Dohme Corp Inc.]) for all adults aged ≥65 years, and for adults aged 19–64 years with certain underlying medical conditions or other risk factors*, who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown. A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP’s deliberations regarding use of these vaccines.

Introduction Footnote

*Alcoholism, chronic heart/liver/lung disease, chronic renal failure, cigarette smoking, cochlear implant, congenital or acquired asplenia, CSF leak, diabetes mellitus, generalized malignancy, HIV, Hodgkin disease, immunodeficiency, iatrogenic immunosuppression, leukemia, lymphoma, multiple myeloma, nephrotic syndrome, solid organ transplants, or sickle cell disease or other hemoglobinopathies.

Methods

A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV15 and PCV20 among age groups for which the vaccines were approved.  Since only immunogenicity and safety data were available for PCV15 or PCV20, the search included PCV13 and PPSV23 efficacy or effectiveness studies to help interpret PCV15 and PCV20 immunogenicity study findings. Literature search for evidence on both PCV15 and PCV20 was done simultaneously given the similarities in the policy questions and given that use of both PCV15 and PCV20 were considered by the ACIP simultaneously. GRADE assessment was performed for PCV15 and PCV20 studies only. As a basis for the GRADE analysis, 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 Question and PICO
Policy question: Should PCV20 be routinely recommended to US adults ≥65 years and older?
Population US adults aged ≥65 years
Intervention One dose of PCV20
Comparison 1. PCV13 followed by PPSV23 (immunocompromised adults aged ≥65 years)

2. PPSV23 (immunocompetent or healthy adults aged ≥65 years)

Outcomes
  • Vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumococcal pneumonia, vaccine-type pneumococcal mortality
  • Serious adverse events following immunization

Table 1. Footnote
PCV13=13-valent pneumococcal conjugate vaccine, PCV20=20-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine

Table 2. Outcomes and Rankings

Table 2: Outcomes and Rankings
Outcome Importance* Included in evidence profile
Vaccine-type invasive pneumococcal disease Critical Yes
Vaccine-type non-bacteremic pneumococcal pneumonia Critical Yes
Vaccine-type pneumococcal mortality Critical Yes
Serious adverse events following immunization Critical Yes

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

We leveraged a systematic review presented to the World Health Organization Strategic Advisory Group of Experts (SAGE) meeting in October 2020, which included literature up to March 2019 (1). To identify literature published during April 2019 to February 2021, we searched Pubmed, Medline, Embase, CINAHL, Scopus, Epistemonikos and Cochrane library databases. The search terms are included in the appendix I. Search results were supplemented by an updated Pubmed search using “V114*”, “PCV15”, “PCV20”. Unpublished data were provided by the vaccine manufacturers.

Studies were included if they presented primary data on PCV20 use in adults aged 50≥ years. Of the 2,499 titles screened for WHO SAGE and 923 titles screened for the updated review in 2021, 1 unpublished and 1 published PCV20 studies were included in the GRADE analysis (2, 3). Characteristics of these studies are presented in appendix II. Beneficial and harmful outcomes for the GRADE assessment were selected by the ACIP Pneumococcal Vaccines Work Group calls and via an email survey in which Work Group members were asked to rank the relative importance of each outcome. Vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumococcal pneumonia, vaccine-type pneumococcal mortality, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).

Methods Footnote
*V114 is the name used for Merck’s investigational 15-valent pneumococcal conjugate vaccine candidate

Table 3a. Summary of Studies Reporting Immunogenicity

Table 3a. Summary of Studies Reporting Immunogenicity
Study Age or other characteristic of importance N intervention N comparison Comparator vaccine OPA GMT Ratios* [range (serotype)] Absolute difference in % seroresponders
(serotype)
Interpretation Study limitations (Risk of Bias)
B7471007 Adults ≥60 years 1435 1420 PCV13 0.76 (6A) to 1.00 (14) -5.6 (3) to -0.5 (7F) GMT ratios
  • PCV20<PCV13 in 12/13 PCV13 serotypes
  • Noninferiority criteria met for all 13/13 PCV13 serotypes

% seroresponders

  • PCV20<PCV13 in 12/13 serotypes
  • Significantly lower for 1/12 (3)
Not serious
1433 1383 PPSV23
(7 common ST†– PCV13 ST)
0.55 (8) to 3.12 (15B) -9 (8) to 14 (15B) GMT ratios
  • PCV20>PPSV23 in 6/7 serotypes
  • Noninferiority criteria met for 6/7 serotypes (not met for serotype 8)

% seroresponders

  • PCV20>PPSV23 in 6/7 serotypes (all significant)
  • PCV20<PPSV23 in 1/7 (significant for serotype 8)
Hurley 2020 Adults 60 – 64 years 195-210 194-208 PCV13 0.62 (19F) to 0.90 (6B) -9.8 (19F) to 1.3 (6A) GMT ratios
  • PCV20<PCV13 in 13/13 serotypes
  • CI did not overlap in 4/13

% seroresponders

  • PCV20<PCV13 in 12/13 shared serotypes (all non-significant)
Not serious
185-207 181-204 PPSV23
(7 common ST – PCV13 ST)
0.64 (8) to 2.64 (10A) -4.9 (8) to 14.7 (10A) GMT ratios
  • PCV20>PPSV23 in 6/7 shared serotypes (CI did not overlap in 3/6)
  • PCV20<PPSV23 in 1/7 shared serotype (serotype 8, CI did not overlap)

% seroresponders

  • PCV20>PPSV23 in 6/7 shared serotypes (significantly higher in 2/6)
  • PCV20<PPSV23 in 1/7 shared serotype 8 (non-significant)
195-204 196-203 PCV13+PPSV23 PCV13 serotypes: 0.50 (3) to 0.78 (6B)

7 common serotypes in addition to PCV13 types: 0.64 (8) to 2.64 (10A)

Data not presented GMT ratios
  • PCV20<PCV13+PPSV23 in 13/13 shared serotypes (PCV13 serotypes)
  • PCV20>PCV13+PPSV23 in 6/7 shared serotypes (additional serotypes in PCV20)

Table 3a. Footnotes
CI=confidence interval, GMT=geometric mean titers, OPA=opsonophagocytic activity, PCV13=13-valent pneumococcal conjugate vaccine, PCV20=20-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine

*Ratio calculated as [GMT (PCV20)] / [GMT (comparator vaccine)]. Range of GMT ratios for 13 serotypes common to PCV13 and PCV20 is shown
ST: serotype

Table 3b. Summary of Studies Reporting Safety

Table 3b. Summary of Studies Reporting Safety
Study Age or other characteristic of importance N intervention N comparison Comparator vaccine Absolute % difference (% SAE PCV20 – % SAE comparator) N related to vaccine Study limitations (Risk of Bias)
B7471007 Adults ≥60 years 1461 1445 PCV13 or PCV13+PPSV23 (6-month observation period) 0.5
(CI overlaps)
0 Not serious
Hurley 2020 Adults 60 – 64 years 221 222 PCV13 (1-month observation period) -0.5
(CI overlaps)
0 Not serious
213 214 PCV13+PPSV23 (12-month study period) -0.9
(CI overlaps)
0

Table 3b. Footnotes
CI=confidence interval, PCV13=13-valent pneumococcal conjugate vaccine, PCV20=20-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine, SAE=serious adverse events

Table 4. GRADE Summary of Findings Table

Table 4. GRADE Summary of Findings Table
Certainty assessment № of patients Results Certainty Importance
№ of studies (reference) Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Intervention Comparison Relative effect Absolute effect
Vaccine effectiveness (Vaccine-type invasive pneumococcal disease, Vaccine-type non-bacteremic pneumococcal pneumonia, Vaccine-type pneumococcal mortality)
2 (2, 3) Randomized studies Not serious Not serious Serious* Not serious Not serious 1630 – 1645 1614 – 1628 PCV20 v PCV13: Non-inferiority met for all 13 shared serotypes
PCV20 had slightly lower immune responses vs. PCV13 for all 13 shared serotypes
PCV20 v. PPSV23: Non-inferiority met for 6 of 7 serotypes (not met for serotype 8).
PCV20 had greater immune responses vs. PPSV23 for 6 of 7 shared serotypes.
2 Critical
Serious adverse events
2 (2, 3) Randomized studies Not serious Not serious Not serious Serious† None 0/1682 0/1687 non estimable 2 Critical

Table 4. Footnotes
PCV13=13-valent pneumococcal conjugate vaccine, PCV20=20-valent pneumococcal conjugate vaccine, PPSV23=23-valent pneumococcal polysaccharide vaccine, SAE=serious adverse events
*These are all immunogenicity studies and there are no correlates of protection
No vaccine-related serious adverse events reported; sample size relatively small

Table 5: Summary of Evidence for Outcomes of Interest

Table 5: Summary of Evidence for Outcomes of Interest
Outcome Importance Included in profile Certainty
Vaccine-type invasive pneumococcal disease Critical Yes 2, moderate
Vaccine-type non-bacteremic pneumococcal pneumonia Critical Yes 2, moderate
Vaccine-type pneumococcal mortality Critical Yes 2, moderate
Serious adverse events following immunization Critical Yes 2, moderate

Summary

The evidence type for use of PCV20 in adults aged ≥65 years was determined to be 2 (moderate certainty of evidence). The ACIP reviewed the results of both GRADE analysis and the Evidence to Recommendations (EtR) framework in June 2021. An updated EtR table was shared with the ACIP in September 2021. In October 2021, the ACIP recommended use of PCV20 for all adults aged ≥65 years who have not previously received a pneumococcal conjugate vaccine or whose previous vaccination history is unknown.

References

  1. World Health Organization. Strategic Advisory Group of Experts on Immunization 5-7 October 2020. 2020 [cited 2021 July 28]; Available from: https://terrance.who.int/mediacentre/data/sage/SAGE_eYB_October_2020.pdf?ua=1pdf iconexternal icon.
  2. Hurley D, Griffin C, Young M, Scott DA, Pride MW, Scully IL, et al. Safety, Tolerability, and Immunogenicity of a 20-Valent Pneumococcal Conjugate Vaccine (PCV20) in Adults 60 to 64 Years of Age. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2020 Jul 27.
  3. Essink B, Sabharwal C, Xu X, Sundaraiyer V, Peng Y, Moyer L, et al. 3. Phase 3 Pivotal Evaluation of 20-valent Pneumococcal Conjugate Vaccine (PCV20) Safety, Tolerability, and Immunologic Noninferiority in Participants 18 Years and Older. Open Forum Infect Dis. 2020;7(Suppl 1):S2-S.

Appendix I. Search Strategy

Appendix I. 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. 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. (201904* OR 201905* OR 201906* OR 201907* OR 201908* OR 201909* OR 201910* OR 201911* OR 201912* OR 2020* OR 2021*).ed,ep,yr,dp,dt.
20. 17 and 18
02/18/2021 351
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. (201904* OR 201905* OR 201906* OR 201907* OR 201908* OR 201909* OR 201910* OR 201911* OR 201912* OR 2020* OR 2021*).dc
20. limit 19 to (conference abstracts or embase)
02/18/2021 521


duplicates

=
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 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,ab
02/18/2021 56


duplicates

=
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))Limiters – Published Date: 20190401-20210218; Exclude MEDLINE records
02/18/2021 43


duplicates

=
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”)

Limit April 2019 –

02/18/2021 458


duplicates

=
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 2019-2021Search 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 2019-2021
02/18/2021 19 + 10


duplicates

=
unique items

Appendix II. Studies Included in the Review of Evidence

Appendix II. Studies Included in the Review of Evidence
Study Study design Country (or more detail, if needed) Age Total population N Intervention N comparison Outcomes Funding source
B7471007 Phase III randomized controlled trial (pivotal trial) US and Sweden Adults ≥60 years 2855 1435 1420 Immunogenicity,
Safety
Pfizer
2816 1433 1383
Hurley 2020 Phase II randomized controlled trial US Adults 60 – 64 years 389-418 195-210 194-208 Immunogenicity,
Safety
Pfizer
366-411 185-207 181-204
Page last reviewed: January 27, 2022