1

National Center for HIV, Viral Hepatitis, STD, and TB Prevention

PreHevbrio for adult hepatitis B vaccination

Evidence to Recommendation and GRADE

LCDR Mark K. Weng, MD MSc

Hepatitis Vaccines Work Group, Advisory Committee on Immunization Practices

Wednesday February 23, 2022

Division of Viral Hepatitis
2

PICO and 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 hepatitis B vaccines licensed for adults in the US (TWINRIX, 

Engerix-B, Recombivax-HB, HEPLISAV-B)*

Outcomes

• Hepatitis B virus infection (CRITICAL)

• Serious adverse events (CRITICAL) 

• Mild adverse events (IMPORTANT but not critical)

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.

*Studies that were ultimately included used only Engerix-B out of this list of possible comparators
3

Background

Adult HepB

vaccine* Derivation Adjuvant Dose of HBs Antigens Schedule

PreHevbrio

mammalian 

(Chinese hamster 

ovary) Cell

alum 10μg

3 doses at 

0, 1, 6 mo

Engerix-B yeast alum 20μg

3 doses at 

0, 1, 6 mo

Recombivax

HB yeast alum 10μg

3 doses at 

0, 1, 6 mo

Heplisav-B yeast CpG 1018 20μg

2 doses at 

0, 1 mo

*See ACIP Recommended Immunization Schedule for Adults Aged 19 Years or Older — United States, 2022 for 

more dosing details (http://dx.doi.org/10.15585/mmwr.mm7107a1). Twinrix not shown (combination HepAHepB). FDA Approval of PreHevbrio, a three-antigen HepB vaccine – Nov 30, 2021

,
4

Public Health Problem: Work Group Interpretation

• In 2021, ACIP approved universal HepB vaccine 

recommendations for adults ages 19 through 59 years.

• An additional HepB vaccine that is safe and non-inferior to 

existing ACIP-approved HepB vaccines could be a beneficial 

adjunct in achieving HHS goals of eliminating hepatitis B as a 

public health threat in the United States by 2030.
5

Studies identified through database 

search by Librarian (n= 4148)

Records removed before screening:

Duplicate records removed (n = 1660)

Records removed for other reasons (n = 51)

• Studies not involving the vaccines of interest

• Animal studies

• Conference notes/minutes

Records screened by titles (n = 2437) Titles excluded using PICO criteria (n = 1739)

Shortlisted abstracts for review (n = 698) Abstracts excluded using PICO criteria (n = 634)

Full text studies shortlisted for review (n = 

64)

Full text studies excluded (n = 57):

• Duplicate studies with different titles

• Studies on non/hypo responders

• Single arm studies

• Studies with different schedules/doses of vaccine

• Review articles

• Clinical trial registries with no results

• Studies with wrong vaccine

• Others: Dose response studies, Lot to lot consistency studies, vertical 

transmission studies, therapeutic vaccination, patients with end stage 

renal disease

Studies included in review

(n = 7 randomized trials)

PRISMA Flow Diagram: Identification of PreHevbrio* studies

Identification Screening Included

*PreHevbrio vaccine is also known as: Sci-B-Vac, Bio-Hep-B, Hepimmune, 3AV, or TAV
6

Explanations CI: confidence interval; RR: risk ratio

a. 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)

b. I2 = 89%, studies at high risk of bias may contribute to the heterogeneity observed

c. All studies considered seroprotection as anti-HBs ≥10 mIU/mL as a surrogate for prevention of HepB infection

d. 4/7 studies have high risk of bias for randomization/allocation concealment and blinding (Diaz-Mitoma, Etzion, Raz, Yap)

e. I2 = 67%; heterogeneity due to 2 studies contributing 81% of the weight of this outcome 

analysis (CONSTANT and PROTECT)

f. 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

Benefits and Harms: GRADE Summary of Findings Table

Certainty assessment No of patients Effect

No of Certainty Importance

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations PreHevbrio Comparator (Engerix-B)

Relative

(95% CI)

Absolute

(95% CI)

Hepatitis B 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)

Low CRITICAL

Severe Adverse Events (e.g. syncope, atrial fibrillation, congestive cardiac failure, death*)

7 randomized 

trials

seriousd not 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)

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)

Low IMPORTANT 

BUT NOT 

CRITICAL
7

Benefits and Harms: Conclusions from GRADE*

 The evidence suggests that seroprotection conferred by PreHevbrio is noninferior (little or no difference) compared with seroprotection conferred by EngerixB.

 PreHevbrio may result in little to no difference in serious adverse events when 

compared with serious adverse events due to Engerix-B.

 PreHevbrio may result in little to no difference in mild adverse events when 

compared with mild adverse events due to Engerix-B.

*Assumption: equivalent non-inferiority among currently U.S.-recommended 3-dose HepB vaccines 

for the population of interest, since all currently recommended HepB vaccines have undergone ACIP 

review
8

Domain Question Work Group Judgments 

Public Health 

Problem

Is the prevention of hepatitis B a problem of public health importance?

Is the problem of public health importance? Yes

Benefits and 

Harms

For prevention of HBV infection (seroprotection), how substantially different are 

the desirable anticipated effects of PreHevbrio compared with Engerix-B?

How substantial are the desirable anticipated effects?

Minimal

For the outcomes of serious and mild adverse events, how substantially different 

are the undesirable anticipated effects of PreHevbrio compared with Engerix-B?

How substantial are the undesirable anticipated effects?

Minimal

Does the balance between desirable effects and undesirable effects favor 

PreHevbrio or Engerix-B?

Do the desirable effects outweigh the undesirable effects?

Favors Both

What is the overall certainty of evidence for the critical outcomes? Probably not important uncertainty

Equity What would be the impact of the PreHevbrio compared to Engerix-B on health 

equity? Probably no impact

Values

Based on similarities of dosage schedule, adjuvant, and vaccine mechanism, ACIP Hepatitis Work Group perceived that 

these domains of Values, Acceptability, Resource Use and Feasibility for PreHevbrio are comparable with Values, 

Acceptability, Resource Use and Feasibility of Engerix-B.

Acceptability 

Resource Use

Feasibility
9

Balance of 

consequences

Undesirable 

consequences 

clearly 

outweigh 

desirable 

consequences 

in most 

settings

Undesirable 

consequences 

probably 

outweigh 

desirable 

consequences 

in most 

settings

The balance 

between 

desirable and 

undesirable 

consequences 

in closely 

balanced or

uncertain

Desirable 

consequences 

probably 

outweigh

undesirable 

consequences 

in most 

settings

Desirable 

consequences 

clearly 

outweigh

undesirable 

consequences 

in most 

settings

There is 

insufficient 

evidence to 

determine the 

balance of 

consequences

EtR Balance of Consequences

Based on EtR considerations, the balance between PreHevbrio and currently used HepB

vaccines is closely balanced, and therefore the Work Group judgment on adding 

PreHevbrio as an option for HepB vaccination of adults is as follows:
10

ACIP Policy Statement for PreHevbrio

Recommendation PreHevbrio may be used as a HepB vaccine in persons aged 

≥18 years recommended for vaccination against HBV infection.

Additional 

Considerations

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.
11

References

• Vesikari T, Langley JM, Segall N, et. al. Immunogenicity and safety of a tri-antigenic hepatitis B vaccine, Sci-B-Vac®, compared with a 

mono-antigenic HepB vaccine, Engerix-B®, in adults: The PROTECT randomized clinical trial. The Lancet Infectious Diseases. 2021.

• Vesikari T, Finn A, van Damme P, et al. Immunogenicity and safety of a 3-antigen hepatitis B vaccine vs a single-antigen hepatitis B 

vaccine: a phase 3 randomized clinical trial. JAMA Network Open. 2021; 4(10). 

• Diaz-Mitoma F, Popovic V, Spaans JN. Assessment of immunogenicity and safety across two manufacturing lots of a 3-antigen 

hepatitis B vaccine, Sci-B-Vac®, compared with Engerix-B® in healthy Asian adults: A phase 3 randomized clinical trial. Vaccine. 2021 

Jun 29;39(29):3892-3899. Epub 2021 Jun 8. 

• Raz R, Koren R, Bass D. Safety and immunogenicity of a new mammalian cell-derived recombinant hepatitis B vaccine containing 

Pre-S1 and Pre-S2 antigens in adults. Isr Med Assoc J. 2001 May;3(5):328-32. 

• Esaulenko EV, Yakovlev AA, Volkov GA, et. al. Efficacy and Safety of a 3-Antigen (Pre-S1/Pre-S2/S) Hepatitis B Vaccine: Results of a 

Phase 3 Randomized Clinical Trial in the Russian Federation. Clin Infect Dis. 2021 Nov 2;73(9).

• Etzion O, Novack V, Perl Y, et. al. Sci-B-VacTM Vs ENGERIX-B Vaccines for Hepatitis B Virus in Patients with Inflammatory Bowel 

Diseases: A Randomised Controlled Trial. J Crohns Colitis. 2016 Aug;10(8):905-12. Epub 2016 Feb 29. 

• Yap I, Guan R, Chan SH. Study on the comparative immunogenicity of a recombinant DNA hepatitis B vaccine containing pre-S 

components of the HBV coat protein with non pre-S containing vaccines. J Gastroenterol Hepatol. 1995 Jan-Feb;10(1):51-5.

• Murthy N, Wodi AP, Bernstein H, McNally V, Cineas S, Ault K. Advisory Committee on Immunization Practices Recommended 

Immunization Schedule for Adults Aged 19 Years or Older — United States, 2022. MMWR Morb Mortal Wkly Rep 2022;71:229–233. 

• GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University and Evidence Prime, 2021. Available from 

gradepro.org.

• Review Manager (RevMan) [Computer program]. Version 5.4. The Cochrane Collaboration, 2020.
12

ACIP Hepatitis Work Group

Consultants

Sharon Frey (SLU)

Robert Frenck (CCHMC)

Prabhu Gounder (LA-DPH)

Kathleen Harriman (CDPH)

Brian McMahon (ANTHC)

Kelly Moore (IAC)

David Nace (AMDA)

Jennifer Rosen (NYC-DOH)

Ann Thomas (OR-DHS/OHA)

Jennifer Zipprich (MDPH)

CDC Subject Matter Experts

Erin Conners

Mona Doshani

Brian Edlin

Ruth Gallego

Megan Hofmeister

Neil Murthy

Lakshmi Panagiotakopoulos

Noele Nelson

Priti Patel

Tom Shimabukuro

Phil Spradling

Mark Weng

Carolyn Wester

ACIP Voting Members

Kevin Ault (Chair)

Sybil Cineas

Liaison Representatives

Elizabeth Barnett (AAP)

Marci Drees (SHEA)

Sharon McMullen (ACHA)

Brenna Hughes (ACOG)

Susan Lett (CSTE)

Pamela Rockwell (AAFP)

Matthew Zahn (NACCHO)

Ex Officio Members 

Marian Major (FDA) 

Darcie Everett (FDA)

Rajen Koshy (NIAID/NIH)

Chinedu Okeke (HHS)

Jessica Deerin (HHS)

Acknowledgements

Doug Campos-Outcalt

Rebecca Morgan

Nida Ali, for conducting 

the PreHevbrio

systematic review and 

creating the GRADE 

evidence profiles
Thank you

The findings and conclusions in this report are those of the authors and do not necessarily represent the official 

position of the Centers for Disease Control and Prevention.
14

GRADE Tables
15

Table 1: Policy Question and PICO

Should PREHEVBRIO be recommended as an option for adults 

recommended for hepatitis B vaccination?

Population Adults greater than or equal to 18 years of age

Intervention PREHEVBRIO – 3 doses over 6 months 

Comparison Existing hepatitis B vaccines licensed for adults in the US (TWINRIX, 

Engerix-B, Recombivax-HB, HEPLISAV-B)

Outcomes

• Hepatitis B virus infection (CRITICAL)

• Serious adverse events (CRITICAL) 

• Mild adverse events (IMPORTANT)

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. 
16

Table 2: Outcomes and Rankings

Outcome Importance* Included in evidence 

profile

Hepatitis B virus infection Critical Yes

Serious adverse events Critical Yes

Mild adverse events Important but 

not critical

Yes

*Three options: 1. Critical; 2. Important but not critical; 3. Not important for decision making
17

Evidence retrieval

• Systematic review of 

data for Hepatitis B 

vaccination including a 

search of PubMed, 

Medline and EMBASE 

from 1987 through 2021

• No language restrictions 

on initial searches and 

included articles from 

any country

Search Terms

Hepatitis b vaccines/ OR ((hepatitis b ADJ5 vaccin*) OR (hepb ADJ5 vaccin*) OR (HBV ADJ5 vaccin*)) 

(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 (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*"))

(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))

Trial* OR study OR studies OR randomised OR double blind OR rct* OR efficacy OR effective* OR evidence* OR 

immunogenicity 
18

Exclusion Criteria

• Non-human studies

• Studies addressing population <18 year old (pediatric studies) 

• Studies addressing pregnant people 

• Studies without the vaccine of interest (PreHevbrio*)

• Studies without a U.S. HepB vaccine as comparator

• Non-RCTs

Evidence retrieval

*PreHevbrio vaccine is also known as: Sci-B-Vac, Bio-Hep-B, Hepimmune, 3AV, or TAV
19

Studies identified through database 

search by Librarian (n= 4148)

Records removed before screening:

Duplicate records removed (n = 1660)

Records removed for other reasons (n = 51)

• Studies not involving the vaccines of interest

• Animal studies

• Conference notes/minutes

Records screened by titles (n = 2437) Titles excluded using PICO criteria (n = 1739)

Shortlisted abstracts for review (n = 698) Abstracts excluded using PICO criteria (n = 634)

Full text studies shortlisted for review (n = 

64)

Full text studies excluded (n = 57):

• Duplicate studies with different titles

• Studies on non/hypo responders

• Single arm studies

• Studies with different schedules/doses of vaccine

• Review articles

• Clinical trial registries with no results

• Studies with wrong vaccine

• Others: Dose response studies, Lot to lot consistency studies, vertical 

transmission studies, therapeutic vaccination, patients with end stage 

renal disease

Studies included in review

(n = 7 randomized trials)

Identification of PreHevbrio* studies

Identification Screening Included

*PreHevbrio vaccine is also known as: Sci-B-Vac, Bio-Hep-B, Hepimmune, 3AV, or TAV
20

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 Hepatitis B 

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 Hepatitis B 

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 Hepatitis B 

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 Hepatitis B 

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 Hepatitis B 

infection/ seroprotection

• Any severe or mild 

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 Hepatitis B 

infection/ seroprotection

• Any severe or mild 

adverse events

Not Available

Yap 1995 RCT Singapore

17 – 45 years

26 (18-45) intervention

25 (17-44) comparison

200 100 100

• Prevention of Hepatitis B 

infection/ seroprotection

• Any severe or mild 

adverse events

Scitech Genetics 

Ltd

Studies Included in the PreHevbrio* Review of Evidence

*PreHevbrio vaccine is also known as: Sci-B-Vac, Bio-Hep-B, Hepimmune, 3AV, or TAV
21

Tables 3a-b: Summary of Studies 

Reporting Outcomes
22

Table 3a. studies 

reporting 

seroprotection (SPR)*

Age (study site), SPR measurement time 

after complete 3-dose series

N 

intervention

N 

comparison

Comparator 

vaccine

Absolute 

difference/effec

t 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

1753 592 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
23

Table 3b. Studies 

reporting serious 

adverse events (SAE)*

Age (study site) N 

intervention

N 

comparison

Comparator 

vaccine

Absolute 

difference/effec

t 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 1.04 [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%])

796 811 Engerix-B 1.21 [1.14, 

1.28] not serious

Esaulenko 2021, CID healthy adults 18–45 years (Russian 

Federation) 50 50 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
24

Table 3c. Studies 

reporting mild 

adverse events 

(MAE)*

Age (study site) N 

intervention

N 

comparison

Comparator 

vaccine

Absolute 

difference/effec

t 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
25

Explanations CI: confidence interval; RR: risk ratio

a. 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)

b. I2 = 89%, studies at high risk of bias may contribute to the heterogeneity observed

c. All studies considered seroprotection as anti-HBs ≥10 mIU/mL as a surrogate for prevention of HepB infection

d. 4/7 studies have high risk of bias for randomization/allocation concealment and blinding (Diaz-Mitoma, Etzion, Raz, Yap)

e. I2 = 67%; heterogeneity due to 2 studies contributing 81% of the weight of this outcome 

analysis (CONSTANT and PROTECT)

f. 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

Benefits and Harms: GRADE Summary of Findings Table

Certainty assessment No of patients Effect

No of Certainty Importance

studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations PreHevbrio Comparator (Engerix-B)

Relative

(95% CI)

Absolute

(95% CI)

Hepatitis B 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)

Low CRITICAL

Severe Adverse Events (e.g. syncope, atrial fibrillation, congestive cardiac failure, death*)

7 randomized 

trials

seriousd not 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)

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)

Low IMPORTANT 

BUT NOT 

CRITICAL
26

Table 5: Summary of Evidence for Outcomes of 

Interest

Outcome Importance* Included in 

evidence profile Certainty

Hepatitis B virus 

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
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GRADE Summary
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GRADE Evidence Type

 High certainty: We are very confident that the true effect lies close to 

that of the estimate of the effect.

 Moderate certainty: We are moderately confident in the effect 

estimate: The true effect is likely to be close to the estimate of the effect, 

but there is a possibility that it is substantially different.

 Low certainty: Our confidence in the effect estimate is limited: The true 

effect may be substantially different from the estimate of the effect.

 Very low certainty: We have very little confidence in the effect 

estimate: The true effect is likely to be substantially different from the 

estimate of effect.
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GRADE Criteria

 Initial evidence type (certainty level) determined by study design

• Initial evidence (high certainty): A body of evidence from randomized controlled 

trials

• Initial evidence (low certainty): A body of evidence from observational studies

 Risk of bias: Can include failure to conceal allocation, failure to blind, loss to follow- up. Risk of bias may vary across outcomes.

 Inconsistency: Criteria for evaluating include similarity of point estimates, extent of 

overlap of confidence intervals, and statistical criteria including tests of heterogeneity 

and I2.

 Indirectness: Considers the generalizability of the evidence to the original PICO 

components 

 Imprecision: Considers the fragility of the relative and absolute effect measures based 

on the interpretation of the 95% CIs and the optimal information size.

 Other considerations: Includes publication bias or indications of dose-response 

gradient, large or very large magnitude of effect, and opposing residual confounding.
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GRADE Conclusions*

 The evidence suggests that there may be little to no difference in seroprotection

conferred by PreHevbrio compared with other U.S.-recommended 3-dose HepB

vaccines.

 PreHevbrio may result in little to no difference in serious adverse events when 

compared with other U.S.-recommended 3-dose HepB vaccines.

 PreHevbrio may result in little to no difference in mild adverse events when 

compared with other U.S.-recommended 3-dose HepB vaccines.

*Assumption: equivalent non-inferiority among currently U.S.-recommended 3-dose HepB vaccines for 

the population of interest, since all currently recommended HepB vaccines have undergone ACIP review