Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Pfizer’s Pentavalent Meningococcal Vaccine (MenACWY-TT/MenB-FHbp)

Introduction

On October 20, 2023, the U.S. Food and Drug Administration approved the use of a pentavalent meningococcal vaccine (MenACWY-TT/MenB-FHbp [Penbraya, Pfizer]) for prevention of invasive disease caused by Neisseria meningitidis serogroups A, B, C, W, and Y among persons aged 10–25 years.1 On October 25, 2023, CDC’s Advisory Committee on Immunization Practices (ACIP) recommended MenACWY-TT/MenB-FHbp may be used when both MenACWY and MenB are indicated at the same visit for 1) healthy individuals aged 16–23 years (routine schedule) when shared clinical decision-making favors administration of MenB vaccination and 2) individuals aged 10 years and older at increased risk of meningococcal disease (e.g., due to persistent complement deficiencies, complement inhibitor use, or functional or anatomic asplenia).

A systematic review and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to inform ACIP’s deliberations regarding use of MenACWY-TT/MenB-FHbp. The policy questions under consideration were 1) Should the pentavalent vaccine be included as an option for people currently recommended to receive MenACWY and MenB?, 2) Should the pentavalent vaccine be included as an option for people currently recommended to receive MenACWY only?, and 3) Should the pentavalent vaccine be included as an option for people currently recommended to receive MenB only? (Tables 1a–c).

Methods

Members of ACIP’s Meningococcal Vaccines Work Group (“Work Group”) selected policy questions and prespecified and rated the importance of relevant outcomes (including benefits and harms) before the GRADE assessment (Tables 1a–c, Table 2). All Work Group members and CDC staff participating in the GRADE assessment met ACIP requirements for reporting conflicts of interest.

A systematic literature search was conducted using Medline, Embase, Global Health, CINAHL, Cochrane, Scopus, and clinicaltrials.gov databases. Efforts also were made to obtain unpublished or other relevant data. Two reviewers independently screened titles and abstracts and reviewed full-text records. Records were included if they presented primary data on Pfizer’s pentavalent meningococcal vaccine. Characteristics of all included studies are shown in Appendix 1, and evidence retrieval methods are shown in Appendix 2.234

The GRADE evidence certainty assessment addressed risk of bias, inconsistency, indirectness, imprecision, and other characteristics. The evidence certainty categories include high, moderate, low, or very low certainty.

Results

A summary of the GRADE assessment was presented to ACIP on June 23, 2023. Overall, 48 records were identified and screened; 29 records were excluded based on the title and abstract, and 10 records were excluded based on full text review. The remaining nine records described results from three randomized controlled clinical trials and were included in the evidence synthesis and GRADE assessment (Appendix 1).

No data were identified regarding the outcomes “disease caused by serogroups A, B, C, W, and Y” or “interference with other recommended vaccines administered concurrently.” Data on the remaining outcomes are summarized in the tables below. When the available data applied to all 3 policy questions, only one table is shown; separate tables were created when the data varied by policy question.

Summary

For all outcomes, the initial evidence level was high because the available data were from randomized control trials. The final evidence certainty was the same for all three policy questions. The evidence certainty for short-term immunity was moderate for healthy persons and low for persons at increased risk. The evidence certainty for persistent immunity was low for serogroups A, C, W, and Y for healthy persons, moderate for serogroup B for healthy persons, and low for all serogroups for those at increased risk. For both serious and non-serious adverse events, the level of certainty was low for healthy persons, and very low for those at increased risk.

Table 1a: Policy Question and PICO 1

Table 1b: Policy Question and PICO 2

Table 1c: Policy Question and PICO 3

Table 2: Outcomes and Rankings

Table 3a: Summary of Studies Reporting Short-Term Immunity — PICOs 1, 2, and 3

^a hSBA stands for serum bactericidal assay using human complement. For participants with a baseline hSBA titer <1:4, seroresponse is defined as a titer ≥1:16. For those with a baseline hSBA titer ≥1:4 and <1:8 (<1:16 for A22), seroresponse is a titer ≥4 times the 1:8 (1:16 for A22). For those with a baseline hSBA titer ≥1:8 (≥1:16 for A22), seroresponse is a titer ≥4 times the baseline titer.
^b Serogroup B primed was not assessed.

Table 3b: Summary of Studies Reporting Persistent Immunity — PICOs 1, 2, and 3

^a Seroprotection analyses are staggered for ACWY comparisons with the single dose MenACWY-CRM group starting 6 months after the 2 dose MenABCWY group (e.g., 18 months after the single dose of MenACWY-CRM versus 12 months after the 2 doses of MenABCWY). Seroprotection for the MenB component analyses is not staggered.
^b Serogroup B primed was not assessed.

Table 3c: Summary of Studies Reporting Serious Adverse Events^a — PICOs 1, 2, and 3

^a Serious adverse events were any undesirable experience associated with vaccination in which the patient outcome was death, was life-threatening, required or prolonged hospitalization, caused disability or permanent damage, was a congenital anomaly/birth defect, or was another serious or important medical events as defined by Pfizer.5
^b Vaccination phase refers to the time from the first study vaccination visit through 1 month after the last study vaccination.
^c Nine SAEs occurred in 7 patients: Salmonella gastroenteritis (1 patient), depression (1 patient), anxiety (1 patient), suicide attempt (1 patient), postural orthostatic tachycardia syndrome (1 patient), dyspnea (1 patient), head injury due to motor vehicle accident (1 patient), traumatic spinal cord injury (1 patient), and depression with suicidal ideation (1 patient).
^d Not included in GRADE table 4 given no comparison group.
^e Eight SAEs occurred in 6 patients: cyst (1 patient), tendon injury (1 patient), dyskinesia (1 patient), migraine with aura (1 patient), aggression (1 patient), conversion disorder (1 patient), and suicidal ideation (2 patients).

Table 3d: Summary of Studies Reporting Non-Serious Adverse Events^a — PICOs 1, 2, and 3

^a Nonserious adverse events included all adverse events during the vaccination phase except for serious adverse events. As defined by Pfizer, all adverse events included serious adverse events, nonserious adverse events, medically attended events (nonserious adverse events that resulted in evaluation at a medical facility), and newly diagnosed chronic medical conditions (a disease or medical condition, not previously identified, that is expected to be persistent or is otherwise long-lasting in its effects).
^b Vaccination phase refers to the time from the first study vaccination visit through 1 month after the last study vaccination.

Table 4a: GRADE Summary of Findings for Healthy Persons — PICOs 1, 2, and 3

^a hSBA titers are the established correlate of protection for serogroup C meningococcal disease. This correlation is assumed to extend to other serogroups, but direct evidence for these serogroups is limited.6
^b Calculated based on serogroup B composite data.
^c Comparisons were between 2 doses of MenABCWY and 1 dose of MenACWY-CRM. Comparisons also were staggered by 6 months.
^d Following primary vaccination.
^e Comparisons were between 2 doses of MenABCWY and 1 dose of MenACWY-CRM plus 2 doses of MenB-FHbp.
^f Downgraded because the relative effect confidence intervals are wide.
^g Downgraded because the absolute effect confidence intervals are wide.

Table 4b: GRADE Summary of Findings for Persons at Increased Risk due to Underlying Medical Conditions — PICOs 1, 2, and 3

^a Clinical trials did not include patients at increased risk for invasive disease.
^b hSBA titers are the established correlate of protection for serogroup C meningococcal disease. This correlation is assumed to extend to other serogroups, but direct evidence for these serogroups is limited.6
^c Calculated based on serogroup B composite data.
^d Comparisons were between 2 doses of MenABCWY and 1 dose of MenACWY-CRM. Comparisons also were staggered by 6 months.
^e Following primary vaccination.
^f Comparisons were between 2 doses of MenABCWY and 1 dose of MenACWY-CRM plus 2 doses of MenB-FHbp.
^g Downgraded because the relative effect confidence intervals are wide.
^h Downgraded because the absolute effect confidence intervals are wide.

Table 5: Summary of Evidence, PICO 1

Table 5: Summary of Evidence, PICO 2

Table 5: Summary of Evidence, PICO 3

Appendix 1: Studies Included in Review of Evidence

Appendix 2: Search Strategies

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