Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): 20-valent pneumococcal conjugate vaccine (PCV20) for children aged <2 years

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. 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 (PICO) 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.

Studies were included if they included primary data on PCV20 use in children aged <2 years. Seventy-one studies were initially identified; after screening, deduplication and exclusion, 3 were 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, VT 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 of 20-valent Pneumococcal Conjugate Vaccine Use in Children

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 (PCV20)]/[GMC (comparator vaccine)]; blood draws occurred 30 days or 1-month post-dose.

³ Seroresponse: proportion of participants meeting IgG threshold value of >=0.35μg/mL for all serotypes except ≥ 0.23 μg/mL, ≥ 0.10 μg/mL and ≥ 0.12μg/mL for serotypes 5, 6B and 19A respectively; blood draws occurred 30 days or 1 month post-dose.

⁴ Non-inferiority measured as the lower bound of 2-sided 95% confidence interval of IgG GMC ratio (PCV20/PCV13) >0.5. Additional 7 serotypes contained in PCV20 but not in PCV13 were compared with a PCV13 serotype with the lowest percentage excluding serotype 3.

⁵ Non-inferiority measured as the lower bound of 2-sided 95% confidence interval for percent difference (PCV20-PCV13)>-10% of participants with IgG concentrations above predefined concentrations 1 month after the infant doses; predefined IgG concentration – ≥0.35 μg/mL for all serotypes except ≥ 0.23 μg/mL, ≥ 0.10 μg/mL and ≥ 0.12μg/mL for serotypes 5, 6B and 19A respectively.

Table 3b. Summary of Studies Reporting Safety of 20-valent Pneumococcal Conjugate Vaccine Use in Children

*Reported serious adverse events include those that occurred after dose 1 through 6 months after Dose 4

Table 4. Grade Summary of Findings Table

a. These are all immunogenicity studies and there are no correlates of protection for some critical outcomes considered.

b. Noninferiority for difference in percentages of participants meeting predefined IgG threshold value was defined as the lower bound of 2-sided 95% confidence interval for percent difference (PCV20-PCV13)>-10%. Additional 7 serotypes contained in PCV20 but not in PCV13 were compared with a PCV13 serotype with the lowest percentage excluding serotype 3.

c. Noninferiority for GMC ratio was defined as the lower bound of 2-sided 95% confidence interval of IgG GMC ratio (PCV20/PCV13) >0.5. Additional 7 serotypes contained in PCV20 but not in PCV13 were compared with a PCV13 serotype with the lowest percentage excluding serotype 3.

d. No vaccine-related serious adverse events reported.

References

1. Senders S, Klein NP, Lamberth E, Thompson A, Drozd J, Trammel J, Peng Y, Giardina PC, Jansen KU, Gruber WC, Scott DA, Watson W. Safety and Immunogenicity of a 20-valent Pneumococcal Conjugate Vaccine in Healthy Infants in the United States. Pediatr Infect Dis J. 2021 Oct 1;40(10):944-951. doi: 10.1097/INF.0000000000003277.
2. B7471011. 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study of a 4-Dose Series in Healthy Infants.
3. B7471013. A Phase 3, Randomized, double-blind trial to evaluate the safety of a 20-valent pneumococcal conjugate vaccine in healthy infants.

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 years was determined to be a moderate certainty of evidence for VT-invasive pneumococcal disease, VT-pneumonia, VT-acute otitis media and VT- pneumococcal deaths and was downgraded once for indirectness due to lack of correlates of protection for some of the critical outcomes considered. The evidence type for serious adverse events following immunization was also a moderate certainty of evidence; imprecision was downgraded once 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 of 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.

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.

Senders S, Klein NP, Lamberth E, Thompson A, Drozd J, Trammel J, Peng Y, Giardina PC, Jansen KU, Gruber WC, Scott DA, Watson W. Safety and Immunogenicity of a 20-valent Pneumococcal Conjugate Vaccine in Healthy Infants in the United States. Pediatr Infect Dis J. 2021 Oct 1;40(10):944-951. doi: 10.1097/INF.0000000000003277.

B7471011. 20-valent Pneumococcal Conjugate Vaccine Safety and Immunogenicity Study of a 4-Dose Series in Healthy Infants. Accessed August 24, 2023 at https://clinicaltrials.gov/study/NCT04382326?term=B7471011%20&rank=1.

B7471013. A Phase 3, Randomized, double-blind trial to evaluate the safety of a 20-valent pneumococcal conjugate vaccine in healthy infants. Accessed August 24, 2023 at https://clinicaltrials.gov/study/NCT04379713?term=B7471013&rank=1.

Appendices

Appendix 1. Search strategy

Appendix 2. Studies Included in the Review of Evidence