ACIP Grading of Recommendations Assessment, Development and Evaluation (GRADE) for Hepatitis B (HepB) Vaccine in Adults

About

CDC vaccine recommendations are developed using an explicit evidence-based method based on the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Introduction

Since hepatitis B (HepB) vaccine introduction in 1982, there have been substantial declines in reported hepatitis B cases. However, despite reductions in hepatitis B incidence achieved through incremental HepB vaccine policy over the past four decades, from a high of 26,654 reported cases (287,000 estimated) in 1985 to a low of 2,791 reported cases (19,200 estimated) in 2014, progress has stalled in further reducing hepatitis B incidence (1). In 2018, the reported HepB vaccination coverage (≥3 doses) was overall 30.0% for adults ≥19 years old, demonstrating small increases in coverage throughout the past four decades (2), including low coverage among persons in risk groups recommended for vaccination (e.g., 33% coverage among persons with chronic liver disease).

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 September 2019–October 2021, the ACIP Hepatitis Work Group held monthly conference calls to review and discuss scientific evidence relevant to the use of HepB vaccines in a universal adult vaccination recommendation. 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 (GRADE Evidence Tables – Recommendations in MMWR | Advisory Committee on Immunization Practices (ACIP) | CDC) (Evidence to Recommendations Frameworks | Advisory Committee on Immunization Practices (ACIP) | CDC) (3) (Table 1). In the GRADE approach, evidence certainty can range from type 1 (high certainty) to type 4 (very low certainty). Evidence was found to be available only for the cardiovascular and serious adverse events outcomes. Ultimately, no studies were available comparing the two strategies of universal and risk-based adult HepB vaccination. Thus, only the outcomes of serious adverse events and cardiovascular events associated with Heplisav-B were assessed, as noted below.

  1. 2019 Viral Hepatitis Surveillance Report. 2021, Centers for Disease Control and Prevention.
  2. Lu, P.J., et al., Surveillance of Vaccination Coverage Among Adult Populations -United States, 2018. MMWR Surveill Summ, 2021. 70(3): p. 1-26.
  3. CDC. 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

Policy Question:
Should all hepatitis B (HepB)-unvaccinated adults receive HepB vaccination?
Population
Previously unvaccinated adults age ≥ 18 years
Intervention
Universal vaccination strategy (2- and 3-dose schedules)
Comparison
Current risk-based vaccination strategy (2- and 3-dose schedules)
Outcomes
  • Incidence of hepatitis B
  • Morbidity related to hepatitis B
  • Mortality related to hepatitis B
  • Serious adverse events associated with the 2-dose vaccine*

*This outcome is solely aimed at assessing the 2-dose Heplisav-B vaccine (approved in 2017). The 3-dose HepB vaccines have already been evaluated for their adverse events profiles and recommended by ACIP based on their safety records.

Table 2: Outcomes and Rankings

Outcome Importance* Included in evidence profile
Incidence of hepatitis B Important Yes
Morbidity related to hepatitis B Important Yes
Mortality related to hepatitis B Important Yes
Serious adverse events associated with the 2-dose HepB vaccine* Critical Yes

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

Study Population n/N (%)
HBsAg-1018
(Heplisav-B)
n/N (%)
HBsAg-Eng
(Engerix-B)
Difference (95% CI)
Risk ratio (95% CI)
Study limitations (Risk of Bias)
Hyer, 2018 HBV-10:
2,415 adults
18–55 years
0/1,810 (0%) 0/605 (0%) -- Not serious
HBV-16:
2,449 adults
40–70 years
3/1,968 (0.2%) 2/481 (0.4%) -0.3% (-0.8%, 0.3%)
0.37 (0.06, 2.19)
Not serious
HBV-23:
8,368 adults
18–70 years
28/5,587 (0.5%) 6/2,781 (0.2%) 0.3% (0.03%, 0.5%)
2.32 (0.96, 5.60)
Not serious
Janssen, 2013 516 adults
18–75 years with chronic kidney disease
10/254 (3.9%) 8/262 (3.1%) 0.9% (-2.3%, 4.1%)
1.29 (0.52, 3.21)
Not serious
Bruxvoort, 2021 69,625 adults routinely vaccinated in a US health system 52/31,183 (0.2%) 71/38,442 (0.2%) 0.0% (-0.1%, 0.0%)
HR 0.92 (0.63, 1.39)
Not serious

Table 3b. Summary of Studies Reporting Serious Adverse Events

Study Population n/N (%)
HBsAg-1018
(Heplisav-B)
n/N (%) HBsAg-Eng
(Engerix-B)
Difference (95% CI)
Risk ratio (95% CI)
Study limitations (Risk of Bias)
Halperin, 2006 99 healthy adults
18–28 years
1/51 (2.0%) 4/48 (8.3%) -6.4% (-15.1%, 4.4%)
0.24 (0.03, 2.03)
Not serious
Sablan, 2012 412 healthy adults
40–70 years
10/206 (4.9%) 13/206 (6.3%) -1.5% (-5.9%, 3.0%)
0.77 (0.35, 1.71)
Not serious
Janssen, 2013 516 adults
18–75 years with chronic kidney disease
68/254 (26.8%) 76/262 (29.0%) -2.2% (-10.0%, 5.5%)
0.92 (0.70, 1.22)
Not serious
Hyer, 2018 HBV-10:
2,415 adults
18–55 years
28/1,810 (1.5%) 13/605 (2.1%) -0.6% (-1.9%, 0.7%)
0.72 (0.38, 1.38)
Not serious
HBV-16:
2,449 adults
40–70 years
76/1,968 (3.9%) 23/481 (4.8%) -0.9% (-3.0%, 1.2%)
0.81 (0.51, 1.27)
Not serious
HBV-23:
8,368 adults
18–70 years
345/5,587 (6.2%) 148/2,781 (5.3%) 0.9% (-0.2%, 1.9%)
1.16 (0.96, 1.40)
Not serious

Table 4. Grade Summary of Findings Table

Certainty assessment № of patients HBsAg-1018 № of patients C HBsAg-Eng Effect Relative (95% CI) Effect Absolute (95% CI) Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations
Cardiovascular events - RCTs
4 randomized trials not serious serious a not serious serious b none 41/9619 (0.4%) 16/4129 (0.4%) RR 1.33
(0.58 to 3.08)
128 more per 100,000
(from 163 fewer to 806 more)
Type 3, Low CRITICAL
Cardiovascular events – observational
1 observational studies not serious not serious not serious serious b none 52/31183 (0.2%) 71/38442 (0.2%) HR 0.92
(0.63 to 1.32)
15 fewer per 100,000
(from 68 fewer to 59 more)
Type 4, Very Low CRITICAL
Serious adverse events
6 randomized trials not serious not serious not serious not serious none 528/9876 (5.3%) 277/4383 (6.3%) RR 0.96
(0.79 to 1.16)
253 fewer per 100,000
(from 1,327 fewer to 1,011 more)
Type 1, High CRITICAL

CI: Confidence interval; RR: Risk ratio; HR: Hazard Ratio
a. Heterogeneity of estimates across studies. I2 = 43%
b. Few events suggest fragility of the estimate. 95% CI cannot exclude the possibility of meaningful harm.

Appendix 1: Evidence retrieval strategies used for systematic review*

Database Strategy Run Date
Medline

(OVID)

1946-

hepatitis b vaccines/ OR ((hepatitis B ADJ5 vaccin*) OR (HBV ADJ5 vaccin*) OR recombivax hb OR engerix-b).ti,ab.

AND

Exp Adults/ OR (adult* OR elder* OR senior*).ti,ab.

AND

Ae.fs OR ad.fs OR review.pt OR (dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation*).ti,ab.

Limit to 2006 - ; Abstract Available

12/4/2019, updated 9/20/2021
Embase

(OVID)

1947-

hepatitis b vaccine/ OR recombinant hepatitis B vaccine/ OR ((hepatitis B ADJ5 vaccin*) OR (HBV ADJ5 vaccin*) OR recombivax hb OR engerix-b).ti,ab.

AND

Exp Adults/ OR (adult* OR elder* OR senior*).ti,ab.

AND

Ae.fs OR ad.fs OR do.fs. OR review.pt OR (dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation*).ti,ab.

Limit to 2006 - ; NOT pubmed/medline; Abstract Available

12/4/2019, updated 9/20/2021
CINAHL

(Ebsco)

(MH "Hepatitis B Vaccines+") OR ((“hepatitis B” N5 vaccin*) OR (HBV N5 vaccin*) OR “recombivax hb” OR “engerix-b”)

AND

(MH "Adult+") OR (adult* OR elder* OR senior*)

AND

(dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation* OR review*)

Limit to 2006 - ; exclude Medline records; Abstract Available

12/4/2019, updated 9/20/2021
Cochrane Library [mh “Hepatitis B Vaccines”] OR ((“hepatitis B” N5 vaccin*) OR (HBV N5 vaccin*) OR “recombivax hb” OR “engerix-b”):ti,ab

AND

(dose* OR dosage* OR administration OR schedule* OR routine OR universal OR adverse OR efficacy OR effective* OR safe* OR strateg* OR risk* OR guideline* OR recommendation* OR review*):ti,ab

Limit to 2006- ; Abstract Available

12/4/2019, updated 9/20/2021

*Exclusion criteria: articles dated earlier than year 2006, articles discussing vaccines not licensed in United States, articles not addressing the population of interest, and articles where data could not be abstracted.

View the complete list of GRADE evidence tables‎