Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged 2 through 18 years with underlying medical conditions

Introduction

On June 22, 2023, the CDC’s Advisory Committee on Immunization Practices (ACIP) recommended use of 20-valent pneumococcal conjugate vaccine (PCV20 [Prevnar 20, Wyeth Pharmaceuticals LLC, a subsidiary of Pfizer Inc.]) as an option to 15-valent pneumococcal conjugate vaccine (PCV15 [Vaxneuvance, Merck Sharp & Dohme LLC]) for: routine vaccination of all children aged 2–23 months; catch-up vaccination for healthy children aged 24–59 months who have not received age-appropriate doses; and children aged 24–71 months with certain underlying medical conditions at increased risk for pneumococcal disease* who have not received age-appropriate doses. In addition, recommendations were updated for children aged 2–18 years with any risk conditions. Indications for risk-based pneumococcal vaccine recommendations were expanded to include children with chronic kidney disease (even if not on maintenance dialysis or nephrotic syndrome), chronic liver disease, and moderate persistent or severe persistent asthma (regardless of high-dose oral corticosteroids use). A systematic review and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach was employed to guide ACIP’s deliberations regarding use of this vaccine.

^{*Underlying medical conditions include: cerebrospinal fluid leak; chronic heart disease; chronic kidney disease (excluding maintenance dialysis and nephrotic syndrome, which are included in immunocompromising conditions); chronic liver disease; chronic lung disease (including moderate persistent or severe persistent asthma); cochlear implant; diabetes mellitus; immunocompromising conditions (on maintenance dialysis or with nephrotic syndrome; congenital or acquired asplenia or splenic dysfunction; congenital or acquired immunodeficiencies; diseases and conditions treated with immunosuppressive drugs or radiation therapy, including malignant neoplasms, leukemias, lymphomas, Hodgkin disease, and solid organ transplant; HIV infection; and sickle cell disease or other hemoglobinopathies).}

Methods

A systematic literature search was completed to review all available evidence on the immunogenicity and safety of PCV20 among pediatric age groups for which the vaccine was approved. Since only immunogenicity and safety data were available for PCV20, the search included PCV13 efficacy or effectiveness studies to help interpret PCV20 immunogenicity study findings. GRADE assessment was performed for PCV20 studies only. 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).

Table 1: Policy Question and PICO

This systematic review leveraged strategies used in existing systematic reviews, which captured literature published between January 1994–December 2019 targeting PCV7, PCV10 and PCV13 using various dosing schedules in the general pediatric population. Specifically, we utilized:

• Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules (Loo 2014); searched literature from January 1994 – September 2010
• Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules and Products (Cohen 2017); searched literature from October 2010 – December 2016
• Updated literature search to Cohen 2017, which was conducted to review evidence regarding dosing schedule changes; searched literature from January 2017 – December 2019

In addition, we conducted a search of literature published during January 2010–October 2022 from the following databases: Medline (OVID), Embase (OVID), Cochrane Library, CINAHL (EbscoHost), Scopus (for WOS). The search terms are included in Appendix 1. The updated search sought to capture:

• Pneumococcal vaccine studies specifically targeting children with underlying medical conditions, which were not captured in the previous literature searches,
• Additional literature on pneumococcal vaccines published since January 2020 to update the previous systematic reviews evaluating PCV13 use in the general pediatric populations.

Search results were supplemented by an updated Pubmed search using “PCV20 or 20-valent pneumococcal conjugate vaccine” and a search of clinicaltrials.gov using “20-valent pneumococcal”, limiting to trials in children aged <19 years. Unpublished data were provided by the vaccine manufacturer.

Due to a paucity of evidence in children with underlying medical conditions, studies were included if they included primary data on PCV20 use in children aged 2-18 years. Seventy-one studies were initially identified; after screening, deduplication and exclusion, 1 was included for GRADE. No PCV20 studies directly assessed vaccine effectiveness against the critical outcomes. Characteristics of this study are included in Appendix II. Beneficial and harmful outcomes for the GRADE assessment were selected by the ACIP Pneumococcal Vaccines Work Group during calls and via an email survey in which Work Group members were asked to rank the relative importance of each outcome. Vaccine-type (VT) invasive pneumococcal disease, VT non-bacteremic pneumococcal pneumonia, VT acute otitis media, vaccine-type pneumococcal deaths, and serious adverse events (SAEs) following immunization were deemed to be critical outcomes (Table 2).

Table 2: Outcomes and Rankings

^{*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making
**No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes}

Table 3a: Summary of Studies Reporting Immunogenicity

<sup>1. The range in numbers reflect the differences in number of participants included for assessment by the endpoints that were assessed
2. Ratio calculated as [GMC (before PCV20 dose)]/[GMC (post-PCV20 dose)]; blood draws occurred 30 days or 1 month post-dose.
3. Seroresponse: proportion of participants meeting IgG threshold value of >=0.35μg/mL; blood draws occurred 30 days or 1 month post-dose. Only reported for the 7 additional serotypes unique to PCV20.
4. Study was a non-randomized, single arm trial comparing the immune response of a single PCV20 dose before and 1 month after vaccination; no randomization, no comparison group.</sup>

Table 3b: Summary of Studies Reporting Safety

<sup>1. Reported serious adverse events include those that occurred from vaccination through 6 months after vaccination.
2. Study was a non-randomized, single arm trial comparing the immune response of a single PCV20 dose before and 1 month after vaccination; no randomization, no comparison group.</sup>

Table 4: Grade Summary of Findings Table

^{a. Study design is an open label non-randomized controlled trial with no comparator group. Downgraded for lack of randomization, lack of blinding, and lack of a comparison group.
b. Study population did not include children with underlying conditions.
c. This is an immunogenicity study and there are no correlates of protection for some critical outcomes considered.
d. No vaccine-related serious adverse events reported.}

^References

^{1. B7471014. Safety and Immunogenicity Study of 20vPnC in Healthy Children 15 Months Through 17 Years of Age.}

Table 5. Summary of Evidence for Outcomes of Interest

^{*No clinical evidence available; immunogenicity data used as proxy for vaccine effectiveness of outcomes}

Summary

The evidence type for use of PCV20 in children aged 2-18 years of age with underlying medical conditions was determined to be a very low certainty of evidence for VT-invasive pneumococcal disease, VT-pneumonia, VT-acute otitis media and VT- pneumococcal deaths. The study design was an open label non-randomized clinical trial with no comparator group and risk of bias was downgraded to very serious due to a lack of randomization, lack of blinding, and lack of a comparison group.

Indirectness was downgraded twice to very serious due to lack of correlates of protection for some of the critical outcomes considered and the study population did not include children with underlying conditions. The evidence type for serious adverse events following immunization was a very low certainty of evidence. Risk of bias was downgraded to very serious for lack of randomization, lack of blinding, and lack of a comparison group. Indirectness and imprecision were downgraded to serious; indirectness because the study population did not include children with underlying conditions and imprecision for no vaccine-related serious adverse events reported. The ACIP reviewed the results of both the GRADE evidence assessment and the preliminary Work Group interpretation Evidence to Recommendations (EtR) framework in February 2023. An updated EtR table was shared with the ACIP in June 2023. On June 22 2023, the ACIP recommended use of PCV20 as an option to PCV15 for: routine vaccination of all children aged 2–23 months; catch-up vaccination for healthy children aged 24–59 months who have not received age-appropriate doses; and children aged 24–71 months with certain underlying medical conditions at increased risk for pneumococcal disease who have not received age-appropriate doses. In addition, recommendations were updated for children aged 2–18 years with any risk conditions. Indications for risk-based pneumococcal vaccine recommendations were expanded to include children with chronic kidney disease (even if not on maintenance dialysis or nephrotic syndrome), chronic liver disease, and moderate persistent or severe persistent asthma (regardless of high-dose oral corticosteroids use).

References

Loo JD, Conklin L, Deloria Knoll M, Fleming-Dutra K, et al. Methods for a Systematic Review of Pneumococcal Conjugate Vaccine Dosing Schedules. PIDJ. 2014; 33(1,S2); S182-S187.

Cohen OG. Pneumococcal Conjugate Vaccine (PCV) Product Assessment. Accessed August 2, 2021 at https://www.jhsph.edu/ivac/wp-content/uploads/2018/05/pcv-product-assessment-april-25-2017.pdf.

B7471014. Safety and Immunogenicity Study of 20vPnC in Healthy Children 15 Months Through 17 Years of Age. Accessed August 24, 2023 at https://clinicaltrials.gov/study/NCT04642079?term=B7471014&rank=1.

Appendices

Appendix 1. Search strategy