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.
The SDMCC spoke to Drew Weissman, M.D., Ph.D., the Roberts Family Professor in Vaccine Research at the Perelman School of Medicine at the University of Pennsylvania, part of the Duke CIVIC Vaccine Center (DCVC), about the H1 HA mRNA-LNP vaccine. This vaccine utilizes the mRNA platform encapsulated in lipid nanoparticles (LNPs) to target the full-length hemagglutinin (HA) protein from the A/California/07/2009 (H1N1) influenza virus.
While currently licensed influenza vaccines are a critical public health intervention, their effectiveness can vary from year to year as the HA protein accumulates mutations over time in a process known as antigenic drift. As a result, vaccine formulations must be updated regularly, and even then, the selected strains may not closely match the viruses in circulation because of the six-to-nine-month lag between strain selection and vaccine distribution. This is where mRNA vaccines come in.
According to Dr. Weissman, “What we found to be so novel about RNA LNP delivery of HA was that it gave very broad responses.” Pre-clinical studies found this vaccine induced stalk-specific antibodies in multiple animal models and was associated with protection against homologous, heterologous, and heterosubtypic influenza infection in mice. This is notable as most conventional influenza vaccines generate a strong immune response against the HA head, the part of the protein that is most variable. Anti-stalk antibodies offer enhanced cross-protection as this region of the HA protein is highly conserved across influenza strains and subtypes and mutates considerably less frequently.
In addition to enhanced immune protection, mRNA vaccines offer several other advantages when compared to traditional influenza vaccines. Rapid production shortens the time between vaccine strain selection and administration, decreasing the likelihood of mismatch between vaccine and circulating influenza strains. Additionally, the flexible platform can be used to target many more influenza antigens than traditional quadrivalent influenza vaccines.
The H1 HA mRNA-LNP vaccine is now being evaluated in the clinic, but getting there could not have been accomplished without the partnerships established through the CIVICs Program. As experts in mRNA-LNP design and production, Dr. Weissman’s lab has collaborated with almost every other group in CIVICs. These partnerships not only include basic research, but span vaccine development from ideation to clinical administration. When asked to reflect on what makes the CIVICs Program unique, Dr. Weissman said, “What was probably most exciting about the CIVICs Program, and we hope that it’ll be brought back in some manner, is that it was the entire range of activities. It supported basic science research, ‘How do you develop new vaccines, new approaches?’ and took them all the way into Phase 1 clinical trials. So, you could come up with a new idea, develop it, test it in humans, and see does it work. Very few NIH programs or programs in general do that.” This integrated approach also reflects a broader shift in influenza vaccine development. Influenza vaccine development no longer has to be framed solely as an annual exercise in predicting which strains will circulate. With conserved antigen targets, multiplexed designs, and flexible mRNA manufacturing, researchers can pursue vaccines intended to be broader, faster to produce, and more adaptable.
