GRADE Hepatitis A vaccine for post-exposure prophylaxis in adults >40 years of age

About

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

Summary

Question: Should hepatitis A vaccine be recommended instead of immune globulin (IG) as post-exposure prophylaxis for prevention of hepatitis A disease in adults >40 years of age?

Population: Healthy adults >40 years of age

Intervention: Hepatitis A vaccine administered within 14 days of exposure

Control: Immune globulin administered within 14 days of exposure

Outcomes:

  • Immunogenicity
  • Hepatitis A infection
  • Deaths
  • Hospitalizations
  • Adverse events

Background

Post-exposure prophylaxis (PEP) with HepA vaccine or immune globulin (IG) effectively prevents hepatitis A infection when administered within 2 weeks of exposure. Previous ACIP recommendations for PEP included HepA vaccine for persons aged 1–40 years and IG for persons outside of this age range; if IG was not available, HepA vaccine could be administered for persons older than 40 years. During November 2016 to February 2018, the ACIP Hepatitis Work Group held conference calls to review and discuss relevant scientific evidence, including the use of HepA vaccine versus IG for PEP. The ACIP Hepatitis Work Group evaluated the quality of evidence related to the benefits and harms of administering a dose of HepA vaccine for PEP for persons aged >40 years using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework.

A randomized, double-blind clinical trial among 1,090 persons aged 2–40 years who were contacts of hepatitis A cases and susceptible to hepatitis A virus infection suggested that performance of HepA vaccine, when administered <14 days after exposure, approaches that of IG in healthy children and adults aged <40 years. Only limited data are available comparing HepA vaccine and IG in healthy adults >40 years of age, showing reduced response to vaccine in older age groups compared to younger adults. The body of evidence assessing a dose of HepA vaccine for PEP to prevent HAV infection in adults aged >40 years was determined to be GRADE evidence type 4 for benefits and 3 for harms.

Outcome measures included in evidence profile

Outcomes
Importance
Benefit
1. Immunogenicity
2. Hepatitis A infection
3. Deaths
4. Hospitalizations

Critical
Critical
Critical
Critical
Harms
1. Adverse events

Critical

Evidence types

Initial Evidence Type
Study Design
1
Randomized controlled trials (RCTs) or overwhelming evidence from observational studies
2
RCTs with important limitations, or exceptionally strong evidence from observational studies
3
Observational studies, or RCTs with notable limitations
4
Clinical experience and observations, observational studies with important limitations, or RCTs with several major limitations

GRADE of Evidence for Hepatitis A vaccines in persons aged >40 years: Benefits

Outcome #1-4

Author, year Study Design No. of subjects Population Outcome*
Briem et al., 1994 3 60 40 to 62 years, Iceland Seroconversion (≥20 mIU/mL anti-HAV) at 15 days: 77%

GMT at 15 days: 262 mIU/mL (range: 65-995 mIU/mL)

Reuman et al., 1997a 3 23 ≥ 40 years, U.S. Seroconversion (≥10 mIU/mL anti-HAV) at 2 weeks: 31%

GMT at 2 weeks: 6.1 mIU/mL

Van Der Meeren et al., 2015 3 80 ≥ 40 years, Belgium, Finland, Iceland Seroconversion (≥20 mIU/mL anti-HAV) at 15 days: 79.7% (68.8-88.2%)

GMT at 15 days: 126.5 mIU/mL (88.6-180.7 mIU/mL)

Goilav et al., 1995 3 306 Mean age 24 years (range 18-63),UK, Belgium, Germany, France Seroconversion (≥20 mIU/mL anti-HAV) at 2 weeks: 76.1% (95% CI: 71.2-81.1%)

GMT at 2 weeks: 30.8 mIU/mL (95% CI: 28.1-33.7)

Bertino et al., 1998b 3 153 ≥ 30 years (median age 42 years), U.S. Seroconversion (≥10 mIU/mL anti-HAV) at 2 weeks: 46%

GMT at 2 weeks: 10.0 mIU/mL

Williams et al., 2000c 1 149 Mean age 42,Alaska Natives See results for Nelson et al., 2014a
Nelson et al., 2014c 3 172 40-49 years; 50-59 years; ≥ 60 years, Alaska Natives Seroconversion (≥20 mIU/mL anti-HAV) at 15 days: 40-49 years: 74% (n=125); 50-59 years: 54% (n=37); ≥ 60 years: 30% (n=10)

GMTs at 15 days: 40-49 years: 26.09 mIU/mL (n=125); 50-59 years: 12.80 mIU/mL (n=37); ≥ 60 years: 1.62 mIU/mL (n=10)

Parrón et al., 2017 3 80 >40 years, Catalonia Hepatitis A infection, deaths, hospitalizations
Freeman et al. 2014 3 40(90) ≥40, Australia Hepatitis A infection, deaths, hospitalizations
Whelan et al., 2013 3 10 ≥41 years, Netherlands Hepatitis A infection, deaths, hospitalizations

*No immune globulin comparator studies were identified in the systematic review

aVAQTA 25U; bVAQTA 50U results shown; cNelson et al. 2014 is a reanalysis of Williams et al., 2000

Three studies included in the final review had direct comparisons between adults ≤40 years of age and adults >40 years of age: 1) Briem (retrospective cohort, conducted in Iceland), 2) Reuman (retrospective cohort conducted in the US) and 3) Van der Meeren (post-hoc retrospective pooled analysis from 3 randomized clinical trials conducted in Belgium, Finland and Iceland). In the Briem study, seroconversion at 15 days occurred in 77% of persons aged 40-62 years. The Reuman study used half the current recommended adult dose of VAQTA (25 U). Thirty-one percent of persons aged ≥40 years seroconverted at 2 weeks. In the Van Der Meeren study, seroconversion occurred in ~80% of persons aged ≥40 years. Two studies included adults aged >40 years of age in the population, but did not present results differentiated by age: 1) Goilav (multicentre, controlled, randomised, open, comparative study performed in the UK, Belgium, Germany and France). Seroconversion occurred in about 76% of adults aged 18-63 years. 2) Bertino et al, an observational study conducted in the US, 46% of persons aged ≥30 years seroconverted. The only study to stratify by age groups >40 years was Nelson et al., a reanalysis of Williams et al., which included adults with a mean age of 41 years; seroconversion occurred in 74% of adults age 40-49 years; 54% of adults age 50-59 years and 30% of adults aged ≥60 years.

Hepatitis A infection was described in 3 studies: Parron et al (included adults aged >40 years in Catalonia), Freeman et al (included adults aged ≥40 years in Australia) and Whelan et al (included adults aged ≥41 years in the Netherlands). Deaths and hospitalization outcomes were evaluated in these studies.

GRADE of Evidence for Hepatitis A vaccines in persons aged >40 years: Harms

Outcome #1

Author, year Study Design No. of subjects Population Outcome
Briem et al., 1994 3 60 40 to 62 years, Iceland Adverse events
Reuman et al., 1997 3 23 ≥ 40 years, U.S. Adverse events
Van Der Meeren et al., 2015 3 80 ≥ 40 years, Belgium, Finland, Iceland Adverse events
Goilav et al., 1995 3 306 Mean age 24 years (range 18-63), UK, Belgium, Germany, France Adverse events
Bertino et al., 1998 3 153 ≥ 30 years (median age 42 years) Adverse events
Nelson et al., 2014 (Williams et al., 2000) 3 172 40-49 years; 50-59 years; ≥ 60 years, Alaska Native Adverse events
Parrón et al., 2017 3 80 >40 years, Catalonia Adverse events
Freeman et al. 2014 3 40 (90) ≥40, Australia Adverse events
Whelan et al., 2013 3 10 ≥41 years, Netherlands Adverse events

Incidence of outcomes

Outcome No. of subjects (# studies) Incidence in comparison group Incidence in vaccinated Vaccine efficacy Absolute risk Number needed to vaccinate
Hepatitis A infection 130(3 observational) N/A 4 cases (3.1%) N/A N/A N/A
Deaths 130(3 observational) N/A None reported N/A N/A N/A
Hospitalizations 130(3 observational) N/A None reported N/A N/A N/A
Serious adverse events 974(9 observational) N/A None reported N/A N/A N/A

Four cases among adults aged >40 years were identified in the 3 studies with information on hepatitis A infection (one case occurred in a 43-year-old man; no other information was provided). Incidence in comparison group could not be assessed because no studies were identified that compared IG and vaccine in adults aged >40 years. Vaccine efficacy, absolute risk and number needed to vaccinate also could not be evaluated.

Grade Summary

Outcome Design (# studies) Risk of bias Inconsistency Indirectness Imprecision Evidence type Overall evidence type
BENEFIT
Immunogenicity 6 observational No serious Serious (-1)b Serious (-1)c Serious (-1)d 4 4
Hepatitis A incidence 3 observational Serious (-1)a No serious No serious No serious 4 4
Deaths 3 observational Serious (-1)a No serious No serious No serious 4 4
Hospitalizations 3 observational Serious (-1)a No serious No serious No serious 4 4
HARMS
Serious adverse events 9 observational No serious No serious No serious No serious 3 3

aTwo of three studies were surveillance, with little information provided about the potential for missed follow-up.

bImmunogenicity results in older adults showed high variability by study, with orders of magnitude differences in GMT results.

cFour of six studies did not provide results broken down by age group, included younger individuals, or did not provide details on age ranges.

dStudies included very few adults in the oldest age groups. Only one study provided results for adults >60 years and this included only 10 subjects.

The benefit outcome immunogenicity was downgraded for inconsistency (Immunogenicity results in older adults showed high variability by study, with orders of magnitude differences in GMT results); downgraded for indirectness (Four of six studies did not provide results broken down by age group, included younger individuals, or did not provide details on age ranges) and downgraded for imprecision (Studies included very few adults in the oldest age groups. Only one study provided results for adults >60 years and this included only 10 subjects.) Hepatitis A incidence, death and hospitalizations was downgraded for risk of bias (Two of three studies were surveillance, with little information provided about the potential for missed follow-up). The overall evidence was type 4 for benefits and type 3 for harms.

View the complete list of GRADE evidence tables‎