An effective vaccine may be necessary to eliminate hepatitis
C virus (HCV) but development has been hampered by several challenges including
the variability of the virus and incomplete natural immunity, according to
presentations at the 5th International Symposium on Hepatitis Care in Substance
Users (INHSU 2016) last week in Oslo, Norway. One promising prime-boost viral
vector vaccine is currently in clinical trials.
estimated 130 to 150 million people worldwide have chronic hepatitis C, many of
whom live in low- and middle-income countries. In the US and Europe HCV
infection has traditionally been most common among 'baby boomers' born between
1945 and 1965, but rates of new infection are increasing among people who
inject drugs in conjunction with a growing opioid epidemic.
exchange, opiate substitution therapy and other harm reduction strategies can
reduce the risk of HCV infection among people who inject drugs and hepatitis C can
now be readily cured with new direct-acting antivirals. But prevention services
and access to treatment are not available to all who need them.
Andrea Cox of Johns Hopkins University presented an overview of HCV vaccine
development and its challenges at INHSU 2016.
control of HCV infection will likely require a combination of mass screening to
identify those with infection, treatment and harm reduction strategies for
uninfected people at risk, including prophylactic HCV vaccination," Prof
Some individuals are genetically predisposed to be
able to naturally control HCV. Around a quarter of people with the infection clear the virus spontaneously without
treatment, while the remainder develop chronic or long-term infection.
generally does not confer full natural immunity and it is possible to contract the infection again after spontaneous viral clearance or successful treatment. A variety of
studies have seen HCV reinfection rates of 10 to 40% among people who inject
drugs and men who have sex with men. Further, there is potential for reinfection
with drug-resistant virus that could limit treatment options.
does appear that with repeated attempts the immune system "gets better and
better at controlling HCV," according to Prof Cox.
People with reinfection typically have lower HCV viral load and shorter duration
of viremia than those with initial infection. In addition, the magnitude and
breadth of their T-cell responses increase and the likelihood of spontaneous
clearance rises with each subsequent infection.
of 113 people with HCV found that 31 (27%) controlled their initial infection.
Of these, 22 were retested and half of them were found to have reinfection with
a different strain of HCV. Within this group – including two people who had had reinfection twice – ten reinfections (83%) spontaneously cleared.
wide genetic variability – even more so than HIV – making it difficult to
develop vaccines that are effective against all the different viral strains. Further,
most animals cannot be infected with HCV and the virus is difficult to culture
in the laboratory.
have explored both preventive vaccines for HCV – for example, attempting to establish
antibodies that can prevent the virus from taking hold in the body – and therapeutic
vaccines that marshal immune responses to control the virus once infection
considered unsafe to use live attenuated (weakened) or killed or inactivated
whole HCV for vaccines due to the risk that it could revert back to being virulent.
Researchers have instead tested vaccines containing HCV proteins, HCV
DNA (genetic material), virus-like particles and viral vectors in non-human
primates, and a few of the best candidates have advanced into human trials.
The most promising strategy uses other viruses as
vectors to carry non-infectious bits of HCV for the immune system to recognise – the approach currently being used for some Ebola virus and HIV vaccine
candidates. But if a person has already been exposed to and developed immunity against
the vector virus, it may be eliminated too fast to be effective. Using animal
virus vectors may overcome this barrier.
A vaccine being developed by GlaxoSmithKline, known as
AdCh3NSmut, uses a chimp adenovirus vector containing the NS3, NS4 and NS5 non-structural
proteins of HCV genotype 1b, the part of the virus that is most conserved, or
consistent across strains. This 'primer' vaccine is followed by a 'booster'
using an attenuated modified vaccinia Ankara (MVA) vector.
In its first human
study, the AdCh3NSmut-MVANSmut combination was safe and
well tolerated. It induced antiviral immunity that worked much like control of
natural infection, with broad and durable poly-functional CD4 and CD8 T-cell
responses across HCV genotypes. All study participants showed some response to
the vaccine and a majority developed responses against multiple HCV proteins.
A double-blind, randomised, placebo-controlled clinical
trial of AdCh3NSmut-MVANSmut – dubbed VIP (Vaccine is Prevention) – is now underway
at Johns Hopkins, the University of California at San Francisco and the
University of New Mexico.
The study aims to enrol 540 people who are active injection drug
users at high risk for HCV infection. They will receive the AdCh3NSmut primer
at the start of the study and the MVANSmut booster 8 weeks later; they will be
followed through 88 weeks to assess safety, induction of HCV-specific immune
responses and efficacy in preventing chronic HCV infection. The first data are
due in early 2017.
effective vaccine would lessen the need for ongoing harm reduction services
for at-risk populations – as one-time vaccination would ideally provide
long-term protection – and it has the potential to prevent liver cancer and
liver failure associated with chronic HCV infection.
"We have a unique opportunity, if we can combine
treatment and a vaccine, to accomplish what we can't with other disease using
only one or the other," Prof Cox concluded.