Intradermal hepatitis B vaccination with or without Imiquimod in cirrhosis after prior vaccine nonresponse: A Randomised Trial.

BACKGROUND AND AIMS: Patients with cirrhosis show impaired immune responses to standard intramuscular (IM) hepatitis B virus (HBV) vaccination, resulting in low seroconversion rates. Intradermal (ID) vaccination and topical imiquimod have been proposed as strategies to enhance vaccine immunogenicity. We conducted a randomized controlled pilot trial to compare three HBV revaccination strategies in patients with advanced chronic liver disease (ACLD) who previously failed standard IM vaccination: IM revaccination, ID revaccination, and ID revaccination combined with imiquimod (ID+IMQ). The primary endpoint was seroconversion at Month 7, defined as anti-HBs titres ≥10 mIU/mL. METHODS: This monocentric, prospective study included 59 patients with ACLD and anti-HBs titres <10 mIU/mL after prior HBV vaccination. Patients were randomized (1:1:1) to receive either IM vaccination (n=19; Engerix-B® 20 μg IM at Months 0, 1 and 6), ID vaccination (n=19; two 10 μg ID injections at the same time points), or ID vaccination preceded by topical imiquimod 5% application (n=21). RESULTS: In the intention-to-treat analysis, seroprotection rates at month 7 were 36.8% in the IM group, 84.2% in the ID group, and 66.7% in the ID+IMQ group (p<0.01). After Bonferroni correction, only the ID versus IM comparison remained statistically significant (p=0.003). Geometric mean anti-HBs titres were significantly higher in the ID (116 mIU/mL) and ID+IMQ (107 mIU/mL) groups compared with the IM group (12 mIU/mL) (p=0.004). No severe vaccine-related adverse reactions were observed. CONCLUSIONS: Intradermal HBV revaccination significantly improves seroconversion in non-responder patients with ACLD compared with IM vaccination, without additional benefit from imiquimod. These results support further evaluation of intradermal vaccination without imiquimod in a phase 3 trial. CLINICAL TRIAL NUMBER: The study protocol has been registered before the patients' recruitment, in the European Clinical Trials Database (EudraCT) of the European Medicine Agency (2021-000644-22), as well as on ClinicalTrials. gov (NCT05028322).