(Inside Science) -- This year, the Nobel Prize in physiology or medicine went to three scientists for their discovery of the hepatitis C virus, a significant global health problem that causes cirrhosis and liver cancer. The discovery led to the development of drugs that have saved millions of lives, but one important piece of the puzzle when it comes to dealing with the disease is still missing: a vaccine.

The two other forms of hepatitis, A and B, have had effective vaccines for decades. The first hepatitis B vaccine came in 1969, just four years after the virus was discovered, and several safer and more effective ones have been developed since. A vaccine for hepatitis A was approved in 1995. But a vaccine for the third type of hepatitis has so far eluded scientists.

Ellie Barnes, a virologist at the University of Oxford who has been working on hepatitis C vaccines for years, said there are several reasons why a workable vaccine has not yet been developed. Some are economic or social. For example, because the virus mostly infects vulnerable groups such as intravenous drug users, there is limited public demand for a vaccine. And compared with the well funded pipeline for hepatitis treatments, vaccines have typically received little investment from drug companies. In 2013 alone there were between 50 and 80 hepatitis C drugs in clinical trials, but only two vaccines have ever made it to human trials, and both failed.  

But the virus itself also presents serious scientific challenges to the vaccine hunters, mainly because of its extreme genetic diversity. Mansun Law, an immunologist at Scripps Research who is working on hepatitis C vaccines, said it is "one of the most mutated viruses in humans, even more so than HIV." Not only do the viral surface proteins that antibodies latch onto vary widely between strains, but the same protein can even have two different shapes.

This diversity makes it hard to develop vaccines that will stimulate the immune system to generate antibodies that can recognise all the different strains of the virus -- in much the same way that one year’s flu vaccine is ineffective against the new strains of flu that crop up the next year, said Barnes. Other viruses -- including the ones that cause hepatitis B and COVID-19 -- have much more stable surface proteins, which makes antibodies more effective.

Because of the difficulty with antibodies, much recent work has focused on vaccines that can generate a response from T cells, which recognise and attack infected cells. T cells look for the parts of the viral machinery that are conserved between strains rather than the variable surface proteins, so the idea was that they should work against multiple versions of the virus.

But that approach did not pan out. After six years and millions of dollars spent on development, and despite some promising early results, last year a T cell vaccine that Barnes had a hand in developing fell at the last hurdle, when it failed to show a protective effect in large-scale human trials.

At the same time, the antibody approach is making a comeback. In studies using mice, Law and his colleagues have shown that some antibodies can have a broad effect across viral strains. The researchers have been able to induce mice to produce these antibodies using engineered proteins mounted on nanoparticles.

Now, Barnes and Law predict that the way forward will involve combining the two approaches, developing vaccines that produce a response from T cells as well as from the B cells that produce antibodies. Around 20% of hepatitis C patients are able to spontaneously clear their infections, and those patients produce both kinds of immune response, said Barnes. "So the best vaccine will be one that makes both T cells and B cells," she said. "But that’s not how current vaccines work -- historically researchers just work on one or the other."

Although there are now effective drug treatments for the majority of hepatitis C patients, Barnes said that vaccines will still be an important part of the toolkit in fighting the disease. "Prevention is always better than cure," she said.