Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for 

Pneumococcal Vaccines for Adults aged ≥65 years 

Methods: GRADE was used to evaluate 13-valent Pneumococcal Conjugate Vaccine (PCV13) 

for routine use among adults aged ≥65 years. Evidence of benefits, harms, values and 

preferences, and cost-effectiveness were reviewed in accordance with GRADE methods.1 The 

primary policy question was "Should PCV13 be administered routinely to all adults aged ≥65 

years?" The intervention evaluated was a single dose of PCV13 compared to a dose of 23-valent 

polysaccharide vaccine (PPSV23). 

The benefits considered critical outcomes in GRADE included prevention of invasive 

pneumococcal disease (IPD), pneumococcal community-acquired pneumonia, and 

hospitalizations due to pneumococcal disease. Evidence used to evaluate efficacy of PCV13 

against IPD and pneumococcal pneumonia was from the randomized placebo-controlled trial 

(RCT) conducted among approximately 85,000 adults aged >65 years in Netherlands 

(CAPiTA).2 Evidence was not available for the critical outcome of hospitalizations due to 

pneumococcal disease. In addition, vaccine-induced immunogenicity was considered as an 

important outcome; immunogenicity evidence was assessed using two phase III RCTs of PCV13 

compared to PPSV23, which measured antibody responses by opsonophagocytic assay (OPA) 

and four RCTs of PCV7 compared to PPSV23, which measured antibody responses by enzymelinked immunosorbent assay (ELISA).3-8

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https://www.cdc.gov/vaccines/acip/recs/grade/pneumo-vac-adult.pdf
 

 

 

 

 

 

 

 

 

The harms considered were overall serious adverse events (SAE), deaths and systemic adverse 

events including fatigue, rash, new generalized muscle pain, and use of medications to treat 

fever. Safety of PCV13 was evaluated based on 6 RCTs in immunocompetent adults, compared 

to PPSV23.

9

Evidence type for each critical outcome was derived through a review of study design, risk of 

bias, inconsistency, indirectness, and imprecision. 

Table 1a. Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years: 

Invasive Pneumococcal Disease and Community-Acquired Pneumonia 

Outcome No. of subjects 

(# studies) 

Incidence in 

unvaccinated 

(cases/100,000) 

Vaccine 

efficacy (95% 

CI) 

Number Needed 

to Vaccinate a

PCV13-serotype 

Invasive 

Pneumococcal 

Disease 

Approximately 

85,000 adults 

(1 RCT)2

6.510 74% (30-90%) b 20,400 

(16,950-37,000)

Inpatient 

community-acquired 

pneumonia 

Approximately 

85,000 adults 

(1 RCT)2

137.511 c 45% (14-65%) 1,620 (1,110 ­

5,130) 

Outpatient 

community-acquired 

pneumonia 

Approximately 

85,000 adults 

(1 RCT)

12

2019 c 45% (14-65%) 1,110 (760­

3,500) 

Total communityacquired pneumonia 

Approximately 

85,000 adults 

(1 RCT)2

-­ -­ 656 (454-2,110) 

September 16, 2014
 

 

 

 

 

 

 

 

 

 

 

a Number needed to vaccinate or NNV=1 / (baseline rate – vaccinated rate) 

b Vaccine Efficacy versus placebo 

c Baseline estimates assume 10% of all CAP due to PCV13 types 

Table 1b. Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years: 

Immunogenicitya

Study No. of 

subjects Population Immunogenicity Results 

Jackson et al 

20133

818 60 to 64 years 

PPSV23 Naïve PCV13 > PPSV23 for 9/13 types (OPA) 

PCV13=PPSV23 for 4/13 types (OPA) 

Jackson et al 

20134 879 

≥70 years 

PPSV23 >5 years 

previously 

PCV13>PPSV23 for 11/13 types (OPA) 

PCV13=PPSV23 for 2/13 types (OPA) 

Goldblatt et 

al 20095 599 

50 to 80 years 

No PPSV23 

within the past 5 

years 

PCV7 = PPSV23 for 3/7 types (ELISA) 

PCV7 > PPSV23 for 3/7 types (ELISA) 

PCV7<PPSV23 for 1/7 types (ELISA) 

De Roux et 

al 20086 217 >70 years 

PPSV Naïve 

PCV7 = PPSV23 for 1 type (ELISA) 

PCV7>PPSV23 for 6/7 types (ELISA) 

Ridda et al 

20097 241 >60 years, frail 

PPSV Naïve 

PCV7 = PPSV23 for 4/4 types tested (ELISA) 

Comparisons of other 3 types not done 

Miernyk et 

al 20098 203 

55 to 70 years, 

Alaska Native 

PPSV Naïve 

PCV7 = PPSV23 for 4/4 types tested (ELISA) 

Comparisons of other 3 types not done 

a Immunogenicity: Antibody response to vaccine serotypes, compared to PPSV23 

September 16, 2014
 

 

 

 

 

 

 

Table 2. Harms of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years 

Outcome 

No. of 

subjects 

(# studies) 

Incidence in 

controls 

Incidence in 

vaccinated 

Risk 

Difference 

per 1000 (95% 

CI) 

Serious adverse events (SAE) 

Overall serious 

adverse events 

6,000 

(6 RCTs)9 -­ 0.2-1.1% No difference a 

Deaths 6,000 

(6 RCTs)9 -­ 16/6000 (0.3%)b No difference a 

Systemic Adverse Events 

Fatigue 

3 RCTs & 

PCV13 phase 

III9 c 

43.3% d 34.0% -9.3 

(-16.4, -2.2) 

Rash 16.4% d 7.3% -9.1 

(-14.3, -4.0) 

New generalized 

muscle pain 44.7% d 36.8% -7.9 (-15.2,-0.6) 

Medications to treat 

fever 17.5% d 8.6% -8.9 (-16.6,-1.9) a No difference between the treatment groups 

b No deaths were considered vaccine related 

c Significant differences reported for 2 out of 3 RCTs (4 out of 13 outcomes); only significant 

findings presented in the table

d Controls received PPSV23 

September 16, 2014
 

 

 

 

 

Table 3. Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate 

Vaccine in Adults aged ≥65 years 

Outcome Study 

design 

Risk of 

bias Inconsistency Indirectness Imprecision Evidence 

type a 

Benefits b 

Invasive 

Pneumococcal 

Disease 

1 RCT No 

serious 

Not 

applicable Serious c No serious 2 

Communityacquired 

pneumonia 

1 RCT No 

serious 

Not 

applicable No serious No serious 1 

Immunogenicity 6 RCT No 

serious No serious Serious d No serious 2 

Harms 

Systemic 

adverse events 3 RCTs No serious No serious No serious No serious 1 

a Evidence type: 

1. Randomized controlled trials (RCTs), or overwhelming evidence from observational 

studies. 

2. RCTs with important limitations, or exceptionally strong evidence from observational 

studies. 

3. Observational studies, or RCTs with notable limitations. 

4. Clinical experience and observations, observational studies with important limitations, or 

RCTs with several major limitations. 

b Immunogenicity data which was considered an important outcome did not contribute to overall 

evidence type. c Indirectness due to different comparison group: 1) Placebo instead of PPSV and 2) PPSV 

efficacy against IPD among older adults = 50-80%

d Indirectness due to different outcome (antibody response without correlates of protection) 

September 16, 2014
 

 

 

Table 4. Summary of Evidence for 13-valent Pneumococcal Conjugate Vaccine in Adults 

aged ≥65 years 

Comparison Outcome Study 

design Findings Evidence type 

Overall 

evidence 

type a

PCV13 vs. no 

vaccination IPD 1 RCT Decreased risk among vaccinated 2 

2 

PCV13 vs. 

no vaccination Pneumonia 1 RCT Decreased risk among vaccinated 1 

PCV7 or PCV13 

vs. 

PPSV23 

Immunogenicity 6 RCTs 

Response better for 

PCV than PPSV23 or 

no difference 

2 

PCV13 vs. 

PPSV23 

Serious and 

systemic 

adverse events 

3 RCTs 

No difference or 

decreased risk with 

PCV13 

1 

a Overall evidence type is based on the weakest evidence type among the critical outcomes. This 

did not include immunogenicity data which was considered an important outcome. 

September 16, 2014
 

Table 5. Considerations for Formulating Recommendations for 13-valent Pneumococcal 

Conjugate Vaccine in Adults aged ≥ 65 years 

Key factors Comments 

Evidence type/quality for benefits 

and harms Data on efficacy against most critical outcomes available 

Balance of benefits versus harms 

Benefits outweigh harms 

Short-term: No uncertainty about the balance 

Long-term: Indirect (herd) effects of infant vaccination 

expected to further reduce burden of pneumococcal 

disease in adults. 

Values General consensus reached on which outcomes are 

critical to prevent 

Cost-effectiveness 

Short-term: The net benefits are worth the costs 

Long-term: Uncertainty about whether the net benefits 

are worth the costs due to continued indirect effects 

Summary 

The evidence supporting PCV13 vaccination of adults 

was determined to be type 2 (moderate level of 

evidence). 

The recommendation was designated as Category A. 

The ACIP Pneumococcal Work Group concluded that broader serotype protection can be 

achieved through use of both PCV13 and PPSV23 among adults >65 years of age; 20-25% of 

IPD among adults in this age group is caused by PCV13 serotypes, and an additional 38.5% by 

serotypes in PPSV23 not included in PCV13.10 Conversely, PCV13 use among older adults will 

protect against inpatient community-acquired pneumonia.2

 Evidence from immunogenicity 

studies demonstrate that antibody response is non-inferior or superior when PCV is given before 

PPSV23 compared to PPSV23 administration before PCV.3-8 Although the optimal interval for 

PCV13 followed by PPSV23 has not been directly studied, studies evaluating the immune 

response following a sequence of PCV7 or PCV13 followed by PPSV23 with intervals of 2, 6, 

September 16, 2014
12 months, or 3-4 years demonstrated that following the PPSV23 dose, antibody levels were 

higher than the pre-PCV baseline, and a non-inferior response was observed when compared 

with post-PCV antibody levels.5,8,13,14 For adults previously immunized with PPSV23, waiting at 

least 1 year after PPSV23 before giving a dose of PCV13 may provide a better immune response 

according to expert opinion. 

September 16, 2014
 

 

 

 

 

 

 

 

 

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https://pneumonia.org.au/public/journals/22/PublicFolder/ABSTRACTBOOKMASTERforwebupd 

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9.	 US Food and Drug Administration. Vaccines and Related Biological Products Advisory Committee 

(VRBPAC) adult indication briefing document: Prevnar 13. Silver Spring, MD2011. 

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2013 ABCs Data on Streptococcus Pneumoniae. Vol 2014: CDC; 2013. 

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