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.