Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) for Pneumococcal Vaccines for Adults aged ≥65 years

Methods

GRADE was used to evaluate 13-valent Pneumococcal Conjugate Vaccine (PCV13) for routine use among adults aged ≥65 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 all adults aged ≥65 years?” The intervention evaluated was a single dose of PCV13 compared to a dose of 23-valent polysaccharide vaccine (PPSV23).

The benefits considered critical outcomes in GRADE included prevention of invasive pneumococcal disease (IPD), pneumococcal community-acquired pneumonia, and hospitalizations due to pneumococcal disease. Evidence used to evaluate efficacy of PCV13 against IPD and pneumococcal pneumonia was from the randomized placebo-controlled trial (RCT) conducted among approximately 85,000 adults aged ≥65 years in Netherlands (CAPiTA).2 Evidence was not available for the critical outcome of hospitalizations due to pneumococcal disease. In addition, vaccine-induced immunogenicity was considered as an important outcome; immunogenicity evidence was assessed using two phase III RCTs of PCV13 compared to PPSV23, which measured antibody responses by opsonophagocytic assay (OPA) and four RCTs of PCV7 compared to PPSV23, which measured antibody responses by enzyme-linked immunosorbent assay (ELISA).345678

The harms considered were overall serious adverse events (SAE), deaths and systemic adverse events including fatigue, rash, new generalized muscle pain, and use of medications to treat fever. Safety of PCV13 was evaluated based on 6 RCTs in immunocompetent adults, compared to PPSV23.9

Evidence type for each critical outcome was derived through a review of study design, risk of bias, inconsistency, indirectness, and imprecision.

Tables

Table 1a Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years:

References in this table:29101112

Invasive Pneumococcal Disease and Community-Acquired Pneumonia

Table 1a Footnotes

^{a Number needed to vaccinate or NNV=1 / (baseline rate — vaccinated rate)
b Vaccine Efficacy versus placebo
c Baseline estimates assume 10% of all CAP due to PCV13 types}

Table 1b Benefits of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years:

References in this table:345678

Immunogenicity^a

Table 1b Footnotes

^{a Immunogenicity: Antibody response to vaccine serotypes, compared to PPSV23}

Table 2. Harms of 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

References in this table:9

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
d Controls received PPSV23}

Table 3. Evidence Type for Benefits and Harms: 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Table 3 Footnotes

^{a Evidence type:}

<sup>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.</sup>

^{b Immunogenicity data which was considered an important outcome did not contribute to overall evidence type.
c Indirectness due to different comparison group: 1) Placebo instead of PPSV and 2) PPSV efficacy against IPD among older adults = 50-80%
d Indirectness due to different outcome (antibody response without correlates of protection)}

Table 4. Summary of Evidence for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥65 years

Table 4 Footnotes

^{a Overall evidence type is based on the weakest evidence type among the critical outcomes. This did not include immunogenicity data which was considered an important outcome.}

Table 5. Considerations for Formulating Recommendations for 13-valent Pneumococcal Conjugate Vaccine in Adults aged ≥ 65 years

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The ACIP Pneumococcal Work Group concluded that broader serotype protection can be achieved through use of both PCV13 and PPSV23 among adults >65 years of age; 20-25% of IPD among adults in this age group is caused by PCV13 serotypes, and an additional 38.5% by serotypes in PPSV23 not included in PCV13.10 Conversely, PCV13 use among older adults will protect against inpatient community-acquired pneumonia.2 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.345678 Although the optimal interval for PCV13 followed by PPSV23 has not been directly studied, studies evaluating the immune response following a sequence of PCV7 or PCV13 followed by PPSV23 with intervals of 2, 6, 12 months, or 3-4 years demonstrated that following the PPSV23 dose, antibody levels were higher than the pre-PCV baseline, and a non-inferior response was observed when compared with post-PCV antibody levels.581314 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 according to expert opinion.