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

Vaccines for Immunocompromised Children Aged 6 through 18 Years 

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

among immunocompromised children aged 6 through 18 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 children aged 

6 through 18 years with immunocompromising conditions?" Due to the limited body of evidence on vaccine 

efficacy and safety among persons with most immunocompromising conditions and varying formulations of 

pneumococcal conjugate vaccines (PCV), 7-,9-, and 13-valent PCVs were evaluated using data for HIV-infected 

adults and children, and children with sickle cell disease. Studies with PCV7 and PCV9 were used as a proxy 

when no PCV13 studies were available; PCV7 and PCV9 have the same formulation as PCV13 with 7 antigens in 

common. The benefits considered in GRADE included critical outcomes of prevention of invasive 

pneumococcal disease (IPD), pneumococcal pneumonia, death, and hospitalizations due to pneumococcal 

disease; 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 two randomized controlled trials (RCT): 

PCV9 among HIV-infected children in South Africa2 and of PCV7 among HIV-infected adults in Malawi.

3 The 

effectiveness of PCV13 against IPD was assumed to be the same as that estimated from a pre/post 

observational study of PCV7 in children <10 years with sickle cell disease (SCD).

4 Evidence used to evaluate 

efficacy of PCV13 to prevent critical outcomes of pneumonia and death was from the same RCT in South Africa 

among HIV-infected children.2 Evidence was not available for critical outcome of hospitalizations. There are 

two studies on immunogenicity for children with SCD: an unpublished pre/post study of immunogenicity of 

PCV13 in children aged 6 through 18,

5 and a published immunogenicity study of PCV7 and PPSV compared to 

PPSV alone.6 There are three published studies for HIV-infected children: one pre/post study and two clinical 

trials for immunogenicity of PCV.

7-9 Four RCTs of PCV7 have been conducted in HIV-infected adults.10-13 Safety 

of PCV13 was evaluated based on a pre/post study in children with SCD5 and three RCTs of PCV7 in HIVinfected adults.10-12 

6/28/2013
 

1 

https://www.cdc.gov/vaccines/acip/recs/grade/pneumo-immuno-child.pdf
 

 

 

 

 

 

 

 

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

Outcome No. of 

subjects 

(# studies) 

Incidence in 

unvaccinated 

(cases/100,000) 

Incidence in 

vaccinated 

(cases/100,000) 

Vaccine 

efficacy 

(95% CI) 

Absolute 

risk per 

100,000 

Number 

needed to 

vaccinate 

Invasive 

Pneumococcal 

Disease 

RCTs in HIV-infected individuals 

39,836 

(1 RCT of 

PCV9, HIV+ 

children, 

South 

Africa)2 

131 45 65% 

(24, 86)a 

N/A N/A 

496 

(1 RCT of 

PCV7, HIV+ 

adults, 

Malawi)

3 

7,661 2,016 74% 

(30, 90)b 

N/A N/A 

197c 61d 69% 

(44, 83)e 

135d 736d 

Retrospective cohort study in children <10 years with sickle cell disease4 

1,247 1.7 0.5 81% 

(19, 96)f 

N/A N/A 

Death 39,836 

(1 RCT of 

PCV9, HIV+ 

children, 

South 

Africa)2 

884 833 6% 

(P-value 

=0.63)a 

N/A N/A 

Pneumonia 39,836 

(1 RCT of 

PCV9, HIV+ 

children, 

South 

Africa)2 

1,049 914 13% 

(-7, 29)a 

N/A N/A 

Immunogenicity- Antibody response to vaccine serotypes 

2 

6/28/2013
 
 

 

Outcome Study 

design 

Number in study Results 

GMFR PCV13 in children with SCD 

Pre/Post5 158 A single dose of PCV13 was immunogenic in 

SCD patients; none to modest increases in 

titers post-dose 2 of PCV13 administered 6 

months later vs. dose 1 

Study 

design 

Number in 

PCV arm 

Number in 

PPSV23 arm 

PCV7 in children with SCD 

GMC RCT6 

(2 doses of 

PCV7 

+PPSV23 

vs. PPSV23 

only) 

11 12 Significant increases in GMC post 1 dose PCV7, 

no additional benefit post dose 2 of PCV7; 

response as good or better for some serotypes 

post 1 dose PCV7 vs. PPSV23 

PCV7 in HIV+ adults 

% with >4-fold 

increase in GMT 

RCT10 

(2 doses of 

PCV7 vs. 

PPSV23) 

15 16 GMTs higher for PCV7 vs. PPSV23 (significance 

not assessed post 1st dose of PCV7); % with >4­

fold increase in GMT higher for PCV7 vs. 

PPSV23 for 4/5 serotypes (significant for 1/4 

serotypes) 

% with >2-fold 

rise in IgG levels 

and >1μg/ml 

RCT11 106 106 No significant difference in outcome between 

PCV7 and PPSV23 (OR: 1.36, 95%CI 0.82-2.25) 

RCT12 102 100 No significant difference in outcome between 

PCV7 and PPSV23 

RCT13 131 73 Greater response for PCV7 vs. PPSV23 (57% vs. 

36%, respectively; OR: 2.6 [95% CI, 1.4–5.0]) 

Study 

design 

Number in PCV 

group 

Number in 

placebo group 

6/28/2013
 

3 
 

 

 

 

 

 

 

 

 

PCV7 in HIV+ children 

GMC Pre/post7 225 N/A 76–96% achieved >0.5 μg/mL after 1 dose and 

62–88% achieved >1.0 μg/mL after 2 doses of 

PCV7 for five serotypes tested 

RCT8 30 36 Proportion >0.35 μg/mL: 63-93% (1 month 

after 3rd dose of PCV9)a; 

Proportion ≥0.2 μg/mL and ≥0.35 μg/mL (5.3 

years after 3rd dose of PCV9): 

39-100% achieved ≥0.2 g/mL and 

19-81% achieved ≥0.35 μg/mL 

for each of seven serotypes tested 

RCT9 30 15 >95% achieved 0.15 μg/mL and 80% achieved 

0.5 μg/mL after 3rd PCV7 dose; 88–100% 

achieved a 4-fold rise after 3rd PCV7 dose for 

each of seven serotypes tested 

a

Vaccine efficacy for a 3-dose primary series of PCV9 administered at 6, 10, and 14 weeks of age 

b

Vaccine efficacy for 2 doses of PCV7 administered 4 weeks apart estimated using hazard ratios c

Incidence of PCV13 type IPD among children aged 6–18 years with HIV/AIDS in the US, Active Bacterial Core 

surveillance (ABCs), CDC unpublished 2007–09, ABCs incidence data was only used to compute the number needed to 

vaccinate and not used in the evidence profile

d

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

RCTs2,3 and applying it to baseline incidence of PCV13 type IPD in the US population with HIV/AIDS e

Summary vaccine efficacy estimated using data from two RCTs2,3 

f

Vaccine effectiveness for >1 doses of PCV7 adjusted for herd effects 

Abbreviations: 

GMC= Geometric Mean Concentration 

GMT= Geometric Mean Titers 

IgG= Immunoglobulin G 

OR= Odds Ratio 

GMFR=Geometric Mean Fold Rise 

N/A= Not applicable 

RCT= Randomized Controlled Trial 

6/28/2013
 

4 
 

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

Outcome Study 

design 

Incidence in 

controls 

Incidence in 

vaccinated 

Comments 

Serious adverse events (SAE) 

Overall SAE 1 Pre/Post,5 

3 RCTs10-12 

N/A 0 No serious adverse events 

reported 

Deaths 1 Pre/Post,5 

3 RCTs10-12 

N/A 0 No deaths 

Systemic Adverse Events 

Proportion reporting 

Fatigue Pre/post 

study, 2 

doses, 

children 

with SCD5 

66.1% 

Headache 53.6% 

New generalized 

muscle pain 

74.8% 

Vomiting 

15.4% 

Diarrhea 15.4% 

New generalized 

joint pain 

39.8% 

Study 

design 

Incidence in 

controls 

Incidence in 

vaccinated 

Comments 

Mild, self- limited 

secondary 

reactions 

1 RCT12 20% 34% P=0.07 

2 RCTs10,11 N/A N/A No serious adverse events; no 

differences in systemic adverse 

events reported 

N/A= Not applicable 

RCT= Randomized Controlled Trial 

5 

6/28/2013
 
 

 

 

 

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

immunocompromised older children: 

Outcome Study design 

(# studies) 

Risk of bias Inconsistency Indirectness Imprecision Evidence 

typea 

Benefits 

Invasive 

Pneumococc

al Disease 

RCT (2) 

Observational 

(1) 

No serious 

No serious 

No serious 

N/A 

Very serious b 

No serious 

No serious 

No serious 

3 

3 

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

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

Antibody 

response to 

vaccine 

types 

Pre/post (2) No serious No serious No serious No serious 3 

RCT (4) adults, 

RCT (2) children 

No serious No serious Very serious c No serious 3 

Harms 

Systemic 

adverse 

events 

Pre/post (1) No serious N/A No serious No serious 3 

RCT (5) No serious No serious Very serious c No serious 3 

N/A= Not applicable 

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

Indirectness due to 1) different intervention (PCV9, 3 doses; PCV7, 2 doses) and 2) different population (South 

Africa, infants; Malawi, adults) c

Indirectness due to 1) different intervention (PCV7 or PCV9) and 2) different population (adults) 

6 

6/28/2013
 
 

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

children: 

Comparison Outcomea Study 

design 

(# studies) 

Findings Evidence 

type 

Overall 

evidence 

type 

PCV9 or PCV7 vs. No 

vaccination 

Invasive 

Pneumococcal 

Disease 

RCT (2) Decreased risk among 

vaccinated 

3 

PCV9 vs. No vaccination Pneumonia RCT (1) Decreased risk among 3

vaccinated 

3 

PCV9 vs. No vaccination Death RCT (1) No change in outcome 3 

PCV13, PCV7, or PCV9 vs 

PPSV or placebo 

Antibody 

response to 

vaccine types 

Pre/post (2) 

RCT (6) 

Increases in antibody titers 

post-vaccination 

3 

PCV13 or PCV7 SAEb Pre/Post (1) 

RCT (5) 

No serious adverse events 3 

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 hospitalizations due to pneumococcal disease 

b SAE= Serious Adverse Events 

7 

6/28/2013
 
 

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

immunocompromised children: 

Key factors Comments 

Evidence type for benefits and 

harms 

Indirectness & lack of evidence for 3 of 4 critical disease outcomes 

Balance between benefits and 

harms 

Benefits outweigh harms 

Very high burden of disease in immunocompromised children 

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 children. (recommendation category A; 

evidence type 3) 

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

of both PCV13 and PPSV23 among immunocompomised children 6 through 18 years old; 49% of IPD in this 

group is caused by PCV13 serotypes, and an additional 23% 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.

11,12,14 Although the optimal 

interval for PCV13 followed by PPSV23 has not been specifically studied, significant increases in antibody as 

well as non-inferior to superior response compared to PPSV23 alone has been observed when PPSV23 was 

given eight weeks after PCV7.14 For children previously immunized with PPSV23, waiting at least 8 weeks after 

PPSV23 before giving a dose of PCV13 may provide a better immune response (expert opinion). 

The Work Group concluded that Category A (desirable consequences clearly outweigh undesirable 

consequences) recommendation for the use of PCV13 (evidence type 3) among PCV13-naïve 

immunocompromised children is warranted because 1) there remains an extremely high burden of 

pneumococcal disease among immuocompromised children, and 2) indirect effects of PCV13 use in young 

children are unlikely to eliminate disease caused by PCV13 serotypes in older children with 

immunocompromising conditions. 

6/28/2013
 

8 
 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References: 

1.	 Ahmed F, Temte JL, Campos-Outcalt D, Schünemann HJ. Methods for developing evidence-based 

recommendations by the Advisory Committee on Immunization Practices (ACIP) of the U.S. Centers for Disease 

Control and Prevention (CDC). Vaccine. 2011;29(49):9171-9176. 

2.	 Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal 

conjugate vaccine in children with and those without HIV infection. New England Journal of Medicine. Oct 2 

2003;349(14):1341-1348. 

3.	 French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected 

adults. The New England journal of medicine. Mar 4 2010;362(9):812-822. 

4.	 Adamkiewicz TV, Silk BJ, Howgate J, et al. Effectiveness of the 7-valent pneumococcal conjugate vaccine in 

children with sickle cell disease in the first decade of life. Pediatrics. Mar 2008;121(3):562-569. 

5.	 Montalembert M, Abboud MR, Fiquet A, et al. A 2-dose schedule of 13-valent pneumococcal conjugate vaccine 

(PCV13) given to children with sickle cell disease previously immunized with 23-valent pneumococcal 

polysaccharide vaccine (PPSV23): results of a phase 3 study. 54th Annual Meeting of the American Society of 

Hematology, Atlanta, GA, USA. December 8-11, 2012. 

6.	 Vernacchio L, Neufeld EJ, MacDonald K, et al. Combined schedule of 7-valent pneumococcal conjugate vaccine 

followed by 23-valent pneumococcal vaccine in children and young adults with sickle cell disease. J Pediatr. 

1998;133(2):275-278. 

7.	 Abzug MJ, Pelton SI, Song LY, et al. Immunogenicity, safety, and predictors of response after a pneumococcal 

conjugate and pneumococcal polysaccharide vaccine series in human immunodeficiency virus-infected children 

receiving highly active antiretroviral therapy. The Pediatric infectious disease journal. Oct 2006;25(10):920-929. 

8.	 Madhi SA, Kuwanda L, Cutland C, Holm A, Kayhty H, Klugman KP. Quantitative and qualitative antibody response 

to pneumococcal conjugate vaccine among African human immunodeficiency virus-infected and uninfected 

children. The Pediatric infectious disease journal. May 2005;24(5):410-416. 

9.	 Nachman S, Kim S, King J, et al. Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in 

infants with human immunodeficiency virus type 1 infection. Pediatrics. Jul 2003;112(1 Pt 1):66-73. 

10.	 Feikin DR, Elie CM, Goetz MB, et al. Randomized trial of the quantitative and functional antibody responses to a 

7-valent pneumococcal conjugate vaccine and/or 23-valent polysaccharide vaccine among HIV-infected adults. 

Vaccine. Nov 12 2002;20(3-4):545-553. 

11.	 Lesprit P, Pedrono G, Molina JM, et al. Immunological efficacy of a prime-boost pneumococcal vaccination in 

HIV-infected adults. Aids. Nov 30 2007;21(18):2425-2434. 

12.	 Penaranda Ma, Payeras Ab, Cambra Ac, Mila Jc, Riera Ma, the Majorcan Pneumococcal Study G. Conjugate and 

polysaccharide pneumococcal vaccines do not improve initial response of the polysaccharide vaccine in HIVinfected adults. Aids. 2010;24(8):1226-1228. 

13.	 Crum-Cianflone NF, Huppler Hullsiek K, Roediger M, et al. A randomized clinical trial comparing revaccination 

with pneumococcal conjugate vaccine to polysaccharide vaccine among HIV-infected adults. J Infect Dis. Oct 1 

2010;202(7):1114-1125. 

14.	 Feikin DR, Elie CM, Goetz MB, et al. Specificity of the antibody response to the pneumococcal polysaccharide 

and conjugate vaccines in human immunodeficiency virus-infected adults. Clin Diagn Lab Immunol. Jan 

2004;11(1):137-141. 

6/28/2013
 

9