In the majority of individuals, lung-infecting viruses like respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) usually lead to mild, cold-like symptoms. However, these viruses can be much more severe for infants and older adults, potentially causing serious pneumonia and even death. Researchers have faced challenges in creating vaccines for these viruses. Recently, scientists at Scripps Research have studied a key protein from RSV and hMPV to enhance the design of effective vaccines.
In the majority of individuals, lung-infecting pathogens such as respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) typically cause mild cold-like symptoms. Nevertheless, in infants and the elderly, these viruses can lead to severe pneumonia and, in some cases, even death.
Developing vaccines for both viruses has proven to be quite challenging. Scripps Research scientists have examined the structure and stability of an important protein found in RSV and hMPV to help design vaccines aimed at it. Their findings, which were published in Nature Communications on November 16, 2024, suggest that RSV vaccines could be more effective than current options, as well as creating a vaccine for hMPV, which currently lacks any commercially available alternatives.
“Developing a combination vaccine for these viruses could substantially decrease hospitalizations due to viral infections in both infants and the elderly,” remarked senior study author Jiang Zhu, PhD, an associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research. “Such a vaccine could lessen the overall health challenges during flu season, a time when many RSV and hMPV cases are reported.”
Researchers have long tried to create vaccines that prompt the immune system to recognize fusion (F) proteins found on the surfaces of RSV, hMPV, and related viruses. These proteins are crucial for enabling the viruses to infect human cells. However, the F protein has a complex structure that swiftly transitions from a “pre-fusion” state to a “post-fusion” state when the viruses merge with cells. The goal is for a vaccine to teach the immune system to identify the closed pre-fusion F protein to prevent infection.
“The challenge lies in the fact that this pre-fusion structure is incredibly delicate and can easily change,” explains Zhu. “Even minor environmental shifts can cause the protein to switch from a ‘car’ to a ‘robot’ in a moment.”
This fragility means that researchers cannot simply use an isolated pre-fusion F protein as a vaccine because its structure would alter too quickly for the immune system to respond. Conversely, a vaccine targeting the post-fusion protein wouldn’t prepare the immune system to combat the virus before it can cause an infection.
With a background in biophysics and experience designing new vaccines for viruses like HIV, SARS-CoV-2, and hepatitis C, Zhu believed that if he could determine why the pre-fusion F protein was so unstable, especially what made it prone to opening, he could create a more resilient version—ultimately leading to a better vaccine.
To start, Zhu and his research team examined the F proteins developed for four existing RSV vaccines—the available Arexvy, mResvia, and Abrysvo, plus one experimental vaccine nearing phase 3 trials. They found that some pre-fusion F proteins were unstable, occasionally shifting to an open form or, worse, a post-fusion state. A detailed structural examination uncovered an “acidic patch” centrally located in the pre-fusion structure, where three positively charged molecules repelled one another, causing the RSV F protein to open at the slightest disturbance, akin to a spring-loaded transformer.
“This ability is a remarkable trait for a virus to gain during evolution, allowing it to manage the movement of a key protein,” adds Zhu. “Fortunately, it’s something we can overcome—either with brute force or, ideally, through intelligent mutations that directly address the root of the issue: the acidic patch.”
Zhu modified the RSV F protein by altering a couple of molecules at its core, transforming the outward repelling force into an attracting one. His team then demonstrated that this new F protein was not only more stable in laboratory settings but also effectively vaccinated mice against RSV.
“This opens the door to apply a similar strategy for other viral F proteins,” Zhu remarks. “At the very least, we can search for similar repulsive features in their structures as we develop vaccines.”
In contrast, with the hMPV F protein, Zhu didn’t discover the same repelling molecules; instead, he utilized a strong chemical bond as a “brute force” fix to stabilize the protein. Once again, the modified protein was robust enough to remain intact for vaccination purposes.
For future research, Zhu aims to create an experimental vaccine using a self-assembling protein nanoparticle (SApNP) platform, which he has recently reported on, to introduce the RSV and hMPV F proteins into the human body. “This would represent our next-generation combo vaccine for RSV and hMPV,” Zhu states.
This work received support from Uvax Bio. Uvax Bio, a spin-off vaccine company from Scripps Research, uses proprietary technology developed in Zhu’s lab to create and commercialize preventive vaccines for various infectious diseases.
