Advancing Vaccine Development for RSV and hMPV: Overcoming Challenges With Pre-Fusion F Protein Stability

Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are lung infecting pathogens that cause mild cold-like symptoms among those infected. However, both viruses can trigger severe pneumonia or fatal outcomes in older adults and individuals with chronic conditions. Both RSV and hMPV are enveloped, non-segmented, negative-sense, single stranded ribonucleic acid (RNA) viruses that belong to the Pneumoviridae family. Notably, vaccines that protect against RSV and hMPV are challenging to design because of the unstable structure of the fusion (F) protein of these viruses.^1,2

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Proteins in RSV and hMPV play a significant role in allowing the viruses to infect human cells. However, the F protein has a delicate structure that changes quickly from a “pre-fusion” form to a “post-fusion” form when the viruses fuse with cells. An indicated vaccine could teach the immune system to recognize the closed pre-fusion F protein to stop infection. However, this is difficult to achieve because scientists cannot use an isolated pre-fusion F protein as a vaccine because of the rapid change in its structure.¹

Investigators from Scripps Research designed a prefusion RSV-F and hMPV-F study based on metastability analysis to evaluate more effective RSV vaccines compared to existing ones, as well as a vaccine against hMPV.¹

The 3 FDA approved RSV vaccines include RSVPreF3 (Arexvy, GSK), RSVpreF (Abrysvo; Pfizer), and mRNA-1345 (mResvia; Moderna). The vaccines are indicated for individuals 60 and older and individuals aged 18 to 59 years at increased risk of severe RSV-associated outcomes.³ There are currently no approved or commercially available vaccine options to prevent hMPV.^1,3

“Creating a combination vaccine for these viruses could significantly reduce viral hospitalizations for both babies and the elderly,” said senior study author Jiang Zhu, PhD, an associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research, in a news release. “This could alleviate the overall health burden during flu season, which is also when most RSV and hMPV cases occur.”¹

The intention of the study was to form a better understanding on the precise mechanism of why the pre-fusion F protein was unstable and easy to open, which could help create a more stable form.^1,2

“The problem is that this pre-fusion structure is so fragile and volatile,” said Zhu in the news release. “If you change the environment even a tiny bit, the protein is like a transformer that suddenly flips from a car into a robot.”¹

The research team evaluated the F proteins used in the development of the 3 commercially available RSV vaccines, along with an experimental vaccine that reached phase 3 trials. The analysis demonstrated that certain pre-fusion F proteins were unstable and converted to an open form or a post-fusion form. Following the initial results, the researchers created a detailed structural analysis that found an “acidic patch” at the center of the pre-fusion structure with 3 positively charged molecules resisting each other, triggering the RSV F protein to push open at the slightest agitation, according to the study authors.^1,2

The preliminary findings allowed Zhu to reengineer the RSV F protein. With help from his research team, Zhu changed a pair of molecules at its center to turn the outward repelling force into an attracting force. This allowed the new F protein to be more stable, displaying positive results in lab research and on vaccination in mice to prevent RSV.¹

“This suggests that we might be able to take a similar approach for other viral F proteins,” said Zhu in the news release. “At the very least, we can look for similar repulsive patches in their structure as we design vaccines.”¹

The study authors noted that the same acidic patch was not found in the hMPV F protein. He reported using a chemical bond as a “brute force” solution to keep the proteins together—which was stable enough to stay intact as a vaccine.¹

The findings will allow the researchers to pursue a next-generation RSV/hMPV combination vaccine to deliver the RSV and hMPV F proteins to the human body.^1,2

REFERENCES

1. Researchers use biophysics to design new vaccines against RSV and related respiratory viruses. EurekAlert!. News release. November 18\9, 2024. Accessed November 27, 2024. https://www.eurekalert.org/news-releases/1065442.

2. Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus. Nature Communications. News release. November 16, 2024. Accessed November 27, 2024. https://www.nature.com/articles/s41467-024-54287-x.

3. Ferruggia K. Study: How mRNA-1345 RSV Vaccine Compares to Previously Approved RSV Vaccines. Pharmacy Times. News release. August 5, 2024. Accessed November 27, 2024. https://www.pharmacytimes.com/view/study-how-mrna-1345-rsv-vaccine-compares-to-previously-approved-rsv-vaccines.