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 5th 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 (https://www.cdc.gov/vaccines/acip/recs/grade/) (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 1.  Policy Question:  Should HEPLISAV-B vaccine be recommended for adults on a 2-dose schedule over 1 month?
Population Adults ≥18 years of age
Intervention HEPLISAV-B administered in 2 doses over 1 month
Comparison Existing hepatitis B vaccines licensed for adults in the U.S.: TWINRIX, Engerix-B, Recombivax HB
Outcomes
  • Hepatitis B infection
  • Mild adverse events
  • Serious adverse events
  • Cardiovascular safety

Table 2. Outcomes included in evidence profile

Table 2. Outcomes included in evidence profile
Outcome Importance
Benefits
Hepatitis B Infection Critical
Harms
Mild adverse events (any) Important
Serious adverse events (any) Critical
Cardiovascular adverse events (any) Critical

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

Table 3. Evidence retrieval
Systematic review of Medline (OVID), CAB Abstracts, Embase, Global Health (OVID), Scopus, Cochrane
Search terms included: “HEPLISAV” or “HBV-ISS” or “HBsAg-1018” or “1018 immunostimulatory sequence” or “hepatitis B surface antigen-1018 ISS”
Articles were included if they presented immunogenicity or disease endpoints or safety data on HEPLISAV
Articles were excluded if:
Non-human primates, basic science
Secondary data analyses
Immunogenicity outcomes for non-licensed formulation or use of HEPLISAV
General review or opinion perspectives or unable to abstract data

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 (4–7). 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

Table 4. Outcome 1:  Hepatitis B infection
Characteristics of included studies
Study Type Population Intervention Comparison Main Outcomes* Funding Site
Halperin, 2006 Vaccine RCT, phase II 99 healthy adults, 18-28 years HEPLISAV at 0 and 8 weeks Engerix-B at 0, 8, and 24 weeks Seroprotection rate (anti-HBs ≥ 10mIU/mL)** Dynavax 2 centers in Canada
Halperin, 2012 Vaccine RCT, Phase III 2415 healthy adults, 18-55 years HEPLISAV at 0 and 4 weeks Engerix-B at 0, 4, and 24 weeks Seroprotection rate (anti-HBs ≥ 10mIU/mL)** Dynavax Canada and Germany
Heyward, 2013 Vaccine RCT Phase III 2452 healthy adults, 40-70 years HEPLISAV at 0 and 4 weeks Engerix-B at 0, 4, and 24 weeks Seroprotection rate (anti-HBs ≥ 10mIU/mL)** Dynavax 29 sites in US, 3 in Canada
Jackson, 2017 Vaccine RCT Phase III 8374 adults, 18-70 years, excluding HIV and history of autoimmune disease HEPLISAV at 0 and 4 weeks Engerix-B at 0, 4, and 24 weeks Seroprotection rate (anti-HBs ≥ 10mIU/mL)** Dynavax USA

*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 5. Outcome 2, 3, 4: Adverse events
Characteristics of included studies
Study Type Population Intervention Comparison Main Outcomes* Funding Site
Halperin, 2006, Vaccine RCT Phase II 99 healthy adults, 18–28 years HEPLISAV at 0 and 8 weeks Engerix-B at 0, 8, and 24 weeks Any mild adverse events (local, systemic), SAE Dynavax 2 sites in Canada
Halperin, 2012, Vaccine RCT Phase III 2415 healthy adults, 18–55 years HEPLISAV at 0 and 4 weeks Engerix-B at 0, 4, and 24 weeks Any mild adverse events (local, systemic), SAE (related not reported) Dynavax Canada, Germany
Sablan, 2012, Vaccine RCT Phase III 412 healthy adults, 40–70 years HEPLISAV at 0, 8, and 24 weeks (placebo at week 4) Engerix-B at 0, 4, and 24 weeks (placebo at week 8) Any mild adverse events (local, systemic), SAE Dynavax 5 sites in Korea, 2 sites in Philippines, and 1 site in Singapore
Heyward, 2013, Vaccine RCT Phase III 2452 healthy adults, 40–70 years HEPLISAV at 0 and 4 weeks Engerix-B at 0, 4, and 24 weeks Any mild adverse events (local, systemic), SAE, cardiovascular events Dynavax 29 sites in US, 3 sites in Canada
Janssen, 2013, Vaccine RCT Phase III 521 adults with chronic kidney disease, 18–75 years HEPLISAV at 0, 4, and 24 weeks Engerix-B at 0, 4, 8, and 24 weeks Any adverse events, SAE, cardiovascular events Dynavax 46 sites in US, 3 sites in Canada, 9 sites in Germany
HBV 23 RCT Phase III 8368 adults, 18–70 years, excluding HIV and history of autoimmune disease HEPLISAV at 0 and 4 weeks Engerix-B at 0, 4, and 24 weeks Any mild adverse events, SAE (related not reported), cardiovascular events Dynavax US

Table 6. Outcome 1:  Hepatitis B infection
Seroprotection rate (SPR), estimates of effect

Table 6. Outcome 1:  Hepatitis B infection
Seroprotection rate (SPR), estimates of effect
Outcome* No. of subjects (# studies) SPR in HEPLISAV SPR in Comparison Difference in SPRs NNV
Seroprotection rate at 24 weeks in adults 18-28 years 48 in HEPLISAV; 51 in Engerix-B (1) 100% 90.2% 9.8% 10
Seroprotection rate at 28 weeks in adults 18-55 years 1511 in HEPLISAV; 521 in Engerix-B (1) 97.9% (97.9–98.7) 81.1% (77.7-84.4) 16.8% (14.3–20.2) 6
Seroprotection rate at 28 weeks in adults 40-70 years 1121 in HEPLISAV; 353 in Engerix-B (1) 90.0% (88.2–91.8) 70.5 (65.5–75.2) 19.5% (14.7–24.7) 5
Seroprotection rate at 28 weeks in adults 18-70 years, excluding HIV and autoimmune 4376 in HEPLISAV; 2289 in Engerix-B (1) 95.4% (94.8–96.0) 81.3% (79.6–82.8) 14.2% (12.5–15.9) 7

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

Table 7. Outcome 1: Hepatitis B infection
Type of evidence

Table 7. Outcome 1: Hepatitis B infection
Type of evidence
Outcome Design (# of studies) Initial evidence level Risk of Bias Inconsistency Indirectness Imprecision Other Considerations Evidence Type
Hepatitis B infection RCT, Phase II (1) 1 No serious No serious Serious (-1)a,b No serious Yesc 2
Hepatitis B infection RCT, Phase III (3) 1 No serious No serious Serious (-1)a No serious Yesc 2

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 (1,4–9). 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 8. Outcome 2: Mild adverse events
Estimates of effect
Outcome No. of subjects (# studies) No. reported in HEPLISAV (%) No. reported in Comparison (%) Difference
Any mild adverse events 14256 (6) 4497 (45.6%) 2003 (45.7%) -0.1%
Injection-site reaction 5888 (5) 1519 (35.5%) 494 (30.8%) 4.6%
Systemic reaction 5888 (5) 1205 (28.1%) 483 (30.1%) -2.0%

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

Table 9. Outcome 3: Serious adverse events (SAE)
Estimates of effect
Outcome No. of subjects (# studies) No. reported in HEPLISAV (%) No. reported in Comparison (%) Difference
Any SAE 14256 (6) 529 (5.4%) 276 (6.3%) -0.9%
SAE considered related to vaccine* 3473 (4) 1 (0.04%) 1 (0.10%) -0.06%

*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

Table 10. Outcome 4: Cardiovascular adverse events
Estimates of effect
Outcome No. of subjects (# studies) No. reported in HEPLISAV (%) No. reported in Comparison (%) Difference
Cardiovascular adverse event 11333 (3) 21 (0.27%)* 5 (0.14%) 0.13%

*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

Table 11. Outcomes 2, 3, 4: Adverse events
Type of evidence
Outcome Design (# of studies) Initial evidence level Risk of Bias Inconsistency Indirectness Imprecision Other Considerations Evidence Type
Mild adverse events RCT (6) 1 No serious No serious No Serious No serious Yes* 1
Serious adverse events RCT (6) 1 No serious No serious No Serious No serious Yes* 1
Cardiovascular adverse events RCT (3) 1 No serious No serious No Serious No serious Yes* 1

*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

Table 12. GRADE Summary
Outcome Design (# of studies) Findings Evidence type Overall evidence type
BENEFITS
Hepatitis B infection RCT (4) HEPLISAV non-inferior seroprotection rate 2 2
HARMS
Mild adverse events RCT (6) No differences detected between vaccinated and comparison populations for mild adverse events HEPLISAV had 4.6% more local injection site reactions 1 1
Serious adverse events RCT (6) No differences detected between vaccinated and comparison populations for serious adverse events 1 1
Cardiovascular adverse events RCT* (1)
RCT** (2)
More events in HEPLISAV group, but not statistically significant 1 1

*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.

References

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  10. Kroger AT, Duchin J, Vázquez M. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP).pdf icon Accessed on Jan 25, 2018.
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Page last reviewed: April 5, 2018