ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE): PreHevbrio for Adults

Introduction

On November 30, 2021, PreHevbrio (VBI Vaccines, Delaware, USA), a 3-antigen recombinant hepatitis B (HepB) vaccine, was approved by the Food and Drug Administration for the prevention of hepatitis B in persons aged ≥18 years. The vaccine consists of 3 doses administered on a 0-, 1-, and 6-month schedule (1). On February 23, 2022, the Advisory Committee on Immunization Practices (ACIP) recommended PreHevbrio for use in persons aged ≥18 years. PreHevbrio is the 7th HepB vaccine recommended for use in the United States. As part of ACIP’s process, a systematic review and Grading of Recommendations Assessment, Development and Evaluation (GRADE) of the evidence of benefits and harms was conducted and presented to ACIP. The GRADE approach for evaluating evidence, which indicates the certainty of estimates from the available body of evidence, was adopted by ACIP in 2010 (3).

Methods

During July 2021–February 2022, the Work Group participated in three teleconference meetings to review the evidence for the seroprotection and safety of PreHevbrio. The Work Group identified critical and important outcomes for inclusion in the GRADE tables, conducted a systematic review of the evidence, and subsequently reviewed and discussed findings and evidence quality (GRADE Evidence Tables – Recommendations in MMWR | Advisory Committee on Immunization Practices (ACIP) | CDC) and (Evidence to Recommendations Frameworks | Advisory Committee on Immunization Practices (ACIP) | CDC) (3) (Table 1). In the GRADE approach, evidence certainty can range from type 1 (high certainty) to type 4 (very low certainty). Key outcomes were designated as critical (HBV infection, severe adverse events) or important (mild adverse events) (Table 2).

1. Food and Drug Administration. Product approval information: package insert. PreHevbrio Available here: https://www.fda.gov/media/154561/download
2. ACIP Presentation February 2022. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-23-24/02-HepWG-weng-508.pdf
3. New Framework (GRADE) for Development of Evidence-Based Recommendations by the Advisory Committee on Immunization Practices. MMWR Recomm Rep 2012;61:327.

Table 1: Policy Question and PICO

*Of the adult HepB vaccines licensed in the United States, the included studies had only Engerix-B as a comparator

Persons on hemodialysis, pregnant persons and persons who are breastfeeding are not discussed in this Evidence to Recommendations Framework. The safety and effectiveness of PreHevbrio have not been established in adults on hemodialysis. There are no adequate and well-controlled studies of PreHevbrio in pregnant women. Available human data on PreHevbrio administered to pregnant women are insufficient to inform vaccine-associated risks in pregnancy. Data are not available to assess the effects of PreHevbrio on the breastfed infant or on milk production/excretion.

Table 2: Outcomes and Rankings

Table 3a. Summary of studies reporting seroprotection (SPR)*

*All studies considered seroprotection as anti-HBs ≥10 mIU/mL.

Table 3b. Summary of studies reporting serious adverse events (SAE)*

*participants reporting ≥1 serious adverse event

Table 3c. Summary of studies reporting mild adverse events (MAE)*

*participants reporting ≥1 mild adverse event

Table 4. Grade Summary of Findings Table

Explanations CI: confidence interval; RR: risk ratio. For seroprotection, an intention-to-treat analytic approach was utilized (https://training.cochrane.org/handbook/current/chapter-08#section-8-2-2).

a. 3/7 studies contributing to 60% of the weight to the analysis and high risk of bias due to unclear random sequence generation /allocation concealment and blinding (Diaz-Mitoma, Raz, Yap)

b. I² = 89%, studies at high risk of bias may contribute to the heterogeneity observed

c. All studies considered seroprotection as anti-HBs ≥10 mIU/mL as a surrogate for prevention of HBV infection

d. 4/7 studies have high risk of bias for randomization/allocation concealment and blinding (Diaz-Mitoma, Etzion, Raz, Yap)

e. I² = 67%; heterogeneity due to 2 studies contributing 81% of the weight of this outcome analysis (CONSTANT and PROTECT)

f. 95% CI cannot exclude the possibility of no meaningful difference

*Sudden cardiac death (1 event) was later assessed as unrelated to vaccination, in a participant with history of open-heart surgery and biventricular hypertrophy

Table 5: Summary of Evidence for Outcomes of Interest

*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making

Appendix 1: Studies Included in the Review of Evidence

Appendix 2: Evidence retrieval strategies used for systematic review*

*Studies discussing Hepagene (AG-3) were later excluded as these were deemed unrelated to PreHevbrio