In a significant stride towards more effective vaccination against respiratory viruses, scientists at Scripps Research have made critical advancements in understanding the complex structure of proteins essential to the Respiratory Syncytial Virus (RSV) and Human Metapneumovirus (hMPV). Published in the prestigious journal Nature Communications on November 16, 2024, the study outlines breakthroughs that may lead to more potent RSV vaccines and potentially the first commercially available vaccine for hMPV.
For years, developing vaccines against these viruses has been a formidable challenge. Scientists have struggled to design vaccines that effectively prompt the immune system to recognize and respond to the fusion (F) proteins found on the viruses' surfaces. These proteins are critical for the viruses to infect human cells, but their inherently unstable structure has posed significant obstacles. The F protein of these viruses shifts rapidly from a "pre-fusion" conformation, ideal for targeting by vaccines, to a "post-fusion" form that occurs after cell entry — a shift that traditional vaccine designs have not been able to control.
Dr. Jiang Zhu, the study's senior author and an associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research, emphasizes the potential impact of their findings. "Creating a combination vaccine for these viruses could significantly reduce viral hospitalizations for both babies and the elderly," Zhu notes. "This could alleviate the overall health burden during flu season, which is also when most RSV and hMPV cases occur."
By delving into the structural mechanics of the pre-fusion F protein, Zhu and his team discovered a destabilizing element at the heart of the RSV protein: an "acidic patch" that acts like a spring-loaded transformer. This patch causes molecules to repel each other, destabilizing the protein's structure. Leveraging insights from biophysics, Zhu modified the protein to turn this repelling force into an attractive one, thereby stabilizing the structure. This engineered RSV F protein demonstrated enhanced stability and effectiveness in vaccinating mice.
The research team applied a similar innovative approach to the hMPV F protein, although they did not find an identical structural instability. Instead, they addressed the problem through a robust chemical bond, ensuring the protein remained intact for vaccine use.
Zhu’s future plans include the development of an experimental vaccine using a self-assembling protein nanoparticle (SApNP) platform, promising a next-generation combination vaccine for RSV and hMPV. Supported by funding from Uvax Bio, a Scripps Research spin-off company employing platform technology from Zhu’s lab, these groundbreaking efforts are setting the stage for new prophylactic vaccines against a range of infectious diseases.
This leap forward not only offers hope for more effective protection against RSV and hMPV but also suggests a roadmap for tackling similar challenges in vaccine design for other viruses.
