NASVAC therapeutic vaccine may lead to functional cure of hepatitis B

17 Nov 2020 Liz Highleyman
Originally published on www.infohep.org

NASVAC, an experimental therapeutic vaccine that targets two different hepatitis B virus (HBV) antigens, led to a reduction in hepatitis B surface antigen levels and several study participants achieved a functional cure after 18 months of follow-up, according to report at the AASLD virtual Liver Meeting this week.

Unlike the widely used vaccines for hepatitis B prevention, NASVAC aims to treat people who already have chronic HBV infection. The nasally administered vaccine contains both hepatitis B surface antigen (HBsAg) and core antigen (HBcAg). The combination triggers the production of anti-HBs antibodies and promotes T-cell activity against the virus.

Osamu Yoshida of Ehime University Graduate School of Medicine in Japan presented updated results from a study of 71 people who received ten doses of NASVAC and were followed for up to 18 months. At last year's Liver Meeting, he reported results after six months of follow-up.

The study included 29 participants taking nucleoside/nucleotide antiviral drugs and 42 asymptomatic untreated people; 22 and 33, respectively, reached the 18-month mark. Antivirals such as tenofovir disoproxil fumarate (Viread), tenofovir alafenamide (Vemlidy) and entecavir (Baraclude) can suppress HBV replication indefinitely during treatment, but they seldom lead to a cure.

In the antiviral group, about 70% were men, the median age was 54 years and about 75% were hepatitis B 'e' antigen (HBeAg) negative. HBV DNA was undetectable and the median HBsAg level was 464 IU/ml. In the untreated group, about half were women, the median age was 53 and 95% were HBeAg negative. The median viral load was 2.4 log10 IU/ml and the median HBsAg level was 1488 IU/ml. Both groups had ALT and AST liver enzyme levels within the normal range and most had HBV genotype C.

All participants received NASVAC every two weeks for a total of ten doses. The study used a modified version of the vaccine (initially developed by the Center for Genetic Engineering and Biotechnology in Cuba) that is formulated with a polymer to increase viscosity and is administered using a special device that disperses it over a larger surface area in the nasal cavity.

About three-quarters of participants in both groups experienced a reduction in HBsAg at six months, and this proportion remained similar at 18 months. HBsAg levels, however, continued to fall.

HBsAg declined by an average of about 16% from baseline in the antiviral group and by about 18% in the untreated group at six months. But by 18 months, the corresponding drops were approximately 25% and 28%, respectively. At that point, the median log reductions in the two groups were -0.159 and -0.299 log10 IU/ml, respectively.

Two participants in each group achieved HBsAg loss by six months – considered a functional cure – and two additional people in the untreated group did so by 18 months. Rates of HBsAg loss among those who remained in the study at 18 months were 9.1% and 12.1%, – considerably higher than rates typically seen in people treated with antiviral therapy alone.

Looking at antibody immune responses in the antiviral group, only one person (3%) tested positive for anti-HBs antibodies prior to receiving the vaccine. This rose to 10 out of 29 people (35%) at six months, but fell slightly to seven out of 22 (32%) at 18 months. In the untreated group, anti-HBs positivity rose from nine people (21%) before vaccination to 25 out of 42 (60%) at six months and fell to 20 out of 33 (58%) at 18 months.

Most participants maintained the same HBeAg and anti-HBe antibody status. However, four initially HBeAg-negative people in the antiviral group developed anti-HBe antibodies, and one initially HBeAg-positive participant in the untreated group became HBeAg negative. Among those who started out HBeAg positive in both groups, HBeAg levels dropped by 44% at six months and by 65% at 18 months.

HBV DNA remained suppressed in the antiviral group and decreased by about 19% in the untreated group. Levels of hepatitis B core-related antigen (HBcrAg), a biomarker of cccDNA, declined slightly, but the change was not statistically significant. This form of DNA persists in liver cells despite antiviral therapy and is a barrier to a cure.

Treatment was generally safe and well tolerated, with no severe adverse events. Yoshida reported last year that ALT levels remained stable in the antiviral group but some people in the untreated group experienced steep increases. One of them went on to experience HBeAg loss after an ALT flare.

In summary, Yoshida said, HBsAg levels continued to decline with longer follow-up after receiving NASVAC. Anti-HBs antibody levels rose after vaccine administration, but then gradually decreased during extended follow-up. A total of six people achieved a functional cure, including two who did so during the extended follow-up period.

"Nasal administration of NASVAC could be an effective and safe immune therapy for achieving functional cure" in chronic hepatitis B patients, the researchers concluded.