Researchers have been trying for decades to develop a vaccine against the globally endemic hepatitis C virus (HCV). Now scientists at The Scripps Research Institute (TSRI) have discovered one reason why success has so far been elusive.
Using a sophisticated array of techniques for mapping tiny molecular structures, the TSRI scientists analyzed a lab-made version of a key viral protein, which has been employed in some candidate HCV vaccines to induce the body’s antibody response to the virus. The researchers found that the part of this protein meant as the prime target of the vaccine is surprisingly flexible. Presenting a wide variety of shapes to the immune system, it thus likely elicits a wide variety of antibodies, most of which cannot block viral infection.
“Because of that flexibility, using this particular protein in HCV vaccines may not be the best way to go,” said co-senior author TSRI Associate Professor Mansun Law.
“We may want to engineer a version that is less flexible to get a better neutralizing response to the key target site and not so many off-target responses,” said co-senior author Ian A. Wilson, TSRI’s Hansen Professor of Structural Biology and a member of the Skaggs Institute for Chemical Biology at TSRI.
The report, published online ahead of print by the Proceedings of the National Academy of Sciences the week of October 24, 2016, is likely to lead to new and better HCV vaccine designs.
A Great Need
A working vaccine against this liver-infecting virus is needed desperately. HCV infection continues to be a global pandemic, affecting an estimated 130 to 150 million people worldwide and causing about 700,000 deaths annually from liver diseases including cancer. Although powerful antiviral drugs have been developed recently against HCV, their extremely high costs are far beyond the reach of the vast majority of people living with HCV infection. Moreover, antiviral treatment usually comes too late to prevent liver damage; HCV infection is notorious for its ability to smolder silently within, producing no obvious symptoms until decades have passed.
The Law and Wilson laboratories have been working together in recent years to study HCV’s structure for clues to successful vaccine design. In 2013, for example, the team successfully mapped the atomic structure of the viral envelope protein E2, including the site where it binds to surface receptors on liver cells.