Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 21-valent Pneumococcal Conjugate Vaccine (PCV21) Use among Adults Aged 50–64 Years Who Currently Do Not Have a Risk-Based Pneumococcal Vaccine Indication

Introduction

On June 27, 2024 the U.S. Advisory Committee on Immunization Practices (ACIP) recommended 21-valent pneumococcal conjugate vaccine (PCV21) as an option for adults aged ≥19 years who currently have a recommendation to receive a dose of pneumococcal conjugate vaccine (PCV). A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach for evidence assessment and decision-making informed ACIP’s deliberations regarding use of this vaccine.

Methods

A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV21 among adults. As a basis for the GRADE evidence assessment, the policy question consisting of the population, intervention, comparison, and outcomes of interest was defined (Table 1).

We updated a previously published systematic review presented to ACIP in October 2022, which included literature published through March 2022.^1,2 Pubmed, Embase, Cinhal, Web of Science, Epistemonikos, and Cochrane databases were searched to include published literature through September 18, 2023 using search terms listed in Appendix 1. In addition, we conducted an additional Pubmed search on October 17, 2023 using search terms specific to PCV21 and the results were further supplemented by a search of clinicaltrials.gov using “V116”, “21-valent pneumococcal conjugate vaccine” or “PCV21” (Appendix 2). Unpublished data from trials identified through clinicaltrials.gov, but not yet publicly available, were provided by the vaccine manufacturers.

Studies were eligible for inclusion into the review if they presented primary data on PCV21 use from phase II or III clinical trials in adults aged ≥19 years. Of the 25 titles identified through the updated Pubmed search and 10 trials identified through clinicaltrials.gov, 6 trials met the inclusion criteria after double-screening of title/abstract and full-text screening. Eligible titles identified through the original search on September 18, 2023 were all captured through the updated Pubmed search in October. Characteristics of these studies are presented in Appendix 3. Outcomes critical and important for decision-making were previously identified by the ACIP Pneumococcal Vaccines Work Group. Work Group members rated and ranked outcomes using a survey, identifying a final list to drive the systematic review (Table 2). Vaccine-type (VT) invasive pneumococcal disease (IPD), VT nonbacteremic pneumococcal pneumonia (NBPP), VT pneumococcal mortality, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).

Table 1: Policy Question and PICO

Table 2: Outcomes and Rankings

Table 3: Summary of Studies Reporting Outcomes of Interest

Table 4 GRADE Summary of Findings Tables

Table 5: Summary of Evidence for Outcomes of Interest

Summary

The certainty of evidence for use of PCV21 for adults aged 50–64 years who currently do not have a risk-based pneumococcal vaccine indication was determined to be moderate for VT-IPD, VT-NBPP, and VT-pneumococcal mortality. Assessment on indirectness was downgraded to serious since only immunogenicity studies were available and there are no established correlates of protection for PCV21 against some of the critical outcomes. The certainty of evidence for SAEs following immunization was determined to be moderate; assessment on imprecision was downgraded to serious because few vaccine-related serious adverse events were reported in studies with small sample sizes. ACIP reviewed the results of both the GRADE evidence assessment and the Evidence to Recommendations (EtR) framework during February and June 2024 ACIP meetings.  On June 27, 2024, ACIP recommended the use of PCV21 as an option for adults aged ≥19 years who currently have a recommendation to receive a dose of PCV.

References

1. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged ≥65 years who previously received a 13-valent pneumococcal conjugate vaccine (PCV13) | CDC. September 25, 2023. Accessed August 25, 2024. https://www.cdc.gov/vaccines/acip/recs/grade/PCV20-prev-vax-older-adults.html
2. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) use among adults aged 19–64 years with an immunocompromising condition, cerebrospinal fluid leak, or cochlear implant who previously received a 13-valent pneumococcal conjugate vaccine (PCV13) | CDC. September 25, 2023. Accessed August 25, 2024. https://www.cdc.gov/vaccines/acip/recs/grade/PCV20-prev-vax-adults-19-64-risk-based.html
3. Platt H, Omole T, Cardona J, et al. Safety, tolerability, and immunogenicity of a 21-valent pneumococcal conjugate vaccine, V116, in healthy adults: phase 1/2, randomised, double-blind, active comparator-controlled, multicentre, US-based trial. The Lancet Infectious diseases. Published online September 15, 2022. doi:10.1016/s1473-3099(22)00526-6
4. Merck Sharp & Dohme LLC. A Phase 3, Randomized, Double-Blind, Active Comparator-Controlled Clinical Study to Evaluate the Safety, Tolerability, and Immunogenicity of V116 in Pneumococcal Vaccine-Naïve Adults. clinicaltrials.gov; 2023. Accessed December 31, 2023. https://clinicaltrials.gov/study/NCT05425732

Appendix 1. Search Strategy

Appendix 2. Updated Search conducted on October 17, 2023

Appendix 3: Studies Included in the Review of Evidence