National Center for Immunization & Respiratory Diseases

GRADE:

15-valent and 20-valent Pneumococcal Conjugate Vaccine 

use in adults

Jennifer Farrar, MPH

June 25, 2021
Policy Options for Cost-Effectiveness Analysis

After reviewing the results of the cost-effectiveness analysis and estimated public health 

impact from each policy option, the Work Group focused on the following 4 options for 

GRADE and EtR. 

Age 19–64 years with underlying conditions All aged ≥65 years

Strategy a PCV15 PCV15

Strategy b PCV20 PCV20

Strategy c PCV15+PPSV23 PCV15+PPSV23

Strategy d PCV20+PPSV23 PCV20+PPSV23

Age 19–49 years with underlying conditions All aged ≥50 years

Strategy a PCV15 PCV15

Strategy b PCV20 PCV20

Strategy c PCV15+PPSV23 PCV15+PPSV23

Strategy d PCV20+PPSV23 PCV20+PPSV23
Methods
Outcomes

Outcome (Benefits) Importance* Description 

Vaccine-type (VT) IPD Critical

VT non-bacteremic

pneumococcal pneumonia 

Critical

VT death Critical

*Rated on a 1 to 9 scale, where 7–9 are critical, 4–6 are important, 1–3 are of limited importance 

Studies on PCV15 or PCV20 

assessing these clinical outcomes 

are currently not available

 PCV15/PCV20 immunogenicity 

studies

Outcome Importance* Description 

Serious adverse events Critical Safety data for PCV15 and PCV20 

are available.
PICO

Should PCV15 be 

routinely recommended 

to US adults ≥65 years 

and older?

Should PCV15 be 

routinely recommended 

to US adults ≥65 years 

and older in series with 

PPSV23?

Should PCV20 be 

routinely 

recommended to US 

adults ≥65 years and 

older? 

Should PCV20 be routinely recommended 

to US adults ≥50 years and older? 

Population

US adults aged ≥65 years US adults aged ≥50 years 

Intervention

One dose of PCV15 One dose of PCV15 

followed by PPSV23 One dose of PCV20

Comparison

1. PCV13 followed by PPSV23 (immunocompromised adults aged ≥65 years*)

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

*immunocompromised adults include adults with immunocompromising condition (chronic renal failure, nephrotic 

syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, human immunodeficiency virus, 

Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplants, congenital or acquired asplenia, sickle 

cell disease, or other hemoglobinopathies), CSF leak, or cochlear implant; immunocompetent adults are those without 

these conditions.

**PCV13 recommended based on shared clinical decision making for immunocompetent adults ≥65 years

1. PCV13 followed by PPSV23 

(immunocompromised adults aged ≥50 

years*)

2. PPSV23 only (adults 50–64 years with 

chronic medical conditions***, 

immunocompetent adults aged ≥65 years **)

3. No vaccination (adults 50–64 years 

without indications)

*** CMC: includes chronic heart/lung/liver disease, cirrhosis, 

diabetes mellitus, alcoholism, and cigarette smoking

Outcome

Vaccine-type invasive pneumococcal disease, vaccine-type non-bacteremic pneumococcal pneumonia, deaths, serious adverse 

events
GRADE Evidence Type

 Type 1 (high certainty): We are very confident that the true effect lies 

close to that of the estimate of the effect.

 Type 2 (moderate certainty): We are moderately confident in the effect 

estimate: the true effect is likely to be close to the estimate of the effect, 

but there is a possibility that it is substantially different.

 Type 3 (low certainty): Our confidence in the effect estimate is limited: the 

true effect may be substantially different from the estimate of the effect.

 Type 4 (very low certainty): We have very little confidence in the effect 

estimate: the true effect is likely to be substantially different from the 

estimate of effect.

Note: Evidence type is not measuring the quality of individual studies, but how 

much certainty we have in the estimates of effect across each outcome. 
GRADE Criteria

 Initial evidence type (certainty level) determined by study design

–

–

Initial evidence type 1 (high certainty): A body of evidence from randomized controlled trials

Initial evidence type 2 (low certainty): A body of evidence from observational studies

 Risk of bias: Can include failure to conceal allocation, failure to blind, loss to follow-up. Risk 

of bias may vary across outcomes.

 Inconsistency: Criteria for evaluating include similarity of point estimates, extent of overlap 

of confidence intervals, and statistical criteria including tests of heterogeneity and I2

 Indirectness: Considers the generalizability of the evidence to the original PICO components*

 Imprecision: Considers the fragility of the relative and absolute effect measures based on the 

interpretation of the 95% CIs and the optimal information size.

 Other considerations: Includes publication bias or indications of dose-response gradient, 

large or very large magnitude of effect, and opposing residual confounding. 

*Patients, Intervention, Comparison, or Outcomes differ from those of interest.

Guyatt GH, Oxman AD, Kunz R et al. GRADE guidelines: 8. Rating the quality of evidence —indirectness. J Clin Epidemiol. 2011. 
Evidence Retrieval (PCV13, PCV15, PCV20)

 Leveraged systematic review presented to WHO/SAGE in 2020

–

–

–

–

Searched literature up to March 2019

 Additional search of literature published during April 2019–Feb 2021 

Databases: Pubmed, Medline, Embase, CINAHL, Web of Science, Scopus, 

Epistemonikos and Cochrane library databases

Inclusion for PCV13: data on 1)human subjects, 2) adults, 3) relevant to vaccine 

efficacy or effectiveness against vaccine-type invasive pneumococcal disease, 

vaccine-type pneumonia, or death

Inclusion for PCV15, PCV20: data on 1) human subjects, 2) formulation considered 

for licensure, 3) adults aged ≥50 years or adults with underlying conditions

 Contacted manufacturers for unpublished and other relevant data

 Title and abstracts were screened independently by two separate reviewers
Evidence Retrieval

WHO SAGE review, 2020

Screened n=2,499

*

33 studies identified

PCV13 (n=7)

VT-IPD (n=4)

VT-pna (n=3)

pneumococcal mortality 

(n=2)

CDC, 2021

*Review conducted by Screened n=923 NIPH (Berild, 2020)

Berild n=1060

Blommaert n=190

Falkenhorst n = 1,199

PCV15 (n=6)

Immunogenicity (n=6)

SAE (n=6)

PCV20 (n=2)

Immunogenicity (n=2)

SAE (n=2)

PPSV23 (n=19)

VT-IPD (n=12)

VT-pna (n=3)

pneumococcal mortality 

(n=7)
Review of evidence

 Review of evidence on clinical outcomes 

–

–

PCV13 data against VT-IPD, VT-pneumonia, VT-mortality

PPSV23 data against VT-IPD, VT-pneumonia, VT-mortality

 Evidence for PCV15 (immunogenicity and SAE data)

 Evidence for PCV20 (immunogenicity and SAE data)
Vaccine effectiveness against clinical outcomes

Background
PCV13 VE against VT-IPD 

Study Population Method VE (95%CI)

Bonten*

Dutch adults ≥65 years old 

Community Acquired Pneumonia Immunization Trial 

in Adults (CAPiTA) RCT (PCV13 vs placebo) 

(n=84,496); per protocol

75% (41, 91)

CAPiTA RCT (PCV13 vs placebo) (n=84,496) + 76% (48, 89)+

Pilishvili US adults ≥65 years old Case-control; Active Bacterial Core Surveillance 

(ABCs) IPD cases and age- and zip code matched 

population-based controls (n=1,530)

59% (11, 81)¶

Pilishvili US adults ≥65 years old Case-control; ABCs IPD cases enrolled in Medicare 

part B matched to controls on age group, census 

tract, and length of enrollment in part B (n=10,851)

47% (4, 71)¶

Lewis* Kaiser Permanente 

Northern California 

members, ≥65 years

Cohort study; KPNC members with no record of 

prior receipt of PPSV23, 2014 – 2018

68% (28, 84)

+All episodes of PCV13-type IPD using modified intent-to-treat (mITT); ¶VE estimate for PCV13+6C types

*Pfizer funded studies
PCV13 against VT-pneumonia 

Study Population Method VE (95%CI)

Bonten* Dutch adults ≥65 

years old 

CAPiTA RCT, non-bacteremic pneumonia, per-protocol 

(PCV13 vs placebo) (n=84,496)

45% (14, 65)

McLaughlin* U.S. adults ≥65 years 

old 

Louisville cohort study nested test negative design casecontrol; any non-PCV13-type non-bacteremic pneumonia as 

controls (n=2,014)

71% (-6, 90)i

Prato* Italian adults ≥65 

years old 

Test-negative design case-control; any non-PCV13-type 

pneumonia as controls (n=186)

38% (-131, 89)ii

i

In the primary analysis, reported here, the controls were defined as all non-PCV13-type pneumonia. In a sensitivity analysis, where controls were defined as nonPCV13-type pneumococcal pneumonia, the VE was 69% (-47, 94). iiS. pneumoniae confirmed in nasopharyngeal, sputum, bronchoalveolar-lavage, or sterile site on polymerase chain reaction (PCR) or culture. The controls were 

defined as all non-PCV13-type pneumonia.

*Pfizer funded study
PCV13 against VT-disease deaths 

*Pfizer funded study

Study Population Method Outcome VE (95%CI)

Bonten* Dutch adults ≥65 

years old 

RCT (PCV13 vs 

placebo) (n=84,496)

PCV13-type

disease mortality

0% (-1280, 93)

Vila-Corcoles

2020

Spanish (Catalonia), 

≥50 years

Population-based 

cohort (EPIVAC study), 

2015-2016

Death from 

pneumococcal 

pneumonia

adjHR= 1.67 (0.61–4.60)
PPSV23 effectiveness data
Pooled VE: 38% (28, 46)

PPSV23 against VT-IPD : pooled VE estimate of observational studies
PPSV23 against VT-Pneumonia

Study Population Method VE (95%CI)

Kim 2019 South Korean 

hospitalized adults, 

≥65 years

Case-control, hospital-based; cases: non-bacteremic 

pneumococcal pneumonia

-2% (-40, 26)

Lawrence 2020 British hospitalized 

adults, ≥65 years

Test-negative design case-control; non-PPV23 serotype 

pneumococcal pneumonia or nonpneumococcal pneumonia as 

control (n=993)

20% (-5, 40)i

Suzuki 2017 Japanese adults, ≥65 

years

Test-negative design case-control; patients who tested negative 

for pneumococcal infection as controls (n=1617)

34% (6, 53)

i

Secondary analysis from a prospective cohort study of adults (aged ≥16 years) with CAP hospitalized in Nottingham, England, from September 2013 to 

August 2018
PPSV23 against pneumococcal mortality

Study Population Method Outcome Measure (95%CI)

Maruyama 2010 Japanese adults, 

≥55 years 

RCT, nursing home residents death from pneumococcal 

pneumonia

Rate: 35.1% 

(placebo) vs. 

0% (vaccine)

P<0.01

Vila-Corcoles 2020 Spanish (Catalonia), 

≥50 years

Population-based cohort (EPIVAC study), 

2015-2016

death from pneumococcal 

pneumonia

adjHR=1.47 (0.96–2.26)

Vila-Corcoles 2006 Spanish 

(Tarragona), ≥65 

years

Prospective cohort (1999 – 2001 death due to pneumococcal 

infection

adjHR=0.50 (0.13–2.02)

Su 2021 Taiwanese adults, 

≥75 years 

Screening method death from any 

pneumococcal infection

VE = 32.5% (17.5, 44.7)

Christenson 2004 Swedish adults, ≥65 

years 

Prospective cohort (1998 – 2000) in-hospital mortality due to 

pneumonia

VE = 7% (-19, 28)

Rose 2020 German adults, ≥60 

years

Retrospective cohort among those 

insured in a large statutory health 

insurance (2008 – 2014)

30-day mortality due to 

pneumonia

VE = 29.6% (-60.9, 69.2) 

Song 2018 South Korean 

adults, ≥65 years 

Multicenter prospective cohort study 

(2014 – 2017)

30-day mortality among ILI 

patients

VE = -29% (-136, 29)
Evidence for PCV15

Immunogenicity and safety
Summary of Phase 2/3 Immunogenicity Study Results

 Outcomes summarized: 

–

–

–

–

–

Ratio of opsonophagocytic activity (OPA) geometric mean titer (GMT)

% Seroresponders1

Point estimates used for descriptive comparison

 Statistical interpretation:

Statistical non-inferiority2 reported whenever assessed

If non-inferiority not assessed, “statistical significance” was defined as:

• 95% CI of GMT ratio did not cross 1

• 95% CI of % ≥4-fold rise in OPA GMT in the PCV15/20 vs comparator group 

did not overlap

1. Defined as subjects with ≥4-fold rise in OPA GMT titer post-vaccination compared to pre-vaccination

2. Noninferiority declared if the lower bound of the 2-sided 95% CI for the GMT ratio for that serotype was >0.5
Immunogenicity in healthy adults who received PCV15 

only

N 

(PCV15)

N 

(Comparison) Comparison GMT ratios1 % Seroresponders2

Ermlich 2018

Phase 2 RCT, adults ≥50 years

230 230 PCV13

• PCV15>PCV13 in 7/13 serotypes

• Significantly higher for 5/13 

serotypes 

• PCV15>PCV13 in 9/13 serotypes

• Non-significant for all serotypes 

(9/9)

230 231 PPSV23

• PCV15>PPSV23 in 12/13 serotypes

• Non-inferior3 for all 13 serotypes

• PCV15>PPSV23 in 10/13 serotypes

• Significantly higher for 3/10 

serotypes (3, 6B, 23F)

V114-019

Phase 3 RCT (Pivotal 

Trial), adults ≥50 years 596-598 597-598 PCV13

• PCV15>PCV13 in 5/13 serotypes

• Non-inferior4 for the 13 serotypes

• Superiority5 criteria met for ST3

• PCV15>PCV13 in 5/13 shared 

serotypes

• Significantly higher for 1/5 

serotypes (ST3)

Peterson 

2019

Phase 2 RCT, adults ≥65 

years, h/o PPSV23 127 126

PCV13 (in those 

with previous 

PPSV23) • PCV15>PCV13 in 7/13 serotypes

• PCV15>PCV13 in 8/13 shared 

serotypes

• Non-significant for all serotypes 

(8/8)

1. Ratio calculated as [GMT (PCV15)]/[GMT (comparator vaccine)].

2. Seroresponse: subjects with >=4-fold rise in OPA GMT titer post-vaccination compared to pre-vaccination. 

3. Non-inferiority was declared if lower bound of two-sided 95% CI of between-group ratio (PCV15/PPV23) of OPA GMTs for each sharedserotype was >0.33 (3-fold non-inferiority 

margin). GMC/GMT ratio estimation

4. The statistical criterion for noninferiority requires the lower bound of the 2-sided 95% confidence interval (CI) of the OPA GMT ratio (V114/ Prevnar 13TM) to be greater than 0.5

5. The statistical criterion for superiority requires the lower bound of the 2-sided 95% CI of the OPA GMT ratio [V114/ Prevnar 13TM] to be greater than 2.0.
Immunogenicity in adults with underlying conditions, 

PCV15 only

N 

(PCV15)

N 

(Comparison) Comparison GMT ratios1 % Seroresponders2

V114-017

Immunocompetent adults 

18-49 years of age at risk of 

pneumococcal disease, 

Phase 3 1004-1019 320-343 PCV13 • PCV15>PCV13 in 6/13 serotypes 

• PCV15>PCV13 in 6/13 shared 

serotypes

• Significantly higher in 1/6 

serotype (ST18C)

V114-018

Adults ≥18 years of age 

with HIV, Phase 3 126-131 116-131 PCV13 • PCV15>PCV13 in 10/13 serotypes

• PCV15>PCV13 in 9/13 

serotypes

1. Ratio calculated as [GMT (PCV15)]/[GMT (comparator vaccine)]. 

2. Seroresponse: subjects with >=4-fold rise in OPA GMT titer post-vaccination compared to pre-vaccination. 
Immunogenicity in adults, PCV15-PPSV23 series

N 

(PCV15)

N 

(Comparison) Comparison GMT ratios1 % Seroresponders2

V114-017

Immunocompetent 

adults 18-49 years 

of age at risk of 

pneumococcal 

disease, Phase 3

830-

844 276-283

PCV13 +PPSV23 

(6 month interval)

• PCV15+PPSV23>PCV13+PPSV23 in 

9/13 serotypes

• PCV15+PPSV23>PCV13+PPSV23 in 

5/13 serotypes

• Non-significant for all 5/5

V114-018

Adults ≥18 years of 

age with HIV, 

Phase3

118-

123 113-117

PCV13 +PPSV23 

(8 week interval)

• PCV15+PPSV23>PCV13+PPSV23 in 

11/13 serotypes

• PCV15+PPSV23>PCV13+PPSV23 in 

10/13 shared serotypes

V114-016

Adults ≥50 years of 

age, Phase 3

320-

321 322-323

PCV13+PPSV23 

(12 month 

interval)

• PCV15+PPSV23>PCV13+PPSV23 in 

13/13 serotypes

• Significantly higher for 3/13 

serotypes (ST1, 14, 23F)

• PCV15+PPSV23>PCV13+PPSV23 in 

11/13 shared serotypes

• Non-significant for all 11/11

1. Ratio calculated as [GMT (PCV15)]/[GMT (comparator vaccine)]. 

2. Seroresponse: subjects with >=4-fold rise in OPA GMT titer post-vaccination compared to pre-vaccination. 
SAE in healthy adults who received PCV15 only

N 

(PCV15)

N 

(Comparison) Comparison

Observation 

period %SAE PCV15

%SAE Comparator 

group

Absolute % 

difference

N related to 

vaccine

Ermlich 2018

Phase 2 RCT, adults ≥50 

years

229 230 PCV13 6 months 1.7 2.2 -0.5 0

229 230 PPSV23 6 months 1.7 3 -1.3 0

Peterson 

2019

Phase 2 RCT, 

adults ≥65 

years, h/o 

PPSV23 127 126

PCV13 (in those 

with h/o PPSV23) 30 days 0 1.6 -1.6 0

V114-019

Phase 3 RCT 

(Pivotal Trial), 

adults ≥50 

years 602 600 PCV13 6 months 1.5 2.2 -0.7 0
SAE in adults with underlying conditions, PCV15 only

N 

(PCV15)

N 

(Comparison) Comparison

Observation 

period %SAE PCV15

%SAE Comparator 

group

Absolute % 

diference

N related to 

vaccine

V114-

017

Immunoco

mpetent 

adults 18-

49 years at 

risk of 

pneumoco

ccal 

disease 1134 378 PCV13 6 months 4.3 3.2 1.1 0

V114-

018

Adults ≥18 

years with 

HIV 152 150 PCV13 6 months 2 0 2 0
SAE in adults, PCV15-PPSV23 series

N 

(PCV15)

N 

(Comparison) Comparison

Observation 

period %SAE PCV15

%SAE Comparator 

group

Absolute % 

difference

N related to 

vaccine

V114-016

Adults ≥50 

years of age 298 302 PCV13+PPSV23

1 month postPPSV23 

(13 months 

post-first dose) 0.3 0.7 -0.4 0

V114-017

Immunocomp

etent adults 

18-49 years at 

risk of 

pneumococcal 

disease 1036 345 PCV13+PPSV23

1 month postPPSV23 (7 

months postfirst dose) 0.3 0.9 -0.6 0

V114-018

Adults ≥18 

years with HIV 150 148 PCV13+PPSV23

6 months post 

first dose 1.3 4.1 -2.8 0
Evidence for PCV20

Immunogenicity and safety
Immunogenicity in healthy adults aged ≥50 years, PCV20 only

N 

(PCV20)

N 

(Comparison) Comparison GMT ratios1 % Seroresponders2

B7471007

Phase 3 RCT, adults ≥60 years

1435 1420 PCV13

• PCV20<PCV13 in 12/13 serotypes

• Noninferiority criteria3 met for all 

13/13 serotypes

• PCV20<PCV13 in 12/13 serotypes 

• Significantly lower for 1/12 (ST3)

1433 1383

PPSV23 

(7 common st)

• PCV20>PPSV23 in 6/7 serotypes

• Noninferiority criteria3 met for 

6/7 serotypes (not met for ST8)

• PCV20>PPSV23 in 6/7 serotypes 

(all significant)

• PCV20<PPSV23 ST8 (significant) 

Hurley 2020

Phase 2 RCT, adults 60-64 years

195-210 194-208 PCV13

• PCV20<PCV13 in 13/13 serotypes

• CI did not overlap in 4/13

• PCV20<PCV13 in 12/13 shared 

serotypes (all non-significant)

185-207 181-204

PPSV23 

(7 common st)

• PCV20>PPSV23 in 6/7 shared 

serotypes (CI did not overlap in 

3/6)

• PSV20<PPSV23 for ST8 (CI did not 

overlap)

• PCV20>PPSV23 in 6/7 shared 

serotypes (significantly higher in 

2/6)

• PCV20<PPSV23 for ST8 (nonsignificant) 1. Ratio calculated as [GMT (PCV20)]/[GMT (comparator vaccine)]. Range of GMT ratios for the common serotypes is shown.

2. Seroresponse: subjects with >=4-fold rise in OPA GMT titer post-vaccination compared to pre-vaccination. Absolute difference calculated as [% seroresponders (PCV20)]-[%seroresponders

(comparator vaccine)]; positive results favor PCV20. Range of absolute differences for common serotypes is shown.

3. Noninferiority for a serotype was declared if the lower bound of the 2-sided 95% CI for the geometric mean ratio (GMR) for that serotype was greater than 0.5 (2-fold criterion).
Immunogenicity in healthy adults aged 50-59 years vs 

older adults

N 

(PCV20)

N 

(Comparison) Comparison GMT ratios1 % Seroresponders2

B7471007

Phase 3 RCT, adults 50-59 

years vs 60-64 years 321 946 PCV20

• 50-59>60-64 years in 15/20 

serotypes

• Non-inferiority criteria3 met for 

all 20 serotypes

Phase 3 RCT, adults 50-59 

years vs ≥60 years 321 1435 PCV20

• 50-59>60+ years group in 18/20 

serotypes (significantly higher in 

1/18)

1. Ratio calculated as [GMT (PCV20)]/[GMT (comparator vaccine)]. Range of GMT ratios for the common serotypes is shown.

2. Seroresponse: subjects with >=4-fold rise in OPA GMT titer post-vaccination compared to pre-vaccination. 

3. Noninferiority for a serotype was declared if the lower bound of the 2-sided 95% CI for the geometric mean ratio (GMR) for that 

serotype was greater than 0.5 (2-fold criterion).
SAE in healthy adults in healthy adults aged ≥50 years

N 

(PCV20)

N 

(Comparison) Comparison

Observation 

period %SAE PCV20

%SAE Comparator 

group

Absolute % 

diference

N related to 

vaccine

B7471007

Phase 3 RCT, adult

1461 1445

PCV13 or 

PCV13+PPSV23

(60 years or older) within 6 months 2.4 1.9

0.5 

(CI overlaps) 0

334 111 PCV13 (50-59 years)within 6 months 0.3 0.9

-0.6 

(CI overlaps) 0

Hurley 2020

Phase 2 RCT, adults 

60-64 years

221 222 PCV13

within 1 month 

following PCV20 

or PCV13 0 0.5

-0.5 

(CI overlaps) 0

213 214 PCV13+PPSV23

Throughout the 

12-mo study 

period, 

PCV20+saline vs 

PCV13+PPSV23) 4.1 5

-0.9 

(CI overlaps) 0
Summary GRADE tables
Should PCV15 be routinely recommended to US adults ≥65 years and older?

Should PCV15 be routinely recommended to US adults ≥65 years and older in series 

with PPSV23?

Type Outcome Importance

Included in evidence 

profile Certainty of evidence

Benefits

VT- IPD Critical Yes 2

VT-pneumonia Critical Yes 2

VT- mortality Critical Yes 2

Harms Serious adverse events Critical Yes 2
Should PCV20 be routinely recommended to US adults ≥50 years and older? 

Should PCV20 be routinely recommended to US adults ≥65 years and older? 

Type Outcome Importance

Included in evidence 

profile

Certainty for healthy 

individuals

Benefits

VT- IPD Critical Yes 2

VT-pneumonia Critical Yes 2

VT- mortality Critical Yes 2

Harms Serious adverse events Critical Yes 2
Acknowledgments

 Lana Childs

 Amadea Britton

 Mahamoudou Ouattara

 Fahmina Akhter

 Tamara Pilishvili
For more information, contact CDC

1-800-CDC-INFO (232-4636)

TTY: 1-888-232-6348 www.cdc.gov

The findings and conclusions in this report are those of the authors and do not necessarily represent the 

official position of the Centers for Disease Control and Prevention.