BACKGROUNDIn 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.OBJECTIVESTo 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 METHODSWe 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 CRITERIARandomised clinical trials comparing HAV vaccine with placebo, no intervention, or appropriate control vaccines in participants of all ages.DATA COLLECTION AND ANALYSISData 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 RESULTSWe 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' CONCLUSIONSHepatitis 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.
