Hepatitis A immunisation in persons not previously exposed to hepatitis A

Abstract

Background: In many parts of the world, hepatitis A infection represents a significant cause of morbidity and socio-economic loss. Whilst hepatitis A vaccines have the potential to prevent disease, the degree of protection afforded against clinical outcomes and within different populations remains uncertain. There are two types of hepatitis A virus (HAV) vaccine, inactivated and live attenuated. It is important to determine the efficacy and safety for both vaccine types.

Objectives: To determine the clinical protective efficacy, sero-protective efficacy, and safety and harms of hepatitis A vaccination in persons not previously exposed to hepatitis A.

Search methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, and China National Knowledge Infrastructure (CNKI) up to November 2011.

Selection criteria: Randomised clinical trials comparing HAV vaccine with placebo, no intervention, or appropriate control vaccines in participants of all ages.

Data collection and analysis: Data extraction and risk of bias assessment were undertaken by two authors and verified by a third author. Where required, authors contacted investigators to obtain missing data. The primary outcome was the occurrence of clinically apparent hepatitis A (infectious hepatitis). The secondary outcomes were lack of sero-protective anti-HAV immunoglobulin G (IgG), and number and types of adverse events. Results were presented as relative risks (RR) with 95% confidence intervals (CI). Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence interval (CI), using intention-to-treat analysis. We conducted assessment of risk of bias to evaluate the risk of systematic errors (bias) and trial sequential analyses to estimate the risk of random errors (the play of chance).

Main results: We included a total of 11 clinical studies, of which only three were considered to have low risk of bias; two were quasi-randomised studies in which we only addressed harms. Nine randomised trials with 732,380 participants addressed the primary outcome of clinically confirmed hepatitis A. Of these, four trials assessed the inactivated hepatitis A vaccine (41,690 participants) and five trials assessed the live attenuated hepatitis A vaccine (690,690 participants). In the three randomised trials with low risk of bias (all assessing inactivated vaccine), clinically apparent hepatitis A occurred in 9/20,684 (0.04%) versus 92/20,746 (0.44%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.03 to 0.30). In all nine randomised trials, clinically apparent hepatitis A occurred in 31/375,726 (0.01%) versus 505/356,654 (0.18%) participants in the HAV vaccine and control groups respectively (RR 0.09, 95% CI 0.05 to 0.17). These results were supported by trial sequential analyses. Subgroup analyses confirmed the clinical effectiveness of both inactivated hepatitis A vaccines (RR 0.09, 95% CI 0.03 to 0.30) and live attenuated hepatitis A vaccines (RR 0.07, 95% CI 0.03 to 0.17) on clinically confirmed hepatitis A. Inactivated hepatitis A vaccines had a significant effect on reducing the lack of sero-protection (less than 20 mIU/L) (RR 0.01, 95% CI 0.00 to 0.03). No trial reported on a sero-protective threshold less than 10 mIU/L. The risk of both non-serious local and systemic adverse events was comparable to placebo for the inactivated HAV vaccines. There were insufficient data to draw conclusions on adverse events for the live attenuated HAV vaccine.

Authors' conclusions: Hepatitis A vaccines are effective for pre-exposure prophylaxis of hepatitis A in susceptible individuals. This review demonstrated significant protection for at least two years with the inactivated HAV vaccine and at least five years with the live attenuated HAV vaccine. There was evidence to support the safety of the inactivated hepatitis A vaccine. More high quality evidence is required to determine the safety of live attenuated vaccines.

Figure 1

PRISM Study flow diagram.

Figure 2

Risk of bias summary: review authors' judgements about each risk of bias item for each included study. Please note that Luo 2004 and Wu 1996 were quasi‐randomised studies and were included in the adverse events review only.

Figure 3

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 4

Trial sequential analysis for trials with low risk of bias. The required information size was 55,961 participants based on the a priori assumption of a relative risk reduction of 90%; an event proportion of 0.1% in the control arm; an alpha of 5%; a beta of 80%; and a heterogeneity correction for the calculation of the required information size. The cumulated Z‐curve crosses the traditional boundary of 5% significance and the trial sequential alpha spending monitoring boundary.

Figure 5

Trial sequential analysis for clinical and contemporarily laboratory confirmed hepatitis A (all included studies). The required information size was 60421 participants based on the a priori assumption of a relative risk reduction of 90%; an event proportion of 0.1% in the control arm; an alpha of 5%; a beta of 80%; and a heterogeneity correction for the calculation of the required information size. The cumulated Z‐curve crosses the traditional boundary of 5% significance and the trial sequential alpha spending monitoring boundary.

Figure 6

Funnel plot of comparison: 1 Clinical hepatitis A, outcome: 1.1 All vaccine types.

Analysis 1.1

Comparison 1 Clinical hepatitis A, Outcome 1 All vaccine types.

Analysis 1.2

Comparison 1 Clinical hepatitis A, Outcome 2 Inactivated HAV vaccines.

Analysis 1.3

Comparison 1 Clinical hepatitis A, Outcome 3 Live attenuated HAV vaccine.

Analysis 1.4

Comparison 1 Clinical hepatitis A, Outcome 4 High titre live attenuated HAV vaccine.

Analysis 1.5

Comparison 1 Clinical hepatitis A, Outcome 5 Low titre live attenuated HAV vaccine.

Analysis 1.6

Comparison 1 Clinical hepatitis A, Outcome 6 High endemicity.

Analysis 1.7

Comparison 1 Clinical hepatitis A, Outcome 7 Low endemicity.

Analysis 1.8

Comparison 1 Clinical hepatitis A, Outcome 8 Single dose regimen.

Analysis 1.9

Comparison 1 Clinical hepatitis A, Outcome 9 Multiple (2 or more) dose regimen.

Analysis 1.10

Comparison 1 Clinical hepatitis A, Outcome 10 Follow‐up duration (1 to 12 months).

Analysis 1.11

Comparison 1 Clinical hepatitis A, Outcome 11 Follow‐up duration (13 to 24 months).

Analysis 1.12

Comparison 1 Clinical hepatitis A, Outcome 12 Follow‐up duration (25 to 36 months).

Analysis 1.13

Comparison 1 Clinical hepatitis A, Outcome 13 Follow‐up duration (49 to 60 months).

Analysis 2.1

Comparison 2 Lack of sero‐protection, Outcome 1 Lack of sero‐protection.

Analysis 3.1

Comparison 3 Adverse event, Outcome 1 Non‐serious local adverse events.

Analysis 3.2

Comparison 3 Adverse event, Outcome 2 Non‐serious systemic adverse events.

Analysis 4.1

Comparison 4 Number of participants, Outcome 1 >1000 participants.

Analysis 4.2

Comparison 4 Number of participants, Outcome 2 < 1000 participants.

Analysis 5.1

Comparison 5 All‐cause mortality, Outcome 1 All vaccine types.