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Grading of Recommendations Assessment, Development and Evaluation (GRADE):  HEPLISAV-B						Print
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			IntroductionMethodsSummary of Key FindingsSummaryRationaleReferences
		
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 (www.cdc.gov/vaccines/acip/recs/grade/table-refs.html) (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 ageIntervention
HEPLISAV-B administered in 2 doses over 1 monthComparison
Existing hepatitis B vaccines licensed for adults in the U.S.: TWINRIX, **Engerix-B**, Recombivax HBOutcomes
Hepatitis B infection
Mild adverse events
Serious adverse events
Cardiovascular safetyTop of Page
Table 2. Outcomes included in evidence profile
Table 2. Outcomes included in evidence profile
Outcome
ImportanceBenefitsHepatitis B Infection
CriticalHarmsMild adverse events (any)
ImportantSerious adverse events (any)
CriticalCardiovascular adverse events (any)
CriticalThe 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, CochraneSearch 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 HEPLISAVArticles 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 dataTop of Page
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
SiteHalperin, 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 CanadaHalperin, 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 GermanyHeyward, 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 CanadaJackson, 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
Top of Page
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
SiteHalperin, 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 CanadaHalperin, 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, GermanySablan, 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 SingaporeHeyward, 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 CanadaJanssen, 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 GermanyHBV 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
USTop of Page
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
NNVSeroprotection rate at 24 weeks in adults 18-28 years
48 in HEPLISAV; 51 in Engerix-B (1)
100%
90.2%
9.8%
10Seroprotection 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)
6Seroprotection 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)
5Seroprotection 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
Top of Page
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 TypeHepatitis B infection
RCT, Phase II (1)
1
No serious
No serious
Serious (-1)a,b
No serious
Yesc
2Hepatitis B infection
RCT, Phase III (3)
1
No serious
No serious
Serious (-1)a
No serious
Yesc
2a There were no studies that looked at hepatitis B infection as outcome; anti-HBs response was used as a surrogateb Intervention was HEPLISAV series at 0 and 8 weeks, which is not the licensed seriesc All studies funded by Dynavax Technologies Corporation
Top of Page
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 (%)
DifferenceAny 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%Top of Page
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 (%)
DifferenceAny 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
Top of Page
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 (%)
DifferenceCardiovascular 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
Top of Page
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 TypeMild adverse events
RCT (6)
1
No serious
No serious
No Serious
No serious
Yes*
1Serious adverse events
RCT (6)
1
No serious
No serious
No Serious
No serious
Yes*
1Cardiovascular 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
Top of Page
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 typeBENEFITSHepatitis B infection
RCT (4)
HEPLISAV non-inferior seroprotection rate
2
2HARMSMild 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
1Serious adverse events
RCT (6)
No differences detected between vaccinated and comparison populations for serious adverse events
1
1Cardiovascular 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
Top of Page
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
Food and Drug Administration. Product approval information: package insert. HEPLISAV-B. Available here.
CDC. Prevention of Hepatitis B Virus Infection in the United States: Recommendations of the Advisory Committee on Immunization Practices. *MMWR* Recomm Rep 2018;67(No.1);1–31.
CDC. New Framework (GRADE) for Development of Evidence-Based Recommendations by the Advisory Committee on Immunization Practices. *MMWR* Recomm Rep 2012;61:327.
Halperin, SA, Dobson S, McNeil S, et al. Comparison of the safety and immunogenicity of hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligonucleotide and a licensed hepatitis B vaccine in healthy young adults. *Vaccine* 2006;24:20–6.
Halperin SA, Ward B, Cooper C, et al. Comparison of safety and immunogenicity of two doses of investigational hepatitis B virus surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide and three doses of a licensed hepatitis B vaccine in healthy adults 18–55 years of age. *Vaccine* 2012;30:2556–63.
Heyward WL, Kyle M, Blumenau J, et al. Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40–70 years of age. *Vaccine* 2013;31:5300–5.
Jackson S, Lentino J, Kopp J, et al. Immunogenicity of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant compared with a licensed hepatitis B vaccine in adults. *Vaccine* 2017;31791–7.
Sablan BP, Kim DJ, Barzaga NG, et al. Demonstration of safety and enhanced seroprotection against hepatitis B with investigational HBsAg-1018 ISS vaccine compared to a licensed hepatitis B vaccine. *Vaccine* 2012;30:2689–96.
Janssen RS, Mangoo-Karim R, Pergola PE, et al. Immunogenicity and safety of an investigational hepatitis B vaccine with a toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared with a licensed hepatitis B vaccine in patients with chronic kidney disease. *Vaccine* 2013;31:5306–13.
Kroger AT, Duchin J, Vázquez M. General Best Practice Guidelines for Immunization. Best Practices Guidance of the Advisory Committee on Immunization Practices (ACIP). Accessed on Jan 25, 2018.
Halperin SA, Ward BJ, Dionne M, et al. Immunogenicity of an investigational hepatitis B vaccine (hepatitis B surface antigen co-administered with an immunostimulatory phosphorothioate oligodeoxyribonucleotide) in nonresponders to licensed hepatitis B vaccine. *Hum Vaccin Immunother* 2013;9:1438–44.Top of Page
							
					
							Last Reviewed:  April 5, 2018						Source: 	National Center for Immunization and Respiratory Diseases
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