A pilot randomized controlled trial of dual‐plasmid HBV DNA vaccine mediated by in vivo electroporation in chronic hepatitis B patients under lamivudine chemotherapy

Abstract

A DNA vaccine against the hepatitis B virus (HBV), enhanced by IL-2/IFN-γ fusion protein expression from a plasmid construct and mediated by in vivo electroporation, was evaluated in a total of 39 HBeAg-positive patients with chronic hepatitis B (CHB). The six of 39 patients with a serum alanine aminotransferase (ALT) value of 1-2 times upper limit of normal (ULN) were assigned to the open-label arm (Group01) receiving vaccine monotherapy; the remaining 33 patients with an ALT of more than two times ULN were enroled to the randomized and controlled arm (Group02) receiving lamivudine (LAM) monotherapy (LAM+placebo) or combined therapy (LAM+DNA vaccine) in 1:2 ratio. In Group01, a significant elevation of HBV-specific IFN-γ-secreting T-cell counts in comparison with baseline was observed. In Group02, the proportion of patients with HBV DNA suppression was higher with LAM+DNA vaccine than with LAM monotherapy at each visit time point after the final injection of DNA vaccine at week 36, revealing a significant difference between the two groups (P = 0.03) at week 60. The incidence of dual-site mutations of rtM204/I/S+rtL180M was significantly lower (P = 0.03) with an identified lower virological breakthrough (VBT) rate (P = 0.03) in patients receiving LAM+DNA vaccine than LAM monotherapy, accompanied with a significant higher positive T-cell response rate in patients receiving LAM+DNA vaccine (P = 0.03). In conclusion, this study provides evidence that HBV DNA vaccination is safe and immunologically effective, and that the HBV-specific T-cell responses induced by DNA vaccination under LAM chemotherapy showed a correlation with the suppression of viral replication in patients with CHB.

Immune-modulators to combat hepatitis B virus infection: From IFN-α to novel investigational immunotherapeutic strategies

“…They can be produced by stimulation with PRR agonist, and TLR8 agonist has been shown to be very potent in this respect in the liver 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 (Jo et al, 2014). Recombinant forms of these cytokines have not yet been widely used, but several trials performed in animal model or in human, and aiming at investigating DNA vaccination as therapeutic approach have used co-injection of vectors encoding these chemokines, and shown that they indeed improved immune responses (Brass et al, 2015;Chow et al, 1998;Saade et al, 2013;Yang et al, 2012).…”

N-glycosylation-mutated HCV envelope glycoprotein complex enhances antigen-presenting activity and cellular and neutralizing antibody responses

“…Female BALB/c mice (6 to 8 weeks old, SPF level) were randomly separated into 13 groups and immunized with each plasmids using in vivo electroporation according to a previously described protocol [22,23,30]. All plasmids were prepared using endotoxin-free purification columns (Omega Bio-Tek, Norcross, GA, USA).…”

Research progress of therapeutic vaccines for treating chronic hepatitis B

“…In conclusion, the trial suggested that the dual-plasmid vaccine was safe and immunologically effective, and the combination of DNA vaccine and LAM achieved a significant higher positive T-cell response rate (P D 0.03) and a lower virological breakthrough (VBT) rate (P D 0.03) than LAM monotherapy in CHB patients. 69 However, in the following phase IIb trial, the dual-plasmid vaccine failed to achieve significant efficacy in drug resistance and viral breakthrough.…”