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

Vaccines for Immunocompromised Adults 

Methods: GRADE was used to evaluate 13-valent Pneumococcal Conjugate Vaccine (PCV13) and 23-valent 

pneumococcal polysaccharide vaccine (PPSV23) for routine use among immunocompromised adults. 

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 adults with 

immunocompromising conditions?" For consistency, evidence for both PPSV23 (recommended for use since 

1983) and PCV13 were evaluated by applying the GRADE framework. Due to the limited body of evidence on 

vaccine efficacy and safety among persons with most immunocompromising conditions, both vaccines were 

evaluated using data for HIV-infected adults. Additionally, studies with 7-valent pneumococcal conjugate 

vaccine (PCV7) were used as a proxy when no PCV13 studies were available; PCV7 has the same formulation 

as PCV13 but contains 6 fewer antigens. The benefits considered critical outcomes in GRADE included 

prevention of death, invasive pneumococcal disease (IPD), pneumococcal pneumonia, hospitalizations due to 

pneumococcal disease, and vaccine-induced immunogenicity was considered an important outcome. The 

harms considered were serious adverse events and systemic adverse events. Evidence type for each critical or 

important outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, and 

imprecision. 

Evidence used to evaluate efficacy of PCV13 to prevent IPD was from a randomized controlled trial (RCT) of 

PCV7 among HIV-infected adults in Malawi.2 Evidence was not available for critical outcomes of pneumonia, 

hospitalizations, or deaths. Immunogenicity of PCV13 compared to PPSV23 was evaluated based on 2 phase III 

RCTs among healthy adults3and 4 RCTs of PCV7 in HIV-infected adults.4-7 Safety of PCV13 was evaluated based 

on 6 RCTs in immunocompetent adults.3 

The evidence used to evaluate efficacy of PPSV23 compared to placebo against IPD, pneumonia, and deaths 

was drawn from one RCT among HIV-infected adults in Uganda8 as well as 9 observational studies in the 

United States and Europe.9-17 Evidence was not available for the critical outcome of hospitalization due to 

pneumococcal disease. Immunogenicity was evaluated in 2 RCTs and 2 observational studies among HIVinfected people.

4,7,18-20 Safety was assessed by review of post-licensure surveillance data.21 

1 

https://www.cdc.gov/vaccines/acip/recs/grade/pneumo-immuno-adults.pdf 6/28/2013
 

 

 

 

 

 

 

Table 1. Benefits: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults: 

Outcome No. of 

subjects 

(# studies) 

Incidence in 

unvaccinated 

(cases/100,000) 

Incidence in 

vaccinated 

(cases/100,000) 

Vaccine 

efficacy 

(95% CI) 

Absolute 

risk per 

100,000d 

Number 

Needed to 

Vaccinate 

Invasive 

Pneumococcal 

Diseasea 

496 

(1 RCT, HIV+ 

adults, 

Malawi) 2 

64c 17 d 74% 

(30, 90)b 

47d 2128d 

Immunogenicity- Antibody response to vaccine serotypes 

Outcome No. of 

studies 

Number in 

PCV13 group 

Number in 

PPSV23 group 

Results 

GMTe ratios PCV13 phase III studies in immunocompetent adults 

1 RCT3 370 370 Statistically significantly greater for PCV13 

vs. PPSV23 for 9/13 serotypes; non-inferior 

response for all types 

1 RCT3 462 462 Statistically significantly greater for PCV13 

vs. PPSV23 for 11/13 serotypes; noninferior response for all types 

PCV7, in HIV+ adults 

% with >4-fold 

increase in GMTe 

1 RCT4 15 16 GMTs higher for PCV7 vs. PPSV23 (stat. 

significance not assessed post 1st dose); % 

with >4-fold increase in GMT higher for 

PCV7 vs. PPSV23 for 4/5 serotypes (stat. 

significant for 1/4) 

% with >2-fold 

rise in IgGf levels 

and >1ug/ml) 

1 RCT5 106 106 No significant difference in outcome 

between PCV7 and PPSV (ORg: 1.36, 95%CI 

0.82-2.25) 

1 RCT6 102 100 No significant difference in outcome 

between PCV7 and PPSV 

1 RCT7 131 73 Greater response for PCV7 vs PPSV (57% vs 

36%, respectively; OR: 2.6 [95% CI, 1.4– 

5.0]) 

RCT, Randomized Controlled Trial. a Caused by vaccine serotypes or type 6A 

b Intention-to-treat analysis (vaccine efficacy estimated using hazard ratios) c Incidence of PCV13 type IPD among adults with HIV/AIDS in the US, Active Bacterial Core surveillance, CDC 

unpublished 2009 

d Incidence in vaccinated, absolute risk, and number needed to vaccinate was estimated using VE estimate from 

2 
 

RCT2 and applying it to baseline incidence of PCV13 type IPD in the US population with HIV/AIDS e

GMT= Geometric Mean Titers 

f

IgG= immunoglobulin 

g

odds ratio 

Table 2. Harms: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults: 

Outcome No. of 

subjects 

(# studies) 

Incidence in 

controls 

Incidence in 

vaccinated 

Risk Difference 

per 1000 (95% CI) 

Serious adverse events (SAE) 

Overall SAE 6,0003 N/A 0.2-1.1% No differencea 

Deaths 6,0003 N/A 16/6000 

(0.003%)b 

No differencea 

Systemic Adverse Events 

Fatigue 3 RCTs3; 

PCV13 

phase IIIc 

43.3% 34.0% -9.3 (-16.4, -2.2) 

Rash 16.4% 7.3% -9.1 (-14.3, -4.0) 

New generalized 

muscle pain 

44.7% 36.8% -7.9 (-15.2,-0.6) 

Use of medications 

to treat fever 

17.5% 8.6% -8.9 (-16.6,-1.9) 

Mild, self- limited 

secondary effects 

1 RCT6 20% 34% P=0.07 

3 RCTs4,5,18 No serious adverse events; no 

differences in systemic adverse 

events reported 

N/A, not applicable

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 

3 
 

 

 

 

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. 

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

immunocompromised adults: 

Outcome Design 

(# studies) 

Risk of bias Inconsistency Indirectness Imprecision Evidence 

typea 

Benefits 

Invasive 

Pneumococcal 

Disease 

RCT (1) No serious N/A Very serious b No serious 3 

Antibody response 

to vaccine types 

RCT (2) No serious No serious Very serious c No serious 3 

Antibody response 

to vaccine types 

RCT (4) No serious No serious Serious d No serious 2 

Harms 

Systemic adverse 

events 

RCT (3) No serious N/A Serious e No serious 2 

N/A= Not applicable 

a Evidence type: 

b Indirectness due to 1) different population (Malawi), 2) different intervention (PCV7, 2 doses), and 3) different 

comparison group (placebo) 

c Indirectness due to 1) different population (immunocompetent) and 2) different outcome (antibody response 

without defined correlates of protection) 

d Indirectness due to 1) different intervention (PCV7) and 2) different outcome (antibody response without 

defined correlates of protection) e Indirectness due to 1)different population (Phase III studies of PCV13 in immunocompetent) or 2) different 

intervention (PCV7 published studies) 

4 
 

 

 

 

 

Table 4. Summary of Evidence: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults: 

Comparison Outcome Study 

design 

(# studies) 

Findings Evidence 

type 

Overall 

evidence 

type 

PCV7 vs. No vaccination Invasive 

Pneumococcal 

Disease 

RCT (1) Decreased risk among 

vaccinated 

2/3 

2/3a PCV13 vs. PPSV23 Antibody 

response to 

vaccine types 

RCT (2) Response improved for 

PCV13 vs. PPSV23 or no 

difference 

3 

PCV7 vs. PPSV23 Antibody 

response to 

vaccine types 

RCT (4) Response improved for 

PCV7 vs. PPSV23 or no 

difference 

2 

PCV13 vs. PPSV23 Systemic 

adverse events 

RCT (3) No difference for SAEb 

Decreased risk for some 

systemic adverse events 

2 

a Overall evidence type is based on the weakest evidence type among the critical outcomes. Evidence was not available 

and, evidence type could not be assessed for critical outcomes of death, hospitalizations due to pneumococcal disease, 

and pneumonia 

b SAE= Serious Adverse Events 

5 
 

Table 5. Considerations for Formulating Recommendations: 13-valent Pneumococcal Conjugate Vaccine in 

immunocompromised adults: 

Key factors Comments 

Evidence type for benefits and Indirectness & lack of evidence for 3 of 4 critical disease outcomes 

harms 

Balance between benefits and 

harms 

Benefits outweigh harms.

Very high burden of disease in immunocompromised adults 

Value ACIP pneumococcal work group consensus regarding the importance of preventing 

critical pneumococcal outcomes 

Cost-effectiveness Uncertainty regarding costs/benefits relative to PPSV23 

Summary: Benefits are greater than potential harms. High values were placed on prevention of the morbidity 

and mortality of pneumococcal infection among immunocompromised adults. (recommendation category B; 

evidence type 2/3) 

6 
 

 

 

 

 

 

 

 

 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. 

Table 6. Evidence type: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults 

Outcome Design 

(# studies) 

Risk of bias Inconsistency Indirectness Imprecision Evidence 

typea 

Death RCT (1)8,22 Serious b N/A Very serious c Not serious 3 

IPDd RCT (1)8 Not serious N/A Very seriousc Not serious 3 

Observational (6)9­

13,17 

Serious e Not serious Not serious Not serious 4 

Pneumonia RCT (1)8 Not serious N/A Very serious c Not serious 3 

Observational 

(5)11,12,14-16 

Serious e Serious f Not serious Not serious 4 

Antibody response 

to vaccine types 

RCT (2)4,7 Not serious Not serious Serious g Not serious 2 

Observational 

(2)19,20 

Not serious Not serious Seriousg Not serious 3 

Systemic adverse 

events 

Post-licensure 

surveillance21 

Not serious Not serious Not serious N/A 3 

a Evidence type: 

b Inconsistent findings of the initial trial and a follow up study. Mortality assessed during a follow up study (Watera et 

al) showed improved mortality among vaccine recipients while initial study (French et al) had a null finding with 

respect to mortality c Indirectness due to different population (highly immunosuppressed, no antiretroviral therapy) 

d Invasive Pneumococcal Disease 

e Observational studies overestimate effectiveness against all IPD or all-cause pneumonia 

f

Test of heterogeneity of odds ratios is highly significant (p=0.0002) 

g

No correlates of protection 

7 
 

 

Table 7. Summary of Evidence: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults 

Comparison Outcome Study design 

(# studies) 

Findings Evidence 

type 

Overall 

evidence 

typea 

PPSV23 vs. Placebo Death RCT (1) Inconclusive data on efficacy 

against mortality 

3 

3/4 

PPSV23 vs. Placebo 

or 

No vaccination 

IPDb RCT (1) 

Observational 

(6) 

Negative efficacy among 

highly immunosuppressed 

adults; effectiveness against 

all IPD 49% (34%, 61%) from 

observational studies 

3/4 

PPSV23 vs. Placebo 

or 

No vaccination 

All-cause 

pneumonia 

RCT (1) 

Observational 

(5) 

Negative efficacy among 

highly immunosuppressed 

adults; effectiveness of 31% 

(27%, 36%) from observational 

studies 

3/4 

PPSV23 Systemic 

adverse 

events 

Post-licensure 

surveillance 

PPSV23 appears safe for use 

among adults with HIV 

3 

a Overall evidence type is based on the weakest critical outcomes evidence type. Evidence was not available and 

evidence type was not assessed for critical outcome of hospitalizations due to pneumococcal infections. 

b

Invasive Pneumoccal Disease 

8 
 

 

 

 

 

 

 

 

 

 

Table 8. Considerations for Formulating Recommendations: 23-valent Pneumococcal Polysaccharide Vaccine in 

immunocompromised adults 

Key factors Comments 

Evidence type for benefits and 

harms 

Inconsistent evidence for all-cause pneumonia; limited data from RCT not 

generalizable to the US HIV+ population 

Balance between benefits and 

harms 

Some uncertainty about benefits.

Vaccine appears to be safe in this population 

Value ACIP pneumococcal work group consensus regarding the importance of preventing 

critical pneumococcal outcomes 

Cost-effectiveness Cost-effectiveness in the general adult population demonstrated; uncertainty around 

the assumptions utilized in cost-effectiveness analysis 

Summary: Benefits are likely greater than harms. High values were placed on prevention of the morbidity and 

mortality of pneumococcal infection among immunocompromised adults.(recommendation category B; evidence 

type 3/4) 

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

of both PCV13 and PPSV23 among immunocompomised adults; half of IPD in immunocompromised adults is 

caused by PCV13 serotypes, and an additional 21% by serotypes in PPSV23 not included in PCV13. 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.

5,6,18 Although the optimal interval for 

PCV13 followed by PPSV23 has not been specifically studied, significant increases in antibody as well as noninferior to superior response compared to PPSV23 alone has been observed when PPSV23 was given eight 

weeks after PCV7.

18 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 (expert opinion). 

The Work Group concluded that Category A recommendation for the use of both PCV13 (evidence type 2/3) 

and PPSV23 (evidence type 3/4) among immunocompromised adults. Category A, (desirable consequences 

clearly outweigh undesirable consequences) is warranted because 1) there remains an extremely high burden

of pneumococcal disease among immuocompromised adults; 2) indirect effects of PCV13 use in children are

unlikely to eliminate PCV13 serotypes from the adult immunocompromised population, and 3) the GRADE

process led to the conclusion that both PCV13 and PPSV23 are effective in this group & that benefits likely 

outweigh harms. 

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