GRADE PCV13 use among adults ≥65 years old_FINAL pg. 1 

Pneumococcal Vaccines: GRADE Tables and Summary

Introduction

On August 13, 2014, ACIP recommended routine use of 13-valent pneumococcal conjugate vaccine (PCV13) in 

series with the 23-valent pneumococcal polysaccharide vaccine (PPSV23) for adults aged ≥65 years. At the time, 

the recommendation was warranted because PCV13-type disease among adults was assessed to be an 

important public health problem. However, in the long-term ACIP recognized that continued reductions in 

PCV13-type disease due to indirect effects from pediatric PCV13 use might limit the utility of this 

recommendation. Therefore, ACIP proposed that the recommendation for routine PCV13 use among adults ≥65 

years old be re-evaluated in 2018 and revised as needed. As part of ACIP’s process, a systematic review and 

Grading of Recommendations, Assessment, Development and Evaluation (GRADE) of the evidence for PCV13 use 

among adults ≥65 years old was conducted. The policy question was “Should PCV13 be administered routinely 

to all immunocompetenti adults aged ≥65 years in the context of indirect effects from pediatric PCV use 

experienced to date?” 

Methods

Evidence of benefits and harms for the routine use of PCV13 among adults aged ≥65 years old was reviewed 

based on the GRADE approach. GRADE was adopted by ACIP in 2010 as the framework for evaluating the 

scientific evidence that informs recommendations for vaccine use 

(https://www.cdc.gov/vaccines/acip/recs/grade/about-grade.html). The benefits and harms considered as 

critical outcomes in GRADE are listed in Table 1. The evidence type for each critical outcome was derived 

through a review of study design, risk of bias, inconsistency, indirectness, and imprecision.

The population was adults aged 65 years and older who do not have an immunocompromising conditionii

cerebrospinal fluid (CSF) leak, or cochlear implant; the intervention was PCV13 in series with PPSV23 versus

PPSV23 alone, in the context of indirect effects; and the outcomes were prevention of invasive pneumococcal 

disease (IPD), pneumonia, mortality, and PCV13 safety. 

Scientific literature was searched in Medline, Embase, Cumulative Index of Nursing and Allied Health Literature 

(CINAHL), Cochrane, and clinicaltrials.gov between January 1, 2014 and July 3, 2018. Search terms are listed in 

the Appendix. This search identified 6,788 references.

The primary reviewer screened title and abstracts. Articles were included if they provided data on vaccination 

with PCV13 and included primary data on outcomes of interest among ≥65 years old who do not have an 

immunocompromising conditionii

. Efforts were made to obtain additional published studies by cross-referencing 

included studies’ reference lists. Additionally, unpublished studies were sought out by consulting with vaccine 

manufacturers and subject matter experts. After title and abstract screening, 364 studies were identified for indepth review. Of these, 344 were among other populations, did not use PCV13, or did not evaluate an outcome 

of interest. Additionally, observational studies were excluded if the coverage in the population was <20% or if

the indirect effects were dissimilar to those experienced in the U.S. (i.e. low pediatric vaccine coverage, no 

pediatric PCV13 program, low-income country). Randomized control trials (RCT) that examined the safety 

i Immunocompetent defined in discussion as adults without an 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. ii Immunocompromising conditions include: chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic 

immunosuppression, generalized malignancy, HIV, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid organ transplants, 

congenital or acquired asplenia, sickle cell disease, or other hemoglobinopathies.

https://www.cdc.gov/vaccines/acip/recs/grade/PCV13-h.pdf 11/21/2019
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 2

outcome were excluded if PCV13 was co-administered with another vaccine, because SAEs could not be 

attributed to PCV13, and if there was no PPSV23 or placebo comparison group. This left 20 studies for the 

GRADE analysis [1-20].

Table 1: Critical Outcomes Included in GRADE

Outcomes Importance Type

PCV13 efficacy, effectiveness, and impact on PCV13-type IPD Critical

Benefits

PCV13 efficacy, effectiveness, and impact on PCV13-type nonbacteremic pneumococcal pneumonia (NIPP) Critical

PCV13 efficacy, effectiveness, and impact on mortality associated with 

PCV13-type disease Critical

Serious adverse events including deaths associated with PCV13 Critical Harms
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 3 

Results

Table 2: PCV13 efficacy, effectiveness, and impact on PCV13-type IPD (critical outcomes)

Study Population Method Outcome VE (95%CI)

Bonten [1]* Dutch adults 

≥65 years old 

Community Acquired 

Pneumonia 

Immunization Trial in 

Adults (CAPiTA) RCT

(PCV13 vs placebo)

(n=84,496)

1st episode of PCV13-

type IPD

75% (41, 91)

Gessner [2]* Dutch adults 

≥65 years old

CAPiTA RCT (PCV13 vs 

placebo) (n=84,496)

All episodes of PCV13-

type IPD using 

modified intent-totreat (mITT) 

76% (48, 89)

Pilishvili [3] 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)

PCV13-type IPD 59% (11, 81)

Pilishvili [4] 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)

PCV13-type IPD 47% (4, 71)

% change (95%CI)

Pilishvili [5] US adults ≥65 

years old

Pre-post analysis 

comparing incidence in 

2013-14 vs 2016-17

PCV13-type IPD -13% (-26, 2)

*Pfizer funded studies
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 4

Table 3: PCV13 efficacy, effectiveness, and impact on pneumonia (critical outcomes)

Study Population Method Outcome VE (95%CI)

Bonten [1]*

Webber [6]*

Gessner [2]*

Dutch adults 

≥65 years old 

CAPiTA RCT (PCV13 vs 

placebo) (n=84,496)

1st episode of PCV13-

type pneumonia

45% (14, 65)

All episodes PCV13-

type pneumonia 

excluding IPD

43% (12, 63)

All episodes clinically 

confirmed pneumonia 

8% (1, 15)

McLaughlin 

[7]*

U.S. adults 

≥65 years old 

Louisville cohort study 

[8] nested test negative 

design case-control; nonPCV13-type pneumonia 

as controls (n=2,034)

PCV13-type 

pneumonia 

71% (6, 91)iii

PCV13-type 

pneumonia excluding 

IPD

70% (4, 91)

Prato [9]* Italian adults 

≥65 years old 

Test-negative design 

case-control; nonPCV13-type pneumonia 

as controlsiv (n=186)

PCV13-type 

pneumonia

38% (-131, 89)

Lessa [10] U.S. adults 

≥65 years old

enrolled in 

Medicare part 

A/B

Cohort; discrete time 

survival model stratified 

by influenza vaccine 

receipt and influenza 

season (n=24,121,625)

All-cause pneumonia 

defined by ICD codes

6–11% (4, 8; 9, 13)

% change (95%CI)

Swerdlow 

[11]*

U.S. adults 

≥65 years old

Louisville cohort study 

[8] pre-post analysis 

comparing incidence in 

June 2014-May 2015 vs 

June 2015-May 2016 

PCV13-type 

pneumonia 

-32% (-8, -49)

Gierke [12] US adults ≥65 

years old 

Surveillance for NonInvasive Pneumococcal 

Pneumonia (SNiPP) prepost analysis comparing 

incidence in 2013-14 vs 

2015-16 

Non-Invasive 

Pneumococcal 

Pneumonia

-35% (-14, -49)v

*Pfizer funded studies

 iii In the primary analysis, the controls were defined as all non-PCV13-type pneumonia. In a sensitivity analysis, controls were defined as 

non-PCV13-type pneumococcal pneumonia (VE 69% [-47, 93]). iv S. pneumoniae confirmed in nasopharyngeal, sputum, bronchoalveolar-lavage, or sterile site on polymerase chain reaction (PCR) or 

culture

v No change observed from 2014–2016 (most recent year of data), p=0.5.
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 5

Table 4: PCV13 efficacy, effectiveness, and impact on mortality (critical outcomes)

Study Population Method Outcome VE (95%CI)

CAPiTA [1]* Dutch adults 

≥65 years old 

RCT (PCV13 vs 

placebo) (n=84,496)

PCV13-type disease 

mortality

0% (-1280, 93)

All-cause mortality 

during 4 year follow 

up period

-0.03% (-5, 5)

% change (95%CI)

Pilishvili [5] US adults ≥65 

years old

Pre-post analysis 

comparing incidence 

in 2013-14 vs 2016-17 

Death during 

hospitalization for 

PCV13-type IPD

2% (-30, 49)

*Pfizer funded studies
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 6

Table 5: PCV13 Safety — serious adverse events (SAEs) reported in randomized control trials (RCT)

Study Population Study Design

Observation 

period

% SAE reported 

among PCV13 

only group

# vaccinated 

with PCV13 

% SAE reported 

among control 

group (placebo 

or PPSV23)

# in the 

control 

group

Bonten [1]vi*

Dutch adults ≥65 

years old RCT (PCV13 vs placebo) 1 month 0.8% 42,237 0.7%vii 42,255

Juergens [13]*

South African adults 

≥65 years old

RCT (PCV13 vs PCV13 without aluminum 

phosphate vs PPSV23) open-labelviii 43 days 0.6%ix 309 0.3% 301

Shiramoto [14]*

Japanese adults ≥65 

years old RCT (PCV13 vs PPSV23) 43 days 0.3%x 382 0% 382

*Pfizer funded studies

 vi Safety sub-study (n=2,011) groups followed for 6 months after vaccination: SAE among PCV13 7% vs placebo 6%, p=0.41 vii No statistically significant difference in all SAEs combined, p=0.61. Safety difference noted were: 23 patients who received PCV13 vs 7 patients who received placebo had general 

disorders and administration site conditions (p=0.003); 12 patients who received PCV13 vs 2 patients who received placebo had non-cardiac chest pain and 5 patients who received PCV13 

vs 1 patients who received placebo had "events of chest pain" though overall 72 patients who received PCV13 v 74 patients who received placebo had cardiac disorders (p=0.9) viii Additional doses of PCV13 given to those who were part of the initial group who received PCV13; among those who received PCV13 again 1 year later (n=136) SAE 2.2% including 1 

death, SAEs deemed not related to the vaccine; among those who received PCV13 again (2 years after previous PCV13 and 1 year after PPSV23) (n=105) SAE 1.9% including 1 death, SAEs 

deemed not related to the vaccine. ix All SAEs deemed not related to the vaccine x 1 SAE which was deemed not related to the vaccine
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 7

Table 6: PCV13 Safety — serious adverse events (SAEs) reported in observational studies

Study Population Study Design

Observation 

period

% SAE among 

PCV13 only 

group

# vaccinated 

with PCV13 

% SAE among 

control group

(placebo or 

PPSV23)

# in the 

control 

group

Durando [15]*

Italian adults ≥70 

years old

Cohort study (voluntary enrollment after 

PCV13 vaccination) 6 months 0.1%xi 871 NA NA

Haber [16]

US adults ≥65 years 

old 

Passive surveillance through the Vaccine 

Adverse Events Reporting System (VAERS) -- <0.01%xii ~9,269,000xiii NA NA

Jackson [17]

US adults 55-74 

years old

Observational cohort for PCV13 SAE (designed 

as RCT with varying number of PCV13 doses) 6 months 2.3%xiv 883 NA NA

Shiramoto [18]*

Japanese adults ≥50 

years old Cohort study, open-label 1 month 0% 271 NA NA

Tinoco [19]*

Mexican adults ≥65 

years old Cohort study, open-label 1 month 1.2%xv 161 NA NA

Tseng [20]

US adults ≥65 years 

old Cohort comparing PCV13 vs PPSV23 6 months 1.2%-5.8% 5,055 2.4%-5.5% 1,124

*Pfizer funded studies

 xi 2 SAEs, 1 of which occurred at 29 days post vaccination and was deemed to be possibly related to PCV13. Less than 40% completed 6 month safety follow-up. xii 14 deaths and 138 other SAEs, percentage calculated as 152/9,269,000=0.00164%

xiii Approximate denominator calculated using Pfizer reported 23% PCV13 coverage among adults ≥65 years old at the end of this study (December 2015)*40,300,000 ≥65 years old 

population from the 2010 U.S. Census=9,269,000 xiv Overall 27 SAEs among 25 patients; all of which researches deemed not to be vaccine related. Among 883 patients, 1,117 doses of PCV13 so SAE rate=27/1,117=2.3% xv 2 SAEs which were both deemed not related to the vaccine
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 8

GRADE Summary

Outcome Design # studies —

[references]

Initial 

Evidence 

Typexvi

Risk of Bias Inconsistency Indirectness Imprecision Evidence 

Typexvi

Benefits

PCV13-type invasive 

pneumococcal disease (IPD)

RCT

1 — [1, 2] 1 Not serious N/A Seriousxvii Serious 3

PCV13-type pneumonia 1 —[1, 2, 6] 1 Not serious N/A Seriousxvii Serious 3

Mortality from PCV13-type 

disease 1 — [1]xviii 1 Not serious N/A Seriousxvii Very serious 4

PCV13-type IPD

Observ

ational

3— [3-5] 3 Seriousxix Not serious Not serious Very serious 4

PCV13-type pneumonia 5 — [7, 9-12] 3 Very seriousxx Very serious Seriousxxi Very serious 4

Mortality from PCV13-type 

disease 1 — [5] 3 Seriousxxii N/A Not serious Very serious 4

Harms

Serious adverse events

RCT 3 — [1, 13, 14] 1 Seriousxxiii Not Serious Seriousxvii --- 3

Observ

ational 6 — [15-20] 3 Seriousxxiv Not Serious Not Serious --- 3xxv

 xvi Evidence levels: 1) High, 2) Moderate, 3) Low, 4) Very Low xvii Downgraded since the RCT (CAPiTA) was among a population with low PCV13 indirect effects from pediatric PCV13 use and low PPSV23 coverage xviii Mortality was not a primary end-point in this RCT, and there were very few deaths caused by PCV13-type disease xix Potential unmeasured confounding, misclassification of vaccine status, and indirectness for impact studies that examined the population level impact xx In addition to the risk of bias for the IPD outcome, the pneumonia outcome studies also had short observation periods and used non-specific outcomes xxi Two studies did not measure specific outcome of interest (i.e. PCV13-type pneumococcal pneumonia) xxii Active Bacterial Core surveillance only captures inpatient mortality or in the outpatient setting, deaths that occur very proximally to the diagnosis of IPD xxiii Modified blinding procedures, open label, and short follow up period xxiv Inadequate or no control/comparison group xxv Upgraded since multiple observational studies with consistent results
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 9

Summary

In 2014, the GRADE conclusion was that PCV13 was efficacious in preventing PCV13-type disease in aged ≥65 

years with an overall moderate level of evidence. Since 2014, there have been 16 studies (2 RCTs and 14 

observational) added to the body of evidence. Observational studies are a lower evidence type in GRADE. 

However, the updated evidence continues to support that PCV13 is efficacious and effective for preventing 

invasive and non-invasive PCV13-type disease among adults aged ≥65 years. Additionally, there have been no 

concerning safety signals detected. In addition to safety and efficacy, the current policy question is “in the 

context of indirect effects from pediatric PCV13 use.” The indirect effects from pediatric PCV used reduced 

PCV13-type disease in older adults to all-time lows prior to 2014. Since 2014, PCV13 coverage among adults ≥65 

years old steadily risen to 40% in 2017 [21]. Since the introduction of PCV13 for all adults aged ≥65 years, no 

impact on PCV13-type IPD at the population-level has been observed [5] and the data across studies that 

measure the impact on pneumonia have been inconsistent [11, 12].

At the June 2019 meeting, after reviewing the Evidence to Recommendation Framework

(https://www.cdc.gov/vaccines/acip/recs/grade/PCV13-etr.html) including the GRADE analysis, ACIP voted to 

change the policy and recommended PCV13 based on shared clinical decision making for adults ≥65 years old

who do not have an immunocompromising conditionii

, cerebrospinal fluid (CSF) leak, or cochlear implant and 

who have not previously received PCV13. For more information see 2019 policy note: Use of 13-Valent 

Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine Among Adults ≥65 Years 

Old: Updated Recommendations of the Advisory Committee on Immunization Practices (ACIP) [21].

APPENDIX: Search Methods

Database Strategy Run Date Records

Medline

(OVID)

1946-

(Pneumococcal ADJ5 Vaccin*) OR (pneumococcus ADJ5 vaccin*) OR (pneumonia* ADJ5 

vaccin*) OR PCV13 OR pneumovax OR PPSV23 OR prevnar* OR pnu-immune 

AND

senior* OR aged OR older adult* OR elderly OR (over ADJ2 65) OR (older ADJ2 65) OR >=65 

OR =>65 

7/3/2018 4407

Embase

(OVID)

1947-

(Pneumococcal ADJ5 Vaccin*) OR (pneumococcus ADJ5 vaccin*) OR (pneumonia* ADJ5 

vaccin*) OR PCV13 OR pneumovax OR PPSV23 OR prevnar* OR pnu-immune 

AND

senior* OR aged OR older adult* OR elderly OR (over ADJ2 65) OR (older ADJ2 65) OR >=65 

OR =>65 

NOT

Pubmed/medline

7/3/2018 4822

-2707

duplicates 

=2115 

unique 

items

CINAHL

(Ebsco) (Pneumococcal N5 Vaccin*) OR (pneumococcus N5 vaccin*) OR (pneumonia* N5 vaccin*) OR 

PCV13 OR pneumovax OR PPSV23 OR prevnar* OR pnu-immune 

AND

senior* OR aged OR older adult* OR elderly OR (over N2 65) OR (older N2 65) OR >=65 OR 

=>65 

exclude Medline records

7/3/2018 122

-26

duplicates 

=96 

unique 

items

Cochrane 

Library (Pneumococcal NEAR/5 Vaccin*) OR (pneumococcus NEAR/5 vaccin*) OR (pneumonia* 

NEAR/5 vaccin*) OR PCV13 OR pneumovax OR PPSV23 OR prevnar* OR pnu-immune 

AND

senior* OR aged OR older adult* OR elderly OR (over NEAR/2 65) OR (older NEAR/2 65) OR 

>=65 OR =>65 

NOT

7/3/2018 198

-109

duplicates 

=89 
GRADE PCV13 use among adults ≥65 years old_FINAL pg. 10

PubMed:so unique 

items

Clinicaltrials.gov Pneumococcal Conjugate Vaccine OR pneumococcal polysaccharide vaccine OR PCV13 OR 

pneumovax OR PPSV23 OR prevnar* OR pnu-immune

7/3/2018 181

 

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