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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) of Pneumococcal Vaccines for Immunocompromised Children Aged 6 through 18 Years

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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 Africa.[2] 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 There are two studies on immunogenicity for children with SCD: an unpublished pre/post study of immunogenicity of PCV13 in children aged 6 through 18,[5] and a published immunogenicity study of PCV7 and PPSV compared to PPSV alone.[6]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 SCD[5] and three RCTs of PCV7 in HIV-infected adults.[10-12]

Tables

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

Outcome No. 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 disease[4]
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
Outcome Study design Number in study Results
GMFR PCV13 in children with SCD
Pre/Post[5] 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 Results
  PCV7 in children with SCD
GMC

RCT[6]
(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

RCT[10]

(2 doses of PCV7 vs. PPSV23)
15 16 GMTs higher for PCV7 vs. PPSV23 (significance not assessed post 1st doe osf 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 RCT[11] 106 106 No significant difference in outcome between PCV7 and PPSV23 (OR: 1.36, 95%CI 0.82-2.25)
RCT[12] 102 100 No significant difference in outcome between PCV7 and PPSV23
RCT[13] 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 Results
  PCV7 in HIV+ children
GMC Pre/post[7] 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
RCT[8] 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

RCT[9] 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

aVaccine efficacy for a 3-dose primary series of PCV9 administered at 6, 10, and 14 weeks of age
bVaccine efficacy for 2 doses of PCV7 administered 4 weeks apart estimated using hazard ratios
cIncidence 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
dIncidence in vaccinated, absolute risk, and number needed to vaccinate was estimated using VE estimate from two RCTs[2],[3] and applying it to baseline incidence of PCV13 type IPD in the US population with HIV/AIDS
eSummary vaccine efficacy estimated using data from two RCTs[2],[3]
fVaccine 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

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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 RCTs[10-12]
N/A 0 No serious adverse events reported
Deaths 1 Pre/Post,[5]
3 RCTs[10-12]
N/A 0 No deaths
Systemic Adverse Events
  Study design Proportion reporting  
Fatigue Pre/post study, 2 doses, children with SCD[5] 66.1%  
Headache Pre/post study, 2 doses, children with SCD[5] 53.6%  
New generalized muscle pain Pre/post study, 2 doses, children with SCD[5] 74.8%  
Vomiting Pre/post study, 2 doses, children with SCD[5] 15.4%  
Diarrhea Pre/post study, 2 doses, children with SCD[5] 15.4%  
New generalized joint pain Pre/post study, 2 doses, children with SCD[5] 39.8%  
  Study design Incidence in controls Incidence in vaccinated Comments
Mild, self-limited secondary reactions 1 RCT[12] 20% 34% P=0.07
2 RCTs[10],[11] N/A N/A No serious adverse events; no differences in systemic adverse events reported

N/A= not applicable
RCT= Randomized Controlled Trial

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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 Pneumococcal Disease

RCT (2)

No serious

No serious

Very seriousb

No serious

3

Observational (1) No serious N/A No serious No serious 3
Pneumonia RCT (1) No serious N/A Very seriousb No serious 3
Death RCT (1) No serious N/A Very seriousb No 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 seriousc 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 seriousc 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)

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

Comparison Outcome 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 3
PCV9 vs. No vaccination Pneumonia RCT (1) Decreased risk among vaccinated 3 3
PCV9 vs. No vaccination Death RCT (1) No change in outcome 3 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 3
PCV13 vs. PCV7 SAEb

Pre/Post (1)

RCT (5)
No serious adverse events 3 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 death, hospitalizations due to pneumococcal disease
b SAE= Serious Adverse Events

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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.

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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 HIV-infected 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.

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