Grading of Recommendations Assessment, Development and Evaluation (GRADE): HEPLISAV-B

Introduction

On November 9, 2017, HEPLISAV-B([HepB-CpG], Dynavax Technologies Corporation, Berkeley, California, USA), a single-antigen hepatitis B (HepB) vaccine with a novel immunostimulatory sequence adjuvant, was approved by the Food and Drug Administration for the prevention of hepatitis B virus (HBV) in persons aged ≥18 years. The vaccine consists of 2 doses administered 1 month apart.1 On February 21, 2018, the Advisory Committee on Immunization Practices (ACIP)* recommended HepB-CpG for use in persons aged ≥18 years. HepB-CpG is the 5^th HepB vaccine recommended for use in the United States.2 As part of ACIP's process, a systematic review and Grading of Recommendations Assessment, Development and Evaluation (GRADE) of the evidence was conducted and presented to ACIP.

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for evaluating evidence was adopted by ACIP in 2010.3 Evidence of benefits and harms were reviewed based on the GRADE approach.

Methods

From February 2016 to January 2018, the ACIP Hepatitis Vaccines Work Group† participated in three teleconference meetings to review the quality of evidence for immunogenicity and safety of HepB-CpG and implementation issues. 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)3 (Table 1). Key outcomes were designated as critical (hepatitis B infection, severe adverse events, and cardiovascular safety) or important (mild adverse events) (Table 2). Factors considered in determining the recommendation included benefits and harms and evidence type. Values and preferences and economic factors were not systematically considered.

Table 1. Policy Question: Should HEPLISAV-B vaccine be recommended for adults on a 2-dose schedule over 1 month?

Table 2. Outcomes included in evidence profile

The scientific literature was searched through a systematic review of Medline (OVID), CAB Abstracts, Embase, Global Health (OVID), Scopus, and Cochrane databases. Search terms included "HEPLISAV", "HBV-ISS", "HBsAg-1018", "1018 immunostimulatory sequence", and "hepatitis B surface antigen-1018 ISS." To qualify as a candidate for inclusion in this review, a study had to present immunogenicity or disease endpoints or safety data on HepB-CpG. Studies were excluded if they were basic science, a secondary data analysis, immunogenicity outcomes for a non-licensed formulation or use of HepB-CpG, a general review or opinion perspective, conducted on non-human primates, or if data could not be abstracted (Table 3).

Table 3. Evidence retrieval

Summary of Key Findings

The body of evidence consisted of four randomized controlled trials assessing prevention of HBV infection (Table 4) and six randomized controlled trials assessing adverse events (mild adverse events, serious adverse events, and cardiovascular adverse events) in adult subjects (Table 5). Outcomes compared HepB-CpG with Engerix-B (GlaxoSmithKline Biologicals, Rixensart, Belgium). Studies assessing prevention of HBV infection used antibody to hepatitis B surface antigen (anti-HBs) ≥10 mIU/mL as a serologic correlate of protection (Table 6). Protection among 7,056 subjects receiving HepB-CpG was compared with that among 3,214 subjects receiving Engerix-B. Seroprotective anti-HBs levels were achieved in 90.0%–100.0% of subjects receiving HepB-CpG, compared with 70.5%–90.2% of subjects receiving Engerix-B.4567 The body of evidence for the benefits of protection against HBV infection was deemed to be GRADE evidence type 2 (i.e., evidence from randomized controlled trials with important limitations, or exceptionally strong evidence from observational studies). The evidence type was downgraded for indirectness because immunogenicity was used as a surrogate for protection (Table 7).

Table 4. Outcome 1: Hepatitis B infection

Characteristics of included studies

^*No studies included disease endpoints
^**Seroprotection rate after receiving complete vaccine series

Table 5. Outcome 2, 3, 4: Adverse events

Characteristics of included studies

Table 6. Outcome 1: Hepatitis B infection

Seroprotection rate (SPR), estimates of effect

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

Table 7. Outcome 1: Hepatitis B infection

Type of evidence

^a There were no studies that looked at hepatitis B infection as outcome; anti-HBs response was used as a surrogate
^b Intervention was HEPLISAV series at 0 and 8 weeks, which is not the licensed series
^c All studies funded by Dynavax Technologies Corporation

Safety profiles among 9,871 subjects receiving HepB-CpG were compared with those among 4,385 subjects receiving Engerix-B. Among subjects receiving HepB-CpG, 45.6%, 5.4%, and 0.27% experienced a mild adverse event (Table 8), serious adverse event (Table 9), or cardiovascular event (Table 10), respectively. Among subjects receiving Engerix-B, 45.7%, 6.3%, and 0.14% experienced a mild adverse event, serious adverse event, or cardiovascular event, respectively.1456789 The body of evidence assessing adverse events was deemed to be GRADE evidence type 1 (evidence from randomized controlled trials, or overwhelming evidence from observational studies) (Table 11).

Table 8. Outcome 2: Mild adverse events

Estimates of effect

Table 9. Outcome 3: Serious adverse events (SAE)

Estimates of effect

^*1 related SAE in HEPLISAV was progression to chronic kidney disease stage IV to end-stage renal disease 28 days after receiving dose 1

^*1 related SAE in Engerix-B was reactive airway disease due to Churg-Strauss syndrome (ANCA+ vasculitis) 42 days after receiving dose 3

Table 10. Outcome 4: Cardiovascular adverse events

Estimates of effect

^*All subjects with cardiovascular adverse event reported more than 1 cardiovascular disease risk factor

Table 11. Outcomes 2, 3, 4: Adverse events

Type of evidence

^*All studies funded by Dynavax Technologies Corporation;

^*Adverse events from HBV23 unpublished

Summary

The evidence type for use of HepB-CpG in adults aged ≥18 years was determined to be type 2 for benefits and type 1 for harms (Table 12). In February 2018, ACIP recommended:

HepB-CpG may be used as a HepB vaccine in persons aged ≥18 years recommended to be vaccinated against HBV.

Table 12. GRADE Summary

^*Not yet published, data abstracted from HEPLISAV package insert

^**Data abstracted from studies that stated most were cardiac deaths not related to vaccine

Rationale

Based on the available immunogenicity evidence, a 2-dose schedule (0, 1 month) of HepB-CpG will be efficacious for the prevention of HBV infection. The risk of adverse events, including cardiovascular adverse events, was reviewed and will be monitored. The benefits of protection with 2 doses administered over 1 month make this an important option for prevention of HBV in at-risk persons.

These recommendations serve as a supplement to the 2018 Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices.2 The Policy Note detailing the 2018 ACIP recommendations for use of HepB-CpG in persons aged ≥18 years is available on the ACIP website.