$16.4 Million NIH Award Launches Multi-Institution Center for Hepatitis C Vaccine Design

The hepatitis C virus has long been one of the most elusive targets in vaccinology, and a new federally funded effort is now aiming to change that. The National Institutes of Health has awarded 16.4 million dollars over five years to establish a new U19 Cooperative Center for Rational HCV Vaccine Design and Evaluation, a multi-institution initiative that unites specialists in hepatitis C virus structural biology, immunology and vaccine technology around a single objective: developing vaccine candidates capable of triggering strong antibody and T cell protection against a virus famed for its ability to evade immune defenses.

The award brings together scientists from Scripps Research, the National Institute of Diabetes and Digestive and Kidney Diseases, the University of Pennsylvania and the Oregon National Primate Research Center. The funding comes through the NIH’s U19 Cooperative Agreements research program, which is designed to unify multiple interdisciplinary projects around a specific goal.

According to the announcement from Scripps Research, the hepatitis C virus owes much of its immune-evasive skill to an especially high mutation rate. That rapid mutation has generated an abundance of viral variants with extreme genetic diversity, and this diversity has so far impeded successful vaccine development. A broadly effective vaccine needs to target viral regions that remain relatively stable across variants, so the center’s researchers will focus on identifying and exploiting conserved regions of the virus that vary less from strain to strain. Research over the last decade, the institute notes, points to a few specific sites on the virus that are recognized by antibodies or T cells, and those sites form the starting point for the new program.

The public health stakes are considerable. Around 50 million people worldwide are living with chronic hepatitis C infection, a condition that can lead to severe diseases including liver cirrhosis, in which damaging scar tissue builds up and impairs liver function, as well as liver cancer and autoimmune disorders. Antiviral drugs can successfully cure most people with the infection, but gaps in diagnosis, the possibility of reinfection and ongoing transmission mean that treatment alone has not eliminated the virus. This persisting gap, the announcement emphasizes, underlines the continuing need for a preventative vaccine.

Project leader Mansun Law, a professor at Scripps Research, frames the long-term ambition in striking terms. “There are certain human viral diseases that can be eradicated if we plan for it, and I think that could happen for hepatitis C,” Law says. “This virus is very strictly human, and that means if there’s a vaccine to prevent new infection, and we have the means to contain the last bit of virus, there’s a chance we could eradicate it like was done in smallpox.” The observation reflects a key biological fact about the virus: because hepatitis C infects humans strictly, a vaccine that blocks new infections combined with means of containing remaining transmission could, in principle, drive it to extinction rather than allowing it to persist in animal reservoirs.

The scientific program is organized around two central projects. The first is devoted to developing a comprehensive understanding of the hepatitis C virus structures recognized by antibodies and how those structures are displayed on the vaccine candidates designed in the second project. The structural team includes Law, Professor Ian Wilson, Institute Investigator Robyn Stanfield and Assistant Professor Donghyun Raphael Park, all at Scripps Research.

Park, who will lead the center’s cryo-EM and cryo-ET experiments, explains why visualizing these interactions in a realistic context matters. “We want to know what specific proteins look like on the surface of HCV, and how they interact with antibodies,” Park says. "While we can always isolate these proteins and look at their behavior, how the antibodies interact with them on a real virus is a different story." Park's point underscores why the center plans to examine these interactions in the context of the actual virus rather than relying solely on isolated proteins.

The second project will generate vaccine prototypes using a range of platform technologies. This effort will be led by Law and Professor Jiang Zhu at Scripps Research; Jake Liang, an NIH Distinguished Investigator and chief of the Liver Diseases Branch at the NIDDK; and Drew Weissman, the Roberts Family Professor in Vaccine Research, and Norbert Pardi, an associate professor of Microbiology, both at the Perelman School of Medicine at the University of Pennsylvania. Each prototype will be optimized for its ability to generate strong antibody and T cell responses, and the candidates will then be compared head-to-head to identify the most promising designs. The dual emphasis on both arms of the immune response is deliberate. “This funding will allow us to take a more detailed and systematic approach, recruiting experts to focus on both the antibody and T cell immune components,” Law says. “Then, we will combine all that knowledge to generate one vaccine candidate that can stimulate both immune arms and hopefully protect people against hepatitis C virus.”

Rigorous, standardized evaluation is a third pillar of the program. Christopher Cottrell, an institute investigator at Scripps Research who will lead the center’s Virology Immunology Data Core, describes a common testing framework designed to make candidate comparisons meaningful. “We have a specific panel of hepatitis C viruses that we’ll use for neutralization so that all of the vaccine candidates are evaluated against the same viruses,” Cottrell says. “We’ll also have standardized peptide libraries that we’ll use to look for T cell responses.” Using a shared panel of viruses for neutralization assays and common peptide libraries for T cell measurements means that differences in performance between candidates can be attributed to the designs themselves rather than to variations in testing methods. In addition to Cottrell, Scripps Research professors Andrew Su, Chunlei Wu and Law will analyze immune responses to the vaccine candidates using these standardized methods. Preclinical testing of the top designs will be conducted by the Law lab and by the lab of Associate Professor Benjamin Burwitz at the Oregon National Primate Research Center.

The center’s goals extend beyond its own pipeline. The grant will also support the generation of a web-based HCV immune response database, which Law describes as a resource both for optimizing the center’s own designs and for the broader HCV vaccine development community. By pooling standardized immune response data in a publicly accessible format, the database is intended to accelerate progress across the field rather than within a single laboratory. The overall objectives of the center are twofold: first, to deliver new mechanistic insights into hepatitis C virus biology and its vulnerabilities, and second, to provide optimized vaccine prototypes that are ready for Good Manufacturing Practice translation, an important manufacturing and quality milestone that must be reached before any candidate can advance toward clinical trials.

Subject of Research: A new NIH-funded multi-institution center for rational hepatitis C virus vaccine design and evaluation

Article Title: NIH awards $16.4 million to establish multi-institution hepatitis C vaccine development center

Article References: NIH awards $16.4 million to establish multi-institution hepatitis C vaccine development center. Original publication (Bibliographic details unavailable.)

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Keywords: hepatitis C virus, NIH funding, vaccine development, Scripps Research, structural biology, antibodies, T cell responses, cryo-electron microscopy, U19 cooperative agreement, viral diversity, preclinical testing, liver disease