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Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Pneumococcal Vaccines for Immunocompromised Adults						Print
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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 adults[3] and 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 Uganda[8] 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 HIV-infected people.[4, 7, 18-20] Safety was assessed by review of post-licensure surveillance data.[21]
Tables
Table 1. Benefits: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Outcome
No. subjects (# studies)
Incidence in unvaccinated (cases/100,000)
Incidence in vaccinated unvaccinated (cases/100,000)
Vaccine efficacy (95% CI)
unvaccinated (cases/100,000)d
Number needed to vaccinateInvasive Pneumococcal Diseasea
496 (1 RCT, HIV+ adults, Malawi)[2]
64c
17d
74% (30, 90)b
47d
2128dImmunogenicity- Antibody response to vaccine serotypesOutcome
No. subjects (# studies)
Incidence in unvaccinated (cases/100,000)
Incidence in vaccinated unvaccinated (cases/100,000)
ResultsGMTe ratios
PCV13 phase III studies in immunocompetent adults1 RCT[3]
370
370
Statistically significantly greater for PCV13 vs. PPSV23 for 9/13 serotypes; non-inferior response for all types1 RCT[3]
462
462
Statistically significantly greater for PCV13 vs. PPSV23 for 11/13 serotypes; non-inferior response for all typesPCV7, in HIV+ adults% with ≥4-fold increase in GMTe
1 RCT[4]
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 RCT[5]
106
106
No significant difference in outcome between PCV7 and PPSV (ORg: 1.36, 95%CI 0.82-2.25)1 RCT[6]
102
100
No significant difference in outcome between PCV7 and PPSV1 RCT[7]
131
73
Greater response for PCV7 vs PPSV (57% vs 36%, respectively; OR: 2.6 [95% CI, 1.4– 5.0])Table 1 Footnotes
RCT, Randomized Controlled Trial.a Caused by vaccine serotypes or type 6Ab 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 2009d Incidence in vaccinated, absolute risk, and number needed to vaccinate was estimated using VE estimate from RCT and applying it to baseline incidence of PCV13 type IPD in the US population with HIV/AIDS
RCT and applying it to baseline incidence of PCV13 type IPD in the US population with HIV/AIDSe GMT= Geometric Mean Titersf IgG= immunoglobuling odds ratio
**Top of Page
Table 2. Harms: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
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
6,000[3]
N/A
0.2-1.1%
No differenceaDeaths
6,000[3]
N/A
16/6000 (0.003%)b
No differenceaSystemic Adverse EventsFatigue
3 RCTs[3]; 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 RCT[6]
20%
34%
P=0.073 RCTs[4, 5, 18]


No serious adverse events; no differences in systemic adverse events reportedTable 2 Footnotes
N/A= not applicablea No difference between the treatment groupsb No deaths were considered vaccine relatedc Significant differences reported for 2 out of 3 RCTs (4 out of 13 outcomes); only significant findings presented in the table
**Top of Page
Table 3. Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Outcome
Design (# studies)
Risk of bias
Inconsistency
Indirectness
Imprecision
Evidence typeaBenefitsInvasive Pneumococcal Disease
RCT (1)
No serious
N/A
Very seriousb
No serious
3Antibody response to vaccine types
RCT (2)
No serious
No serious
Very seriousc
No serious
3Antibody response to vaccine types
RCT (4)
No serious
No serious
Seriousd
No serious
2HarmsSystemic adverse events
RCT (3)
No serious
N/A
Seriouse
No serious
2Table 3 Footnotes
N/A= Not applicablea 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 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)
**Top of Page
Table 4. Summary of Evidence: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Summary of Evidence: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Comparison
Outcome
Study design (# studies)
Findings
Evidence type
Overall evidence typePCV7 vs. No vaccination
Invasive Pneumococcal Disease
RCT (1)
Decreased risk among vaccinated
2/3
2/3aPCV13 vs. PPSV23
Antibody response to vaccine types
RCT (2)
Response improved for PCV13 vs. PPSV23 or no difference
3
2/3aPCV7 vs. PPSV23
Antibody response to vaccine types
RCT (4)
Response improved for PCV7 vs. PPSV23 or no difference
2
2/3aPCV13 vs. PPSV23
Systemic adverse events
RCT (3)
No difference for SAEb Decreased risk for some systemic adverse events
2
2/3aTable 4 Footnotes
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 pneumoniab SAE= Serious Adverse Events
**Top of Page
Table 5. Considerations for Formulating Recommendations: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Considerations for Formulating Recommendations: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
Key factors
CommentsEvidence type for benefits and harms
Indirectness & lack of evidence for 3 of 4 critical disease outcomesBalance between benefits and harms
Benefits outweigh harms. Very high burden of disease in immunocompromised adultsValue
ACIP pneumococcal work group consensus regarding the importance of preventing critical pneumococcal outcomesCost-effectiveness
Uncertainty regarding costs/benefits relative to PPSV23Summary:  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*)
**Top of Page
Table 6. Evidence type: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
Evidence type: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
Outcome
Design
(# studies)
Risk of bias
Inconsistency
Indirectness
Imprecision
Evidence typeaDeath
RCT (1)[8, 22]
Seriousb
N/A
Very seriousc
Not serious
3IPDd
RCT (1)[8]
Not serious
N/A
Very seriousc
Not serious
3Observational (6)[9-13, 17]
Seriouse
Not serious
Not serious
Not serious
4Pneumonia
RCT (1)[8]
Not serious
N/A
Very seriousc
Not serious
3Observational (5)[11, 12, 14-16]
Seriouse
Seriousf
Not serious
Not serious
4Antibody response to vaccine types
RCT (2)[4, 7]
Not serious
Not serious
Seriousg
Not serious
2Observational (2)[19, 20]
Not serious
Not serious
Seriousg
Not serious
3Systemic adverse events
Post-licensure surveillance[21]
Not serious
Not serious
Not serious
N/A
3Table 6 Footnotes
aEvidence 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 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 mortalityc Indirectness due to different population (highly immunosuppressed, no antiretroviral therapy)d Invasive Pneumococcal Diseasee Observational studies overestimate effectiveness against all IPD or all-cause pneumoniaf Test of heterogeneity of odds ratios is highly significant (p=0.0002)g No correlates of protection
**Top of Page
Table 7. Summary of Evidence: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
Summary of Evidence: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
Comparison
Outcome
Study design
(# studies)
Findings
Evidence type
Overall Evidence type aPPSV23 vs. Placebo
Death
RCT (1)
Inconclusive data on efficacy against mortality
3
3/4PPSV23 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
3/4PPSV23 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
3/4PPSV23
Systemic adverse events
Post-licensure surveillance
PPSV23 appears safe for use among adults with HIV
3
3/4Table 7 Footnotes
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
**Top of Page
Table 8. Considerations for Formulating Recommendations: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
Considerations for Formulating Recommendations: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
Key factors
CommentsEvidence type for benefits and harms
Inconsistent evidence for all-cause pneumonia; limited data from RCT not generalizable to the US HIV+ populationBalance between benefits and harms
Some uncertainty about benefits. Vaccine appears to be safe in this populationValue
ACIP pneumococcal work group consensus regarding the importance of preventing critical pneumococcal outcomesCost-effectiveness
Cost-effectiveness in the general adult population demonstrated; uncertainty around the assumptions utilized in cost-effectiveness analysisSummary: 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 non-inferior 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.
References
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.
French N, Gordon SB, Mwalukomo T, et al. A trial of a 7-valent pneumococcal conjugate vaccine in HIV-infected adults. *N Engl J Med*. Mar 4 2010;362(9):812-822.
Food and Drug Administration. FDA expands use of Prevnar 13 vaccine for people ages 50 and older. Silver Spring, MD: US Department of Health and Human Services, Food and Drug Administration. 2011. Accessed May 21, 2012.
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.
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.
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.
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.
French N, Nakiyingi J, Carpenter L. 23-valent pneumococcal polysaccharide vaccine in HIV-1-infected Ugandan adults: double-blind, randomised and placebo controlled trial. *Lancet*. 2000;355:2106 -2111.
Breiman R, Keller D, Phelan M. Evaluation of effectiveness of the 23-valent pneumococcal capsular polysaccharide vaccine for HIV-infected patients. *Arch Intern Med*. 2000;160:2633 -2638.
Grau I, Pallares R, Tubau F, et al. Epidemiologic changes in bacteremic pneumococcal disease in patients with Human Immunodeficiency Virus in the era of highly active antiretroviral therapy. *Arch Intern Med*. 2005;165:1533 -1540.
Hung C-C, Chen M-Y, Hsieh S-M, Hsiao C-F, Sheng W-H, Chang S-C. Clinical experience of the 23-valent capsular polysaccharide pneumococcal vaccination in HIV-1-infected patients receiving highly active antiretroviral therapy: a prospective observational study. *Vaccine*. 2004;22(15–16):2006-2012.
Lopez-Palomo C, Martin-Zamorano M, Benitez E, et al. Pneumonia in HIV-infected patients in the HAART era: Incidence, risk, and impact of the pneumococcal vaccination. *J Med Virol*. 2004;72:517 -524.
Veras M, Enanoria W, Castilho E, Reingold A. Effectiveness of the polysaccharide pneumococcal vaccine among HIV-infected persons in Brazil: a case control study. *BMC Infectious Diseases*. 2007;7(1):119.
Penaranda M, Falco V, Payeras A, et al. Effectiveness of polysaccharide pneumococcal vaccine in HIV-infected patients: a case-control study. *Clin Infect Dis*. Oct 1 2007;45(7):e82-87.
Rodriguez-Barradas MC, Goulet J, Brown S, et al. Impact of pneumococcal vaccination on the incidence of pneumonia by HIV infection status among patients enrolled in the Veterans Aging Cohort 5-Site Study. *Clin Infect Dis*. Apr 1 2008;46(7):1093-1100.
Teshale EH, Hanson D, Flannery B, et al. Effectiveness of 23-valent polysaccharide pneumococcal vaccine on pneumonia in HIV-infected adults in the United States, 1998–2003. *Vaccine*. Oct 29 2008;26(46):5830-5834.
Barry PM, Zetola N, Keruly JC, Moore RD, Gebo KA, Lucas GM. Invasive pneumococcal disease in a cohort of HIV-infected adults: incidence and risk factors, 1990-2003. *AIDS*. Feb 14 2006;20(3):437-444.
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.
Huang K-L, Ruben FL, Rinaldo CR, Kingsley L, Lyter DW, Ho M. Antibody Responses After Influenza and Pneumococcal Immunization in HIV-Infected Homosexual Men. *JAMA*: The Journal of the American Medical Association. April 17, 1987 1987;257(15):2047-2050.
Rodrigue-Barradas MC, Musher DM, Lahart C, et al. Antibody to Capsular Polysaccharides of Streptococcus pneumoniae after Vaccination of Human Immunodeficiency Virus-Infected Subjects with 23-Valent Pneumococcal Vaccine. *The Journal of Infectious Diseases*. 1992;165(3):553-556.
Centers for Disease Control and Prevention. Prevention of pneumococcal disease: recommendations of the Advisory Committee on Immunization Practices (ACIP). *MMWR* Recomm Rep. Apr 4 1997;46(RR-8):1-24.
Watera C, Nakiyingi J, Miiro G, et al. 23-valent pneumococcal polysaccharide vaccine in HIV-infected Ugandan adults: 6-year follow-up of a clinical trial cohort. *AIDS*. 2004;18:1210 -1213.**Top of Page
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							Last Reviewed:  April 15, 2016						Source: 	National Center for Immunization and Respiratory Diseases
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