Challenges Persist in Developing a Hepatitis C Vaccine

Parts of a protein used in some HCV vaccine candidates are far too flexible to be successful.

Although scientists have been trying for years to come up with a vaccine for hepatitis C virus (HCV), the results have been unsuccessful. Recently, researchers have identified one of the reasons for this challenge.

In a study published in the Proceedings of the National Academy of Sciences, investigators used a variety of techniques to map out tiny molecular structures. Next, they analyzed a lab-made version of a key viral protein, which has been used in some candidate HCV vaccines.

It was found that a part of the protein, which is the main target of the vaccine, was surprisingly flexible. Due to this flexibility, researchers believe that this protein may not be the best avenue to pursue for HCV vaccines.

“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 study author Ian A. Wilson.

Previous research in recent years by the study authors involved examining the structure of HCV to find clues for a successful vaccine design. They were able to map the atomic structure of the viral envelope protein E2, including the site where it binds to the surface receptors on liver cells.

This HCV receptor-binding site has been considered an excellent target for a vaccine, according to the study. However, candidate HCV vaccinations that mimic the E2 protein elicited high levels of antibodies against the receptor-binding site. Unfortunately, these antibody responses have not been very effective at preventing HCV infection of liver cells in lab assays.

Researchers wanted to find out why, so they used electron microscopy, as well as several other advanced structural analysis tools to closely examine the E2 protein. The primary focus was on the recombinant form of the E2 protein, which had been produced in the lab and isolated from the rest of the virus.

Researchers noted that recombinant E2 is currently a prime candidate for HCV vaccine design.

The results of the study showed that recombinant E2 had excellent structural stability, with an unusually high melting point of 85°C. However, inside they found that the receptor binding site portion is extremely loose and flexible in the recombinant protein.

“It adopts a very wide range of conformations,” said first study author Leopold Kong.

Other studies have demonstrated that the receptor binding site on HCV is able to adopt a narrow range of conformations when it’s bound by virus-neutralizing antibodies. This suggests that creating a vaccine that can elicit high levels of antibodies against only these key conformations could provide protection.

However, the current study’s findings reveal that the E2 protein used in candidate vaccines has too many other binding-site conformations, resulting in elicited antibodies that fail put a stop to the virus.

Next, researchers plan to study E2 and its receptor binding site as they are presented on the surface of the actual virus. Furthermore, they are looking to design a new version of E2 where the receptor binding site is stabilized in conformations and can elicit neutralizing antibodies.