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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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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| author | Qingrui Huang Qingyun Lang Yao Li Fengjie Wang Xiaonan Han Ling Luo Xiaomin Duan Xuerong Cao Yue Wang Yu Bai Yaxin Song Yanpeng Xu Lianlian Bian Chenyan Gao Linqing Zhao Jinghua Yan |
| author_facet | Qingrui Huang Qingyun Lang Yao Li Fengjie Wang Xiaonan Han Ling Luo Xiaomin Duan Xuerong Cao Yue Wang Yu Bai Yaxin Song Yanpeng Xu Lianlian Bian Chenyan Gao Linqing Zhao Jinghua Yan |
| author_sort | Qingrui Huang |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-de4949e7da5f443082b4919fa5c97dd5 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-de4949e7da5f443082b4919fa5c97dd52025-08-24T11:38:32ZengNature PortfolioNature Communications2041-17232025-08-0116111510.1038/s41467-025-63084-zHighly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protectionQingrui Huang0Qingyun Lang1Yao Li2Fengjie Wang3Xiaonan Han4Ling Luo5Xiaomin Duan6Xuerong Cao7Yue Wang8Yu Bai9Yaxin Song10Yanpeng Xu11Lianlian Bian12Chenyan Gao13Linqing Zhao14Jinghua Yan15Changping LaboratoryChangping LaboratoryChangping LaboratoryLaboratory of Virology, Beijing Key Laboratory of Etiology of Viral Diseases in Children, Capital Institute of PediatricsCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of SciencesChangping LaboratoryChangping LaboratoryChangping LaboratoryCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of SciencesChangping LaboratoryChangping LaboratoryLaboratory of Virology, Beijing Key Laboratory of Etiology of Viral Diseases in Children, Capital Institute of PediatricsChangping LaboratoryChangping LaboratoryLaboratory of Virology, Beijing Key Laboratory of Etiology of Viral Diseases in Children, Capital Institute of PediatricsChangping LaboratoryAbstract 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.https://doi.org/10.1038/s41467-025-63084-z |
| spellingShingle | Qingrui Huang Qingyun Lang Yao Li Fengjie Wang Xiaonan Han Ling Luo Xiaomin Duan Xuerong Cao Yue Wang Yu Bai Yaxin Song Yanpeng Xu Lianlian Bian Chenyan Gao Linqing Zhao Jinghua Yan Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection Nature Communications |
| title | Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection |
| title_full | Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection |
| title_fullStr | Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection |
| title_full_unstemmed | Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection |
| title_short | Highly scalable prefusion-stabilized RSV F vaccine with enhanced immunogenicity and robust protection |
| title_sort | highly scalable prefusion stabilized rsv f vaccine with enhanced immunogenicity and robust protection |
| url | https://doi.org/10.1038/s41467-025-63084-z |
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