Skip directly to site content Skip directly to search


Español  Other Languages


Centers for Disease Control and Prevention. CDC twenty four seven. Saving Lives, Protecting People
 Search
		×
			Vaccines site
			Vaccines site
				All CDC
				Submit
			For a full list of topics:A-Z Index
			Advanced Search
		Advanced Search


Advisory Committee on Immunization Practices (ACIP)








ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE): PreHevbrio for Adults						Print
																Related Pages
										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 (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).
Food and Drug Administration. Product approval information: package insert. PreHevbrio Available here: https://www.fda.gov/media/154561/download
ACIP Presentation February 2022. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2022-02-23-24/02-HepWG-weng-508.pdf
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 ageIntervention
PreHevbrio — 3 doses over 6 monthsComparison
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 profileHBV infection
Critical
YesSerious adverse events
Critical
YesMild adverse events
Important
YesTable 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 seriousVesikari 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 seriousEsaulenko 2021, *CID*
healthy adults 18–45 years (Russian Federation), 30 days
50
50
Engerix-B
1.02 [0.92, 1.14]
not seriousDiaz-Mitoma 2021, *Vaccine*
healthy adults, 18–45 years (Vietnam), 30 days
134
(Lot B)
134
Engerix-B
1.04 [0.95, 1.14]
seriousEtzion 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]
seriousRaz 2001, *IMAJ*
healthy adults 18–60 years (Israel), 1 month
260
258
Engerix-B
1.14 [1.07, 1.21]
very seriousYap 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 seriousVesikari 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 seriousEsaulenko 2021, *CID*
healthy adults 18–45 years (Russian Federation)
47
47
Engerix-B
no SAE reported
not seriousDiaz-Mitoma 2021, *Vaccine*
healthy adults, 18–45 years (Vietnam)
131
133
Engerix-B
0.25 [0.03, 2.24]
seriousEtzion 2016, *J Crohn’s and Colitis*
adults ≥18 years with Crohn’s disease or ulcerative colitis (Israel)
35
37
Engerix-B
no SAE reported
seriousRaz 2001, *IMAJ*
healthy adults 18–60 years (Israel)
249
246
Engerix-B
no SAE reported
very seriousYap 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 eventTable 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 seriousVesikari 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 seriousEsaulenko 2021, *CID*
healthy adults 18–45 years (Russian Federation)
47
47
Engerix-B
0.23 [0.07, 0.76]
not seriousDiaz-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 eventTable 4. Grade Summary of Findings Table
Table 4. Grade Summary of Findings Table
Certainty assessment
No of patients PreHevbrio
No of patients Comparator (Engerix-B)
Effect Relative (95% CI)
Effect Absolute (95% CI)
Certainty
ImportanceNo 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).
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)
I2 = 89%, studies at high risk of bias may contribute to the heterogeneity observed
All studies considered seroprotection as anti-HBs ≥10 mIU/mL as a surrogate for prevention of HBV infection
4/7 studies have high risk of bias for randomization/allocation concealment and blinding (Diaz-Mitoma, Etzion, Raz, Yap)
I2 = 67%; heterogeneity due to 2 studies contributing 81% of the weight of this outcome analysis (CONSTANT and PROTECT)
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 hypertrophyTable 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 makingAppendix 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 LtdAppendix 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 PreHevbrioTop of Page
							
					
							Last Reviewed:  March 30, 2022						Source: 	National Center for Immunization and Respiratory Diseases
					Facebook
        Twitter
        LinkedIn
        Syndicate homeACIP Home
Meeting Information
Committee Informationplus icon
Role of the ACIP in CDC’s Vaccine Recommendations
Charter
Economics Studies
Committee Membersplus icon
ACIP Membership Roster
Apply for ACIP Membership
Work Groupsplus icon
VaST Reportsplus icon
June 28, 2021
May 24, 2021
May 17, 2021
March 29, 2021
Recommendationsplus icon
Shared Clinical Decision-Making Recommendations
Evidence Based Recommendationsplus icon
About GRADE
Grade Evidence Tables
Evidence to Recommendations Frameworks Vaccines & ImmunizationsImmunization SchedulesVFC ResolutionsVaccine Information Statements (VISs)
  1600 Clifton Road, N.E., Mailstop A27
Atlanta, GA 30329-4027acip@cdc.gov


About CDC
					Contact Us
					800-232-4636
 Facebook Twitter Instagram LinkedIn Youtube Pinterest Snapchat
 CONTACT CDC
				Contact Us
							Call 800-232-4636
							Email Us
			ABOUT CDC
				About CDC
							Jobs
							Funding
			POLICIES
				Accessibility
							External Links
							Privacy
							Policies
							No Fear Act
							FOIA
							OIG
							Nondiscrimination
							Vulnerability Disclosure Policy
			CONNECT WITH US
				Facebook
								Twitter
								Instagram
								LinkedIn
							Youtube
								Pinterest
								Snapchat
								Email
			LANGUAGES
				Español
							繁體中文
							Tiếng Việt
							한국어
							Tagalog
							Русский
							العربية
							Kreyòl Ayisyen
							Français
							Polski
							Português
							Italiano
							Deutsch
							日本語
							فارسی
							English


U.S. Department of Health & Human Services
			Accessibility
			External Links
			Privacy
			Policies
			No Fear Act
			FOIA
			Nondiscrimination
			OIG
			Vulnerability Disclosure Policy
			USA.gov


Exit Notification / Disclaimer Policy Close
 Links with this icon  indicate that you are leaving the CDC website. The Centers for Disease Control and Prevention (CDC) cannot attest to the accuracy of a non-federal website.
				Linking to a non-federal website does not constitute an endorsement by CDC or any of its employees of the sponsors or the information and products presented on the website.
				You will be subject to the destination website's privacy policy when you follow the link.
				CDC is not responsible for Section 508 compliance (accessibility) on other federal or private website. Website Disclaimers
 Cancel Continue