Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Pneumococcal Vaccines for Immunocompromised Adults
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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
| 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 vaccinate |
|---|---|---|---|---|---|---|
| Invasive Pneumococcal Diseasea | 496 (1 RCT, HIV+ adults, Malawi)[2] | 64c | 17d | 74% (30, 90)b | 47d | 2128d |
| Immunogenicity- Antibody response to vaccine serotypes | ||||||
| Outcome | No. subjects (# studies) | Incidence in unvaccinated (cases/100,000) | Incidence in vaccinated unvaccinated (cases/100,000) | Results | ||
| GMTe ratios | PCV13 phase III studies in immunocompetent adults | |||||
| 1 RCT[3] | 370 | 370 | Statistically significantly greater for PCV13 vs. PPSV23 for 9/13 serotypes; non-inferior response for all types | |||
| 1 RCT[3] | 462 | 462 | Statistically significantly greater for PCV13 vs. PPSV23 for 11/13 serotypes; non-inferior response for all types | |||
| PCV7, 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 PPSV | |||
| 1 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
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 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/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 | 6,000[3] | N/A | 0.2-1.1% | No differencea |
| Deaths | 6,000[3] | N/A | 16/6000 (0.003%)b | No differencea |
| Systemic Adverse Events | ||||
| Fatigue | 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=0.07 |
| 3 RCTs[4, 5, 18] | No serious adverse events; no differences in systemic adverse events reported | |||
Table 2 Footnotes
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
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 seriousb | No serious | 3 |
| Antibody response to vaccine types | RCT (2) | No serious | No serious | Very seriousc | No serious | 3 |
| Antibody response to vaccine types | RCT (4) | No serious | No serious | Seriousd | No serious | 2 |
| Harms | ||||||
| Systemic adverse events | RCT (3) | No serious | N/A | Seriouse | No serious | 2 |
Table 3 Footnotes
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 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)
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 | 2/3a |
| PCV7 vs. PPSV23 | Antibody response to vaccine types | RCT (4) | Response improved for PCV7 vs. PPSV23 or no difference | 2 | 2/3a |
| PCV13 vs. PPSV23 | Systemic adverse events | RCT (3) | No difference for SAEb Decreased risk for some systemic adverse events | 2 | 2/3a |
Table 4 Footnotes
b SAE= Serious Adverse Events
Table 5. Considerations for Formulating Recommendations: 13-valent Pneumococcal Conjugate Vaccine in immunocompromised adults
| 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 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)
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] | Seriousb | N/A | Very seriousc | Not serious | 3 |
| IPDd | RCT (1)[8] | Not serious | N/A | Very seriousc | Not serious | 3 |
| Observational (6)[9-13, 17] | Seriouse | Not serious | Not serious | Not serious | 4 | |
| Pneumonia | RCT (1)[8] | Not serious | N/A | Very seriousc | Not serious | 3 |
| Observational (5)[11, 12, 14-16] | Seriouse | Seriousf | Not serious | Not serious | 4 | |
| Antibody response to vaccine types | RCT (2)[4, 7] | Not serious | Not serious | Seriousg | Not serious | 2 |
| Observational (2)[19, 20] | Not serious | Not serious | Seriousg | Not serious | 3 | |
| Systemic adverse events | Post-licensure surveillance[21] | Not serious | Not serious | Not serious | N/A | 3 |
Table 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 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
Table 7. Summary of Evidence: 23-valent Pneumococcal Polysaccharide Vaccine in immunocompromised adults
| Comparison | Outcome | Study design (# studies) |
Findings | Evidence type | Overall Evidence type a |
|---|---|---|---|---|---|
| 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 | 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 | 3/4 |
| PPSV23 | Systemic adverse events | Post-licensure surveillance | PPSV23 appears safe for use among adults with HIV | 3 | 3/4 |
Table 7 Footnotes
b Invasive Pneumoccal Disease
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 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.
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