Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) typically cause mild cold-like symptoms in most people. However, for infants and the elderly, these viruses can lead to severe pneumonia and even death. While vaccine for RSV exist, they have limitations, and currently, no commercial vaccines are available for hMPV.
Now, scientists at Scripps Research have made significant progress in developing more stable and effective vaccines for both viruses. Their study, published in Nature Communications on November 16, 2024, details how modifications to a critical viral protein could improve protection against these respiratory threats.
Targeting an Unstable Viral Protein
Vaccines against RSV and hMPV rely on targeting the fusion (F) protein, which allows these viruses to infect human cells. However, this protein rapidly shifts from a “pre-fusion” to a “post-fusion” form, making it difficult for the immune system to recognize and attack the virus before infection occurs.
“The problem is that this pre-fusion structure is so fragile and volatile,” explains study senior author Jiang Zhu, Ph.D., an associate professor at Scripps Research. “If you change the environment even a bit, the protein is like a transformer that suddenly flips from a car into a robot.”
To create a more stable vaccine, Zhu and his team analyzed the F proteins used in four existing RSV vaccines, including Arexvy, mResvia, and Abrysvo. Their structural analysis revealed an “acidic patch” at the center of the protein, where repelling molecules acted like a spring, forcing the protein open.
Engineering a More Stable Vaccine
By modifying a pair of molecules within the F protein, Zhu’s team was able to convert this repelling force into an attractive one, effectively stabilizing the protein. When tested in mice, the new version of the F protein successfully protected against RSV infection.
For hMPV, the researchers used a different approach, employing a strong chemical bond to hold the F protein in its pre-fusion form. This method also effectively maintained the protein’s stability as its component.
“This suggests that we might be able to take a similar approach for other viral F proteins,” says Zhu. “At the very least, we can look for similar repulsive patches in their structure as we design vaccines.”
Toward a Combination Vaccine
Looking ahead, Zhu and his team plan to develop an experimental RSV/hMPV combination of it using a self-assembling protein nanoparticle (SApNP) platform. If successful, this next-generation vaccine could significantly reduce hospitalizations and ease the burden of respiratory infections during flu season.
“This could alleviate the overall health burden during flu season, which is also when most RSV and hMPV cases occur,” Zhu says.
Uvax Bio, a Scripps Research spin-off company, supported the research. The company aims to develop and commercialize it using proprietary technology from Zhu’s lab.
Reference: Yi-Zong Lee, Jerome Han, Yi-Nan Zhang, Garrett Ward, Keegan Braz Gomes, Sarah Auclair, Robyn L. Stanfield, Linling He, Ian A. Wilson, Jiang Zhu. Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus. Nature Communications, 2024.
