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

Table 1 Footnotes

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

Table 2 Footnotes

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

Table 3 Footnotes

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

Table 4 Footnotes

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

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)

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

Table 6 Footnotes

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

Table 7 Footnotes

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

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.

References

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2. 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.
3. 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.
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16. 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.
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19. 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.
20. 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.
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