Hepatitis C Vaccine Disappoints, Another in the Works

Ingrid Hein

September 09, 2019

MONTREAL — The recent failure of a promising hepatitis C vaccine has the medical community eagerly awaiting news on another vaccine candidate to be presented at the upcoming International Conference on Hepatitis Care in Substance Users (INHSU) 2019.

The second-generation vaccine candidate builds on phase I research of a prototype vaccine that was effective in animal models and then in generating cross-neutralizing antibodies against most strains of the virus in humans. (PLOS ONE. 8 (3): e59776)

It is being developed by the scientists who first discovered hepatitis C in 1989.

"We'll be finishing testing the vaccine on rabbits next year, then presenting to regulators," said Michael Houghton, PhD, from the University of Alberta, Canada, who codiscovered hepatitis C along with Qui-Lim Choo, George Kuo, and Daniel Bradley.

With the prototype, "we were able to show statistically that our vaccine substantially reduced the carrier rate in vaccinated animals compared to controls," Houghton told Medscape Medical News.

But then Novartis bought Chiron, who was funding the research, and dropped the hepatitis C program.

Houghton picked up where his work had left off — he's the director of the Li Ka Shing Applied Virology Institute at the University of Alberta — to develop a second-generation vaccine that elicits broad cross-neutralizing antibodies and broad cross-reactive T-cell responses.

"We've improved the prototype in three ways," he said. First, his team has developed a better way to produce and purify the viral envelope antigen.

Second, "to circumvent escape we've made separate antigens — separate from the envelope antigen — which the virus will have a hard time evading from cellular immune responses," he explained. "The virus could maybe escape from one but from several it would be very hard."

Finally, Houghton and his colleagues added a powerful adjuvant to power-up the immune response. "This revs up the immune system, increases the amount of antibody and cellular response to the hepatitis C antigens," he said.

Huge Disappointment

Researchers who were pinning their hopes on Okairos' hepatitis C vaccine, a chimpanzee-derived adenovirus vector with hepatitis C genetic material to stimulate a hepatitis C specific T-cell response, were very disappointed when the phase I/II results were announced earlier this summer.

"There was no difference in incidence, and no difference in chronic HCV in the vaccinated group compared to the placebo group," Naglaa Shoukry, BPharm, PhD, from the University of Montreal, told Medscape Medical News. "It was quite disappointing to the whole community."

In chimpanzee models and phase 1 trials of healthy humans, the AdCh3NSmut1/MVA-NSmut vaccine had stimulated some immune response and had a good safety profile. It showed enough promise to get the National Institutes of Health (NIH) on board with funding for a human trial.

The double-blind, randomized, placebo-controlled phase I/II trial assessed the safety and efficacy of the vaccine in a total of 548 participants, ages 18 to 45 years, all with a recent history of injecting drugs. Of these, 275 were given two doses of the vaccine, and 273 received two placebo doses. In each group, 14 participants developed chronic hepatitis C infection. The vaccine made no difference.

"We need to understand why this vaccine failed," said Shoukry. "What was the immune response that was generated, compared with healthy donors?"

Since this patient cohort involves injection drug users, their immune system may not be as strong, she postulated. "There is evidence to this effect in the literature, but we have not looked at this at an intricate level."

"If you had asked me last year," she recalled, "I would have said we'll have a vaccine in 5 years. Now it’s likely closer to 10."

Since antiretrovirals to cure hepatitis C infection are now available, Shoukry supports researchers who believe vaccinating healthy people — then infecting them to test the virus — should be allowed.

"You cannot depend on direct antiretrovirals; you can't eradicate a viral infection without a vaccine," she said.

The problem with the World Health Organization's 2030 hepatitis C targets is that there is no standardized system globally, Shoukry said. Infection treatment depends on where you are and how good you are at testing and treating.

"Some regions are good, some not," she said. "It's also difficult to find the newly infected, and the vulnerable population amid the opioid epidemic — you may not be able to reach them."

In this week's talk at INHSU 2019, Shoukry will focus on a discussion about the failed trial. She will also cover the science and challenges surrounding vaccine development at the biological level and human trials.

If you want to control a global epidemic you can't rely on diagnostics. You can't rely on antivirals. You need a vaccine. The history of infectious disease has taught us that. Dr Michael Houghton

While Houghton can't pinpoint why the Okairos trial went south, he said "for all vaccines, antibodies really are the correlates of protection against all pathogens so far." The problem with the Okairos vaccine may be that "it only elicited T-cell responses, not neutralizing antibodies."  

He echoed Shoukry’s assertions that hepatitis C won't go away without a vaccine. "If you want to control a global epidemic, you can't rely on diagnostics. You can't rely on antivirals. You need a vaccine. The history of infectious disease has taught us that."

Every year that vaccine development is delayed, Houghton noted, more people die of liver disease. "You have about 400,000 [people] every year that die from this worldwide. If you can speed up clinical trials by 5 years, maybe 2 million less will die."

Shoukry and Houghton have disclosed no relevant financial relationships.

International Conference on Hepatitis Care in Substance Users.

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