John Murphy, MDLinx | January 31, 2018
“There’s a popular misconception that because we have good, potent antivirals now to treat hep C patients, we don’t need a vaccine. That is wrong. We do,” said Michael Houghton, PhD, professor, Department of Medical Microbiology & Immunology, University of Alberta, Edmonton, Canada, in an interview with the Canada Foundation for Innovation.
Dr. Houghton led the team that discovered the hepatitis C virus (HCV) nearly 30 years ago. Ever since, he’s been working on a vaccine to stop it.
“If you want to really control an infectious disease, you really need to develop a vaccine,” said Dr. Houghton, who is also the Canada Excellence Research Chair in Virology at the University of Alberta.
“We need a vaccine for two reasons: to protect people that are at high risk that have not yet been exposed to the virus; and secondly, we need a vaccine to immunize people that have been cured of the virus…so that when they see the virus again, they will not become chronic, persistent carriers,” he explained.
But creating an HCV vaccine hasn’t been simple or straightforward.
“It's been very difficult to develop a vaccine against hepatitis C for several reasons,” Dr. Houghton explained.
Reason 1: “You need to know if antibodies that you can generate through a vaccine can actually inhibit the infection—or as we say, neutralize the infectivity of the virus,” he said. “Even though we discovered (hepatitis C) in 1989, we weren't able to grow it in cell culture until 2005. It's an extremely difficult virus to grow in cell culture even today.”
Reason 2: No animal model is suitably available to predict human infection. “The lack of an animal model with a full immune response has really hindered the development of a hep C vaccine,” Dr. Houghton said.
Reason 3: Because of the first two reasons, “It took a long time for people in the field to figure out what are the correlates of protection,” he explained. “What that means is: What kind of immune response really correlates with protection in people?”
These barriers—and the virus itself—have stymied vaccine researchers. In particular, the conventional methods of vaccine development, using a killed or live-attenuated virus, carry too much risk in humans.
So, for the past few years in HCV vaccine development, researchers have instead taken two basic approaches that provoke an immune response. The first approach aims to produce broadly reactive neutralizing antibodies that would protect against the virus. The second approach seeks to induce potent and durable T-cell responses to fight virus infection.
Both approaches have hit roadblocks because HCV has numerous evasion strategies that enable it to sidestep the vaccines’ immune responses, researchers have found. Dr. Houghton argues that an optimal HCV vaccine should elicit both broad cross-reactive cellular immune responses and cross-neutralizing antibodies.
Dr. Houghton and his team began with the T-cell approach for their vaccine.
They started with the knowledge that more than 20% of people with HCV spontaneously clear the infection without any treatment, and this clearance is associated with strong and broad T-cell responses. They also learned that HCV-specific memory T cells can remain for years after infection, which helps protect these individuals against reinfection.
To that end, Dr. Houghton’s team developed a vaccine that generates similar T-cell immune responses. They eventually discovered in human tests that their vaccine, which targets virion surface proteins, not only produced T-cell responses but also elicited neutralizing antibodies. Dr. Houghton announced the vaccine’s discovery in 2012.
The researchers are now manufacturing the vaccine for human use at the Li Ka Shing Institute of Virology at the University of Alberta, and hope to begin clinical trials for its safety and efficacy later this year or early 2019.
Other research teams, including those at the University of Oxford, Oxford, UK, and at University of Ulsan College of Medicine, Seoul, South Korea, have also developed promising vaccines that are now undergoing further investigation.
But until a vaccine arrives on the scene, much work still needs to be done, Dr. Houghton pointed out.
“We need to screen the baby boomers because we know the baby boomers have a much higher prevalence of infection than other age cohorts,” he said.
Also, potent direct-acting antiviral drugs should be made available to everyone. “In some (areas), they’re only available to people with quite severe liver disease. We need to give it to all carriers of the virus, because if we wait, some of those people will develop liver cancer, and we cannot cure that.”