Phase IIb trial ofin vivoelectroporation mediated dual-plasmid hepatitis B virus DNA vaccine in chronic hepatitis B patients under lamivudine therapy

Abstract

AIMTo assess the efficacy and safety of in vivo electroporation (EP)-mediated dual-plasmid hepatitis B virus (HBV) DNA vaccine vs placebo for sequential combination therapy with lamivudine (LAM) in patients with chronic hepatitis B.METHODSTwo hundred and twenty-five patients were randomized to receive either LAM + vaccine (vaccine group, n = 109) or LAM + placebo (control group, n = 116). LAM treatment lasted 72 wk. Patients received the DNA vaccine or placebo by intramuscular injection mediated by EP at weeks 12 (start of treatment with vaccine or placebo, SOT), 16, 24, and 36 (end of treatment with vaccine or placebo, EOT).RESULTSIn the modified intent-to-treat population, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 after EOT compared with the control group. A trend toward a difference in the number of patients with undetectable HBV DNA at week 28 after EOT was obtained. Adverse events were similar. In the dynamic per-protocol set, which excluded adefovir (ADV) add-on cases at each time point instantly after ADV administration due to LAM antiviral failure, more patients had a decrease in HBV DNA > 2 log10 IU/mL in the vaccine group at week 12 and 28 after EOT compared with the control group. More patients with undetectable HBV DNA at week 28 after EOT in the vaccine group were also observed. Among patients with a viral load < 1000 copies/mL at week 12, more patients achieved HBeAg seroconversion in the vaccine group than among controls at week 36 after EOT, as well as less virological breakthrough and YMDD mutations.CONCLUSIONThe primary endpoint was not achieved using the HBV DNA vaccine. The HBV DNA vaccine could only be beneficial in subjects that have achieved initial virological response under LAM chemotherapy.

Therapeutic vaccination for chronic hepatitis B: A systematic review and meta‐analysis

“…For adverse events, there were some or serious concerns with 11 studies (73%), due to combined concerns with randomization, the potential impact of dropouts and selective reporting. Four studies Lok et al, Xu et al, Xu et al and Yang et al were appraised as low risk for overall risk of bias for both the efficacy and AE outcomes.…”

“…The third strategy was the exploration of a wide variety of alternative TV approaches: increasing TV doses did not seem to have improved outcomes—typically, TV was given either as a subcutaneous or intramuscular injection at 3‐6 doses at varying intervals usually 4 weeks apart, but up to 12 doses were administered. Other novel TV approaches include DNA vaccination, which showed improved reduction in HBV DNA, a yeast‐derived immune complex vaccine enhanced with IL12, which showed no efficacy, and a DNA plasmid prime followed by a modified Vaccinia Ankara boost vaccine strategy, which did not have convincing efficacy. While it is certainly possible that the strategies to optimize TV can be further improved, there are no early indicators from this review that any particular strategy or approach would be successful.…”

“…TV alone may be insufficient to demonstrate efficacy; hence, combining TV with antiviral therapy would be the most promising strategy. In the combination therapy approach, the SOC tested was interferon in one study, 23 lamivudine in five studies, 24,27,28,34,36 nucleos(t)ide analogues in two studies 21,29 and a mixture of oral antivirals in one study (NAs, or combinations). 25 For…”

Stable Immune Response Induced by Intradermal DNA Vaccination by a Novel Needleless Pyro-Drive Jet Injector

“…Recently developed DNA vaccines have been proposed as a promising new vaccination method [18–20]. In traditional vaccine production, antigen preparation has required the cultivation of pathogenic bacteria or viruses to obtain the appropriate bacterial or viral strains.…”

Designing the next‐generation therapeutic vaccines to cure chronic hepatitis B: focus on antigen presentation, vaccine properties and effect measures

“…However, ex vivo (above) and in vivo (Tables 2–4) evidence suggests targeting HBsAg alone may not be very effective. Treatment of cHBV patients with peptide‐based GenVacB or Sci‐B‐Vac (Table 2), protein‐based YIC (Table 2) or DNA vaccines pCMV‐S2.S and ED‐DNA (Table 3) targeting HBsAg only, induced a decrease or even disappearance of HBV DNA, but always transiently 49–54 . HBsAg TV did induce HBsAg‐directed antibody responses in several cases, but ultimately without lasting effect on HBsAg levels 50,55 .…”