NIH-Funded Center Aims to Crack Hepatitis C Vaccine Design Using Conserved Viral Targets

The National Institutes of Health has committed $16.4 million over five years to a new research center with a single, difficult aim: a vaccine that works against hepatitis C. The award establishes a U19 "Cooperative Center for Rational HCV Vaccine Design & Evaluation," and it ties together four institutions: Scripps Research, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the University of Pennsylvania, and the Oregon National Primate Research Center (ONPRC).

The problem they are taking on is the virus itself. Hepatitis C mutates at an especially high rate, which has produced a large pool of variants with extreme genetic diversity. That diversity has stalled vaccine development so far, because a broadly effective vaccine has to aim at regions of the virus that stay relatively stable from one variant to the next. Research over the past decade has pointed to a few such sites that antibodies or T cells can recognize.

The stakes are measured in people. Around 50 million worldwide live with chronic HCV infection, which can progress to liver cirrhosis, liver cancer and autoimmune disorders. Antiviral drugs cure most patients, but gaps in diagnosis, reinfection and continuing transmission keep the case for a preventive vaccine open.

Mansun Law, a Scripps Research professor and the project leader, says the funding allows a more detailed and systematic approach, with experts focused on both the antibody and T cell sides of immunity. The plan is to merge that knowledge into one vaccine candidate able to stimulate both arms. Law also raises a larger possibility: because the virus infects only humans, a vaccine to prevent new infections, combined with a way to contain the last remaining virus, could make eradication possible, as happened with smallpox.

The work is organized into two projects. The first aims to understand the HCV structures that antibodies recognize and how those structures appear on the vaccine candidates built in the second. Law, Professor Ian Wilson, Institute Investigator Robyn Stanfield and Assistant Professor Donghyun Raphael Park, all at Scripps, will determine them using X-ray crystallography, cryo-electron microscopy and cryo-electron tomography. Park will lead the cryo-EM/ET experiments. He notes that proteins can be isolated and studied alone, but how antibodies interact with them on a real virus is a different matter.

The second project will build vaccine prototypes on several platform technologies. Those come from Law and Scripps Professor Jiang Zhu; Jake Liang, an NIH Distinguished Investigator and chief of the Liver Diseases Branch at NIDDK; and Drew Weissman, the Roberts Family Professor in Vaccine Research, and Norbert Pardi, an associate professor of Microbiology, both at Penn's Perelman School of Medicine. Each prototype will be optimized for strong antibody and T cell responses, then compared head-to-head to find the best designs.

Standardization is built in. Christopher Cottrell, a Scripps institute investigator who will lead the Virology Immunology Data Core, says a specific panel of hepatitis C viruses will be used for neutralization so every candidate is tested against the same viruses, along with standardized peptide libraries to look for T cell responses. Scripps professors Andrew Su, Chunlei Wu and Law will join Cottrell in analyzing responses. Preclinical testing of the top designs will take place in Law's lab and in the ONPRC lab of Associate Professor Benjamin Burwitz.

The grant also funds a web-based HCV immune response database, which Law says will be opened to the broader vaccine development community. The center's goals are twofold: new mechanistic insight into HCV biology and its vulnerabilities, and optimized prototypes ready for Good Manufacturing Practice translation, a step that precedes clinical trials. That, rather than a finished vaccine, is the five-year target.