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 (https://www.cdc.gov/vaccines/acip/recs/grade/) (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. https://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

Table 1: Policy Question and PICO
Policy question: Should PreHevbrio be recommended as an option for adults recommended for hepatitis B (HepB) vaccination?
Population Adults greater than or equal to 18 years of age
Intervention PreHevbrio — 3 doses over 6 months
Comparison Existing HepB vaccines licensed for adults in the US (Twinrix, Engerix-B, Recombivax-HB, Heplisav-B)*
Outcomes
  • Hepatitis B virus (HBV) infection (CRITICAL)
  • Serious adverse events (CRITICAL)
  • Mild adverse events (IMPORTANT but not critical)

*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 2: Outcomes and Rankings
Outcome Importance* Included in evidence profile
HBV infection Critical Yes
Serious adverse events Critical Yes
Mild adverse events Important Yes

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

Table 3a. Summary of studies reporting seroprotection (SPR)
Age (study site), SPR measurement time after complete 3-dose series N intervention N comparison Comparator vaccine Absolute difference/effect estimate (RR)
(95% CI)
Study limitations (Risk of Bias)
Vesikari 2021, JAMA Network Open
CONSTANT study
healthy adults 18–45 years (United States [26%], Canada [4%], Europe/UK [69%]), 1 – 3 months 2126 712 Engerix-B 1.04 [0.99, 1.08] not serious
Vesikari 2021, Lancet Inf Dis
PROTECT study
healthy adults ≥18 years: mean age 56.6y (United States [42%], Canada [16%], and Europe [42%]), 28 days 796 811 Engerix-B 1.21 [1.14, 1.28] not serious
Esaulenko 2021, CID healthy adults 18–45 years (Russian Federation), 30 days 50 50 Engerix-B 1.02 [0.92, 1.14] not serious
Diaz-Mitoma 2021, Vaccine healthy adults, 18–45 years (Vietnam), 30 days 134
(Lot B)
134 Engerix-B 1.04 [0.95, 1.14] serious
Etzion 2016, J Crohn’s and Colitis adults ≥18 years with Crohn’s disease or ulcerative colitis (Israel), 1–3 months 36 37 Engerix-B 0.82 [0.62, 1.09] serious
Raz 2001, IMAJ healthy adults 18–60 years (Israel), 1 month 260 258 Engerix-B 1.14 [1.07, 1.21] very serious
Yap 1995, J of Gastro and Hep healthy adults 17–45 years (Singapore), 3 months 98 98 Engerix-B 1.05 [1.00, 1.11] very serious

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

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

Table 3b. Summary of studies reporting serious adverse events (SAE)
Age (study site) N intervention N comparison Comparator vaccine Absolute difference/effect estimate (RR)
(95% CI)
Study limitations (Risk of Bias)
Vesikari 2021, JAMA Network Open
CONSTANT study
healthy adults 18–45 years (United States [26%], Canada [4%], Europe/UK [69%]) 2124 712 Engerix-B 4.69 [1.46, 15.09] not serious
Vesikari 2021, Lancet Inf Dis
PROTECT study
healthy adults ≥18 years: mean age 56.6y (United States [42%], Canada [16%], and Europe [42%]) 796 811 Engerix-B 1.55 [0.90, 2.67] not serious
Esaulenko 2021, CID healthy adults 18–45 years (Russian Federation) 47 47 Engerix-B no SAE reported not serious
Diaz-Mitoma 2021, Vaccine healthy adults, 18–45 years (Vietnam) 131 133 Engerix-B 0.25 [0.03, 2.24] serious
Etzion 2016, J Crohn’s and Colitis adults ≥18 years with Crohn’s disease or ulcerative colitis (Israel) 35 37 Engerix-B no SAE reported serious
Raz 2001, IMAJ healthy adults 18–60 years (Israel) 249 246 Engerix-B no SAE reported very serious
Yap 1995, J of Gastro and Hep healthy adults 17–45 years (Singapore), 3 months 98 98 Engerix-B no SAE reported very serious

*participants reporting ≥1 serious adverse event

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

Table 3c. Summary of studies reporting mild adverse events (MAE)
Age (study site) N intervention N comparison Comparator vaccine Absolute difference/effect estimate (RR)
(95% CI)
Study limitations (Risk of Bias)
Vesikari 2021, JAMA Network Open
CONSTANT study
healthy adults 18–45 years (United States [26%], Canada [4%], Europe/UK [69%]) 2124 712 Engerix-B 1.00 [0.92, 1.09] not serious
Vesikari 2021, Lancet Inf Dis
PROTECT study
healthy adults ≥18 years: mean age 56.6y (United States [42%], Canada [16%], and Europe [42%]) 796 811 Engerix-B 0.89 [0.76, 1.05] not serious
Esaulenko 2021, CID healthy adults 18–45 years (Russian Federation) 47 47 Engerix-B 0.23 [0.07, 0.76] not serious
Diaz-Mitoma 2021, Vaccine healthy adults, 18–45 years (Vietnam) 131 133 Engerix-B 2.46 [1.67, 3.63] serious

*participants reporting ≥1 mild adverse event

Table 4. Grade Summary of Findings Table

Table 4. Grade Summary of Findings Table
Certainty assessment № of patients PreHevbrio № of patients Comparator (Engerix-B) Effect Relative (95% CI) Effect Absolute (95% CI) Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations
HBV Infection (all studies considered seroprotection as anti-HBs ≥10 mIU/mL, between 1-3 months after completion of 3-dose series)
7 randomized trials seriousa seriousb not seriousc not serious none 2929/3500 (83.7%) 1611/2100 (76.7%) RR 1.07 (1.01 to 1.14) 5,370 more per 100,000
(from 767 more to 10,740 more)
Type 3, Low CRITICAL
Severe Adverse Events (e.g. syncope, atrial fibrillation, congestive cardiac failure, death*)
7 randomized trials seriousd seriouse not serious seriousf none 75/3480 (2.2%) 28/2084 (1.3%) RR 1.62 (0.50 to 5.22) 833 more per 100,000
(from 672 fewer to 5,670 more)
Type 3, Low CRITICAL
Mild Adverse Events (reported up to 6 months after completion of 3-dose series)
4 randomized trials not serious seriousb not serious seriousf none 1612/3864 (41.7%) 826/2481 (33.3%) RR 1.09
(0.76 to 1.55)
3,266 more per 100,000
(from 8,709 fewer to 19,959 more)
Type 3, Low IMPORTANT BUT NOT CRITICAL

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).

  1. 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)
  2. I² = 89%, studies at high risk of bias may contribute to the heterogeneity observed
  3. All studies considered seroprotection as anti-HBs ≥10 mIU/mL as a surrogate for prevention of HBV infection
  4. 4/7 studies have high risk of bias for randomization/allocation concealment and blinding (Diaz-Mitoma, Etzion, Raz, Yap)
  5. I² = 67%; heterogeneity due to 2 studies contributing 81% of the weight of this outcome analysis (CONSTANT and PROTECT)
  6. 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

Table 5: Summary of Evidence for Outcomes of Interest
Outcome Importance* Included in evidence profile Certainty
HBV infection Critical Yes Low
Serious adverse events Critical Yes Low
Mild adverse events Important but not critical Yes Low

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

Appendix 1: Studies Included in the Review of Evidence

Studies Included in the Review of Evidence
Last name first author, Publication year Study design Country (or more detail, if needed) Age (mean/SD) Total population N Intervention N comparison Outcomes Funding source
Vesikari 2021 (CONSTANT) RCT United States (26%), Canada (4%), Europe/UK (69%) Median 35.0 years (range 18-45) 2838 2126 712
  • Prevention of HBV infection (seroprotection)
  • Any severe or mild adverse events
VBI Vaccines Inc.
Vesikari 2021 (PROTECT) RCT United States (42%), Canada (16%), and Europe (42%) 56.6 years
range 18-90y intervention,
18-86y comparison
1607 796 811
  • Prevention of HBV infection (seroprotection)
  • Any severe or mild adverse events
VBI Vaccines Inc.
Esaulenko 2021 RCT Russian Federation 18–45 years
28.38 ± 7.72, intervention; 30.56 ± 8.13 comparison
100 50 50
  • Prevention of HBV infection (seroprotection)
  • Any severe or mild adverse events
VBI Vaccines Inc. and Pharmsynthez PAO
Diaz-Mitoma 2021 RCT Vietnam 18–45 years
20.6 (1.6) intervention
20.5 (1.7) comparison
268 134
(Lot B)
134
  • Prevention of HBV infection (seroprotection)
  • Any severe or mild adverse events
VBI Vaccines Inc.
Etzion 2016 RCT Israel ≥18 years
37.6 (14.5) intervention
38.0 (12.7) comparison
73 36 37
  • Prevention of HBV infection (seroprotection)
  • Any severe adverse events
Scigen Ltd. (previous iteration of VBI Vaccines Inc)
Raz 2001 RCT Israel 18–60 years
42.81 (18-60) intervention
42.99 (20-60) comparison
518 260 258
  • Prevention of HBV infection (seroprotection)
  • Any severe adverse events
Not Available
Yap 1995 RCT Singapore 17–45 years
26 (18-45) intervention
25 (17-44) comparison
200 100 100
  • Prevention of HBV infection (seroprotection)
  • Any severe adverse events
Scitech Genetics Ltd

Appendix 2: Evidence retrieval strategies used for systematic review*

Appendix 2: Evidence retrieval strategies used for systematic review
Database Strategy Run Date
Medline

(OVID)

1946-

 Hepatitis b vaccines/ OR ((hepatitis b ADJ5 vaccin*) OR (hepb ADJ5 vaccin*) OR (HBV ADJ5 vaccin*)).ti,ab,hw,kf.

AND

(Sci-B-Vac OR 3 antigen* OR tri-antigen* OR three antigen* OR 3AV OR 3A-HBV OR pre-s* OR pres1* OR s?preS1?preS2 OR s?pre-S1?pre-S2 OR pres?s OR TAV OR third generation* OR Bio-Hep-B OR Hepimmune OR AG-3 OR Hepagene OR 3 dose* OR three dose*).ti,ab,hw,kf.

AND

Trial* OR study OR studies OR randomi?ed OR double blind OR rct* OR efficacy OR effective* OR evidence* OR immunogenicity

 

08/11/2021, updated 12/02/2021
Embase

(OVID)

1988-

Hepatitis b vaccine/ OR ((hepatitis b ADJ5 vaccin*) OR (hepb ADJ5 vaccin*) OR (HBV ADJ5 vaccin*)).ti,ab,hw,kw.

AND

(Sci-B-Vac OR 3 antigen* OR tri-antigen* OR three antigen* OR 3AV OR 3A-HBV OR pre-s* OR pres1* OR s?preS1?preS2 OR s?pre-S1?pre-S2 OR pres?s OR TAV OR third generation* OR Bio-Hep-B OR Hepimmune OR AG-3 OR Hepagene OR 3 dose* OR three dose*).ti,ab,hw,kw.

AND

Trial* OR study OR studies OR randomi?ed OR double blind OR rct* OR efficacy OR effective* OR evidence* OR immunogenicity

NOT pubmed/medline

08/11/2021, updated 12/02/2021
Cochrane Library [mh “Hepatitis b vaccines”] OR ((“hepatitis b” NEAR/5 vaccin*) OR (hepb NEAR/5 vaccin*) OR (HBV NEAR/5 vaccin*)):ti,ab

AND

(Sci-B-Vac OR “3 antigen*” OR tri-antigen* OR “three antigen*” OR 3AV OR 3A-HBV OR pre-s* OR pres1* OR s?preS1?preS2 OR s?pre-S1?pre-S2 OR pres?s OR TAV OR “third generation*” OR Bio-Hep-B OR Hepimmune OR AG-3 OR Hepagene OR “3 dose*” OR “three dose*”):ti,ab

AND

(Trial* OR study OR studies OR randomi?ed OR “double blind” OR rct* OR efficacy OR effective* OR evidence* OR immunogenicity):ti,ab

08/11/2021, updated 12/02/2021
CINAHL

(EbscoHost)

(MH ” Hepatitis b vaccines”) OR (TI ((“hepatitis b” N5 vaccin*) OR (hepb N5 vaccin*) OR (HBV N5 vaccin*))) OR (AB ((“hepatitis b” N5 vaccin*) OR (hepb N5 vaccin*) OR (HBV N5 vaccin*)))

AND

(TI (Sci-B-Vac OR “3 antigen*” OR tri-antigen* OR “three antigen*” OR 3AV OR 3A-HBV OR pre-s* OR pres1* OR s?preS1?preS2 OR s?pre-S1?pre-S2 OR pres?s OR TAV OR “third generation*” OR Bio-Hep-B OR Hepimmune OR AG-3 OR Hepagene OR “3 dose*” OR “three dose*”)) OR (AB (Sci-B-Vac OR “3 antigen*” OR tri-antigen* OR “three antigen*” OR 3AV OR 3A-HBV OR pre-s* OR pres1* OR s?preS1?preS2 OR s?pre-S1?pre-S2 OR pres?s OR TAV OR “third generation*” OR Bio-Hep-B OR Hepimmune OR AG-3 OR Hepagene OR “3 dose*” OR “three dose*”))

AND

(TI (Trial* OR study OR studies OR randomi?ed OR “double blind” OR rct* OR efficacy OR effective* OR evidence* OR immunogenicity)) OR (AB (Trial* OR study OR studies OR randomi?ed OR “double blind” OR rct* OR efficacy OR effective* OR evidence* OR immunogenicity))

08/11/2021, updated 12/02/2021
Scopus TITLE-ABS-KEY((“hepatitis b” W/5 vaccin*) OR (hepb W/5 vaccin*) OR (HBV W/5 vaccin*)) AND TITLE-ABS-KEY(Sci-B-Vac OR “3 antigen*” OR tri-antigen* OR “three antigen*” OR 3AV OR 3A-HBV OR pre-s* OR pres1* OR s?preS1?preS2 OR s?pre-S1?pre-S2 OR pres?s OR TAV OR “third generation*” OR Bio-Hep-B OR Hepimmune OR AG-3 OR Hepagene OR “3 dose*” OR “three dose*”) AND TITLE-ABS-KEY(Trial* OR study OR studies OR randomi?ed OR “double blind” OR rct* OR efficacy OR effective* OR evidence* OR immunogenicity) AND NOT INDEX(medline) 08/11/2021, updated 12/02/2021

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

Page last reviewed: March 30, 2022