Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection
Abstract Stabilizing the RSV F protein in its prefusion conformation is crucial for effective vaccine development but has remained a significant challenge. Traditional stabilization methods, such as disulfide bonds and cavity-filling mutations, have been labor-intensive and have often resulted in su...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-08-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-63084-z |
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| Summary: | Abstract Stabilizing the RSV F protein in its prefusion conformation is crucial for effective vaccine development but has remained a significant challenge. Traditional stabilization methods, such as disulfide bonds and cavity-filling mutations, have been labor-intensive and have often resulted in suboptimal expression levels. Here, we report the design of an RSV prefusion F (preF) antigen using a proline-scanning strategy, incorporating seven proline substitutions to achieve stabilization. The resulting variant, preF7P, is structurally and biochemically validated to maintain the correct prefusion state. PreF7P demonstrates superior immunogenicity with a 1.8-fold increase in neutralizing antibody titers when compared to DS-cav2, and provides protection from clinical disease against both RSV A and B strains in female murine and female cotton rat models. In clinical development, preF7P exhibits high expression levels (~10 g/L) in clinical-grade CHO cells. The clinical-grade vaccine elicits robust immunogenic responses across female mice, female SD rats, and both male and female cynomolgus macaques, significantly boosting RSV pre-infection neutralizing antibody titers, and providing sustained protection for at least six months in female mice. This proline-scanning strategy offers a streamlined approach for stabilizing class I fusion proteins, potentially accelerating the development of vaccines for other pathogens. |
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| ISSN: | 2041-1723 |