March 03, 2026

Nanoparticle vaccine approach takes on a new target: Hepatitis C virus Scripps Research scientists reengineer critical proteins on the surface of HCV, paving the way for a new vaccine design.

March 03, 2026

LA JOLLA, CA Hepatitis C virus (HCV) infects an estimated 50 million people worldwide, according to the World Health Organization, and remains a leading cause of cirrhosis and liver cancer. While antiviral drugs can cure most infections, global access remains limited and these drugs do not stop reinfection.

This is why a durable vaccine is critically needed. Developing one has proven exceptionally challenging, however, as HCV evades immune detection using two distinct proteins that coat its surface. These proteins, known collectively as the E1E2 glycoprotein complex, have been historically difficult to produce in the stable, native form needed for vaccination.

In a new Nature Communications study, scientists at Scripps Research have now engineered that native-like, stabilized version of HCV's E1E2 complex and used it to build a nanoparticle-based vaccine candidate. The approach uses a technology called self-assembling protein nanoparticles, or SApNPs, which organizes many copies of the proteins into virus-like clusters that the immune system can more easily recognize. The study was published as an article-in-press on February 11, 2026.

Our lab focuses on all the major virus families, including those with surface proteins that are too unstable to use in traditional vaccines, says senior author Jiang Zhu, professor at Scripps Research. For HCV, the central problem for decades has been that the two surface proteins, E1 and E2, fall apart or misassemble when removed from the virus. In this study, we were able to stabilize the native E1 E2 interface and generate a soluble complex that faithfully mimics the viral surface.

On HCV's viral surface, E1 and E2 form tightly linked pairs known as heterodimers. Together, they both shield the virus from immune attack and allow it to attach to and enter human cells. Because vaccines train the immune system to recognize viral proteins, scientists must first recreate accurate copies of them in the lab. However, the E1 and E2 glycoproteins are notoriously difficult and labor-intensive to manufacture: once removed from the virus, they often misfold or fall apart.

For more than two decades, scientists been attempting to produce this stable, soluble E1E2 complex that preserves the correct interface between the two proteins. Without it, vaccines cannot teach the body's immune system to recognize HCV's true viral structure. It's remained a major unsolved challenge in the HCV field at large.

In the new study, Zhu and his team approached the challenge from a structural engineering perspective. They designed a molecular scaffold to hold E1 and E2 together in their native orientation, reinforcing key contact points that normally destabilize outside the viral membrane. The researchers then trimmed flexible regions that disrupted folding and added molecular connectors known as protein scaffolds to lock the pair into the correct alignment. Using various electron microscopy imaging techniques, they confirmed the engineered proteins preserved their native structure.

Normally, these glycoproteins are extremely fragile, Zhu adds. In the redesigned version, they became rock solid, while keeping the same shape the immune system requires to recognize them. That stability is essential because antibodies that neutralize HCV recognize a very specific arrangement of E1 and E2. If that interface isn't preserved, the vaccine won't present the right target.

Sixty copies of the stabilized proteins were then displayed on Zhu's proprietary SApNP technology. By clustering them together in this way, the particles mimic how viruses appear in nature and amplify the body's immune response. When tested in animal models, the HCV nanoparticle vaccine candidates triggered immune responses directed at the viral surface.

The soluble, stabilized E1E2 complex serves as the foundation for this multivalent display, potentially enabling a vaccine format that was previously not feasible, Zhu says.

Zhu's lab has spent years developing his nanoparticle-based platform for different vaccine targets. The approach relies on rational, structure-based design: researchers analyze viral surface proteins in fine detail, engineer stable versions and then mount them on virus-like protein particles to trigger a strong antibody response. Variations of the SApNP system have already been explored for multiple viruses, including HIV, influenza and most recently filoviruses like Ebola, Sudan, and Marburg.

HCV was one of the most challenging because it's a very difficult vaccine target, Zhu says. Our rational design approach allowed us to first identify why the virus' surface glycoproteins are so unstable, and then engineer solutions to overcome those challenges. Solving the soluble E1E2 problem removes a major bottleneck that has limited structure-based HCV vaccine design for decades.

Beyond a single vaccine candidate, Zhu echoes that the work shows promise in also benefitting the broader HCV field. Because the stabilized E1 and E2 proteins can now be produced reliably, they provide a template for researchers developing both vaccines and antibody-based therapies. It also opens new possibilities for structural studies and therapeutic antibody discovery.

For now, the team will refine the HCV vaccine candidates to strengthen immune responses and evaluate protection in future studies. Zhu is also working on solving another broader challenge in his vaccine design at large.

Over the last seven to eight years, I've been focused on solving protein designs for the major virus families, he says. Now, I'm also exploring strategies to further

LINK:	https://www.scripps.edu/news-and-events/press-room/2026/20260303-zhu-n...
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