Reuters Health Information (2013-06-05): Anti-HBV vaccine fails against chronic hepatitis B
Drug & Device Development
Anti-HBV vaccine fails against chronic hepatitis B
Last Updated: 2013-06-05 15:10:26 -0400 (Reuters Health)
NEW YORK (Reuters Health) - A therapeutic vaccine candidate, aimed at breaking immune tolerance to the hepatitis B virus, failed in a recent trial, but the researchers believe the problem is that the adjuvant itself was too potent.
The vaccine consists of hepatitis B surface antigen (HBsAg) complexed to anti-HBs antibodies, with alum as an adjuvant. The idea is that antigen-presenting cells will take up the HbsAg-Ab complex, process the HBsAg, and present it to T cells, triggering an immune response against HBV.
An earlier trial had shown promise with a six-dose course. The failed trial tested the effect of 12 doses.
One of the researchers told Reuters Health that some members of the team had been afraid before the study started that overstimulating the immune system with 12 doses would lead to immune fatigue.
"I do not believe that there is lack of efficacy of (the immune complexes) in this phase III trial. I find the problem is that alum showed therapeutic efficacy," Dr. Yu-Mei Wen from Shanghai Medical College, Fudan University, Shanghai, China told Reuters Health in an email. "Based on the recent progress of the immune stimulating effects of alum alone revealed in the past few years, obviously, alum is not suitable to serve as a blank control for therapeutic vaccination."
Dr. Wen and colleagues tested the vaccine against "sham" therapy with just the alum adjuvant, in a double-blind phase III trial of 450 patients with chronic hepatitis B
Participants received 12 weekly intramuscular injections at four-week intervals, with an eight-week break between the 6th and 7th injections, and were followed up for 24 weeks after termination of immunization.
The per-protocol analysis, reported online May 13 in the Journal of Hepatology, included 303 (90.4%) vaccine recipients and 108 (93.9%) patients from the control group.
The main endpoint was the HBeAg seroconversion rate. (HBeAg is the extracellular form of the hepatitis B core antigen.) At the end of follow-up, there was no difference between the vaccine and control groups (14.0% vs 21.9%, respectively; p>0.05).
Compared to the previous IIb trial, in which patients received six doses, the seroconversion rate with the vaccine decreased by about a third (from 22.4%), whereas the seroconversion rate with alum more than doubled (from 9%).
Seroconversion rates in both groups were higher among patients with genotype B than among patients with genotype C, but there was no significant difference between vaccine and alum for either genotype.
"The therapeutic effects of alum in this clinical trial was quite surprising and we will pursue further, as this is the first vaccination with alum alone in humans," Dr. Wen said.
Serious adverse events included transient flares in alanine aminotransferase in 22 vaccine patients and four alum patients, all of whom recovered after hospitalization.
"In fact, we were not surprised by the results with 12 injections of (vaccine), but we were surprised by the results of alum," Dr. Wen explained. "Unlike antiviral drugs and interferon, the mechanism for therapeutic vaccination is to stimulate or modify host immune responses, and thus needs proper timing and schedule for vaccination."
Dr. Wen added, "Based on our prediction that overstimulation of specific immune response would lead to immune fatigue (which we had a hot debate with the principal investigator clinician, who insisted that patients should be given 12 injections instead of six injections in phase II B) we decided to do a proof of concept study in mice, which showed that indeed overstimulation with (the immune complexes) resulted in immune fatigue in specific immune responses towards (complexes), while innate immune responses towards alum remained to be enhanced."
"Therapeutic vaccination for persistent infections is a new and hopeful approach," Dr. Wen said. "Therapeutic vaccination is less expensive, easy to employ, and can be used in a large number of patients, especially among those from developing countries."
"We hope physicians will support this new approach in clinical trials, as scientists urgently need collaboration with clinicians to make real contribution to mankind," Dr. Wen added.
J Hepatol 2013.