CIVICs Vaccine Candidate and Human Challenge Study Capstone Series
The SDMCC is highlighting the vaccine candidates and human challenge studies developed and led by CIVICs to share how the Program’s efforts improved influenza vaccine science and disease outcomes. To read about other candidates and studies, check out the entire CIVICs Vaccine Candidate and Human Challenge Study Capstone Series.
Currently licensed influenza vaccines target the hemagglutinin (HA) from three influenza subtypes that circulate in humans: influenza A H1N1 and H3N2 and influenza B-Victoria. These vaccines offer protection against influenza viruses within these subtypes when the vaccine and circulating strains are closely matched. However, when circulating viruses evolve or new strains emerge, these vaccines lose efficacy. The SDMCC interviewed Ted Ross, Ph.D. and James Allen, Ph.D. from the Center for Influenza Vaccine Research for High Risk Populations (CIVR-HRP) about an alternative approach to induce broad protection against influenza: computationally optimized broadly reactive antigens (COBRAs). COBRAs were developed by analyzing the genomic sequences of circulating influenza viruses across seasons to generate HA antigens that induce broadly reactive antibodies. Using this method, CIVR-HRP researchers created optimized antigens for each influenza subtype that could extend beyond the viruses that are currently circulating. “Our approach allows us to include the epitopes from the dominant and sub-dominant viral lineages across multiple seasons. Therefore, you’re actually anticipating what’s going to evolve in the future, since viral families that are sub-dominant in one season often become dominant in subsequent seasons,” Dr. Ross explained in the interview.
One of the major advantages of COBRAs is that the antigens are computationally designed and can be tested using many vaccine platforms, including mRNA or protein-based approaches. Both H1 and H3 COBRAs delivered via mRNA induced higher neutralizing antibody titers in mice than mRNA vaccines encoding wildtype HA protein. These antibodies were reactive against antigenically distinct contemporary and future drifted virus strains and were effective in preventing illness in animal models.
The Ross group has been working on the COBRA methodology for nearly twenty years. These antigens were first conceived to anticipate and prepare for novel influenza virus outbreaks, particularly H5N1; later, their design and use were expanded to seasonal influenza viruses. Though Dr. Ross and collaborators generated a few prototypes at the time, there was no clear path to move these vaccines forward for manufacturing and clinical use. The CIVICs Program provided a pipeline to do just that. “CIVICs has forced us to think more like a manufacturing product development company than just wanting to know the science of what’s going on. We’re much more educated today than we were seven years ago,” says Dr. Ross.
According to Dr. Allen, CIVICs also “allowed us to generate a plethora of pre-clinical data. And I think, from where we started to where we are now, we now have a much better understanding of what it takes to bring a vaccine from the bench all the way to a manufactured human grade product.” This pre-clinical data has included generating pre-immune animal models in which subjects are exposed to influenza viruses prior to vaccination. This model more closely mimics human influenza exposure history and provides better insights into how these vaccines may react in humans with multiple vaccination or infection histories. Additionally, structural modeling of antibody binding to COBRAs elucidated where antibodies bind to the antigen and why they’re more broadly reactive. That knowledge is being used to design new COBRAs that are even more effective.
When asked to reflect on CIVICs, Dr. Ross said, “I think one of the biggest advantages of the CIVICs Program has been the integrated network of investigators across multiple institutions, both academic and corporate, and with the government. This Program should be a template for many NIH and other government funded agencies to use because the impact was broader than it could have been if each of these investigators worked alone.” Dr. Allen added, “CIVICs did a great job at moving these candidates forward, but it also provided a lot of great training opportunities for the next generation of scientists. There are a number of people who have gotten Ph.D.’s or advanced degrees based off CIVICs funding. There were travel grants and training grants awarded to individuals to attend conferences and network and grow as scientists.”
